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GOOD AFTERNOON, EVERYONE,

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WELCOME TO THE WEDNESDAY

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AFTERNOON LECTURE SERIES  I AM

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IAN FRAZIER FROM NIAID AND IT'S

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A GREAT PRIVILEGE FOR ME TODAY

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TO INTRODUCE OUR SPEAKER

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DR. JAMES CHEN WHO'S DONE

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REMARKABLE WORK IN HIS CAREER IN

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REBALDING PATHWAYS AND  PATHWAYS

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THAT TRIGGER RESPONSES, AND FOR

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THOSE THAT WATCH THE VIDEOCAST

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WE ENCOURAGE TO YOU PARTICIPATE

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IN THE DNA AFTER THE SESSION,

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YOU CAN DO SO BY USING LIVE

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FEEDBACK LINK BELOW THE

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VIDEOCAST WINDOW AND WE'RE

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OFFERING CONTINUING

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METRICSICATION--[LAUGHTER] 

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CONTINUING MEDICAL EDUCATION,

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50095.

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SO BACK TO OUR SPEAKER AND THIS

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AFTERNOON, SO JAMES CHEN IS THE

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GEORGE Mc GREGOR DISTINGUISHED

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CHAIR IN BIOMEDICAL SCIENCE AND

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THE DIRECTOR OF INFLAMMATION

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RESEARCH CENTER AT THE

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UNIVERSITY OF TEXAS SOUTHWESTERN

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MEDICAL CENTER.

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HE RECEIVED HIS Ph.D.

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PRACTICES THE STATE UNIVERSITY

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OF NEW YORK AND AFTER WORKING IN

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THE SALT INDUSTRY, HE STARTED

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ACADEMICS AT 1997 AND ROSE TO

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FULL PROFESSOR THERE BY 2 THIS

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HAPPENED 5 AND BECAME A HOWARD

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HUGHES INVESTIGATOR IN THAT SAME

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YEAR AND EARLY IN HIS CAREER,

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JAMES REALLY MADE SOME MAJOR

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DORPHYS IN HOW CELLS USE

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DIFFERENTLY LINKED CHANGE UP OF

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SMALL PROTEIN UBIQUITIN AND

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REGULATE CELLULAR RESPONSES

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SHOWING IN PARTICULAR CASE 63

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LINK CHAINS OF UBIQUITIN WOULD

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MARK PROTEINS AND NOT FOR THE

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TYPICAL DEGRADATION PATHWAY BUT

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INSTEAD TO LEAD TO KIND OF

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SPECIFIC SIGNATURES MALAND

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OUTCOMES.

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HE THEN WENT ON TO DISCOVER AND

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DESCRIBE THE MITOCHONDRIA

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PROTEIN MAVS WHICH IS A CRITICAL

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COMPONENT IN THE HOST CELL

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RESPONSE WITH THE VIRUSES SUCH

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AS EBOLA AND CONTINUING THE

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THEME OF CELLS TO NUCLEIC ACIDS,

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JAMES IS SAID TO HAVE TACKLED

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THE MYSTERY OF THE PROTEIN FOR

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MICROBIAL DNA AND THED LESTO A

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MAJOR DORPHY PRACTICES JAIM'S

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LAB OF THE CYCLIC GMP, AMP

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SYNTHASE OR C-GAS AND A PAIR OF

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REALLY BEAUTIFUL BACK-TO-BACK

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PAPERS IN THE ISSUE OF SCIENCE,

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HIS LAB SHOWED A NOVEL SECOND

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MESS ESMGER MOLECULE CALLED

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CGAMWHICH TURNED OUT TO BE THE

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NUCLEOTIDIFYINGER TO MICROBIAL

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DNA, PATHWAY REALLY GOES WELL

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YAWBD MICROBIAL INFECTION, AS

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DNA SENSOR FUNCTION IS CRITICAL

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IN 19 DISEASES INCLUDING CANCER,

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AND AUTOIMMUNITY.

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SO IN RECOGNITION OF THIS REALLY

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GROUND BREAKING WORK IN 2019

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JAMES RECEIVED THE BREAK THROUGH

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PRIZE IN LIFE SCIENCES AND IN

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AKIGZ TO THIS HIGHLY PRESTIGIOUS

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AWARD HE RECOGNIZED WITH THE

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BILL PAUL DISTINGUISHED AWARD

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AND AUTOIMMUNITY, THE PRIZE IN

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BIOMEDICAL CONSCIENCES FROM THE

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FNIH AND THE [INDISCERNIBLE]

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ROSE HOROWITZ PRIZE THIS YEAR

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FROM COLUMBIA, LAST BUT NOT

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LEAST, JAIM SYSTEM A MEMBER OF

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THE NATIONAL ACADEMY OF SCIENCES

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AND TODAY IS THE DARK SIDE OF

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DEFICIENCY NA HAVE THEM IN

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SYSTEMS SINCE HIS DINITIATIVESA

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AS A DANGER SIGNAL SO PLOAZ JOIN

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ME IN WELCOMING YAIMS TO THE

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NIH.

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[ APPLAUSE ]

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OKAY, THANK YOU VERY MUCH IAN

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FOR A VERY KIND INTRODUCTION.

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I KNOW IT IS REALLY A GREAT

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HONOR FOR ME TO COME HERE AND TO

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GIVE THIS TALK.

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SO I WANT TO THANK ALL OF YOU

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FOR ATTENDING THIS TALK, EITHER

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IN PERSON OR VIRTUALLY.

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I ALSO WANT TO THANK THE

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CONGRESS FOR KEEPING THE

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GOVERNMENT OPEN AND THAT GIVES

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ME A SMALL WINDOW OF OPPORTUNITY

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TO COME HERE AND TELL YOU ABOUT

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OUR WORK.

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YOU KNOW JUST 3 WEEKS EARLIER OR

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3 WEEKS LATER THIS WOULD BE

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QUITE [INDISCERNIBLE].

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SO TODAY I WILL TELL YOU ABOUT A

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DARK SIDE OF DNA.

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MOST PEOPLE HERE WORK ON THE

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BRIGHT SIDE OF DMA AND THAT IS

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HOW DNA FUNCTIONS AS A GENETIC

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MATERIAL, HOW DNA IS REPLICATED

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AND TRANSCRIBED BUT DNA ALSO HAS

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A DARK SIDE AND THAT IS IT CAN

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TRIGGER IMMUNE RESPONSES AND

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SOMETIMES IT CAN CAUSE

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AUTOIMMUNE DISEASES AND IT HOLDS

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UP OTHER DISEASES.

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ALL RIGHT SO THESE ARE THE MAJOR

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PLAYERS IN MY TALK, THESE ARE

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THE SWROAT ENZYMES C-GAS WHICH

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IS ACTIVATED BY BYPASSING TO THE

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DOUBLE STRANDED DNA AND THE

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ACTIVATED ENZYME CONVERTS

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CTP AND ATP TO THE CYCLIC CAMP

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FOR SHOWS AND IT BYPASSEDS IN

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ACTIVATES ER-MEMBRANE PROTEIN

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CALLED STAIN, ASK STAIN

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SIGNALING A CASCADE LEADING TO

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INNATE IMMUNE RESPONSE.

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SO THIS IS THE TIELT OF MY TALK.

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FIRST I WILL BRIEFLY TALK ABOUT

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HOW BEE DISCOVER CGAS IN CGAMP

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AND I HOPE TO USE THESE AN

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EVIDENCE TO ILTRAIT TO STUDENTS

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AND POST DOCS NAIN THIS SINGLE

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CELL GENOMIC ERA IT'S POSSIBLE

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TO MAKE AN IMPORTANT DISCOVERY

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USING OLD FASHIONED

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BIOCHEMISTRY.

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OKAY?

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AND THEN WE WILL TALK ABOUT 2

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RECENT STORIES, FIRST 1 CGAS

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STAIN SIGNALING IN ANIMAL CELLS

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AND THEN I WILL TALK ABOUT

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BACTERIAL CGAS IN ANTIIMMUNE

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DEFENSE.

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SO WHY DO WE WANT TO START AN

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IMMUNE SENSING OF DNA?

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AND WITHIN THAT RECOGNITION OF

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FOREIGN DNA IS 1 OF THE MOST

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FUNDAMENT AMILLIO MECHANISMS OF

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HOST DIFFERENCE AND EVEN

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BACTERIA CAN DO THAT, THE

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CLASSICAL EXAMPLES ENCLUED

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RESTRICTION ENZYMES THAT CUT THE

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CURE OF DNA OR THE PLASMA OF DNA

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AND A MORE RECENT EXAMPLE IS THE

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CRSPR SYSTEM WHICH IS THE

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ADAPTER IMMUNE SYSTEM THAT CUTS

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FOREIGN DNA.

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IN HUMANS DNA WAS KNOWN TO

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STIMULATE IMMUNE RESPONSES MORE

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THAN A HUNDRED YEARS AGO.

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--THERE ARE SURGEONS IN FRANCE

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AND GERMANY WHO INTRODUCE THE

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ABDOMINAL CAVITY OR UNDER THE

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SKIN OF THE PATIENTS EITHER 1

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[INDISCERNIBLE] DNA, AND THE

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OBLIGATIONS YECT WITH THE

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PROTECTIVE AMIOFAIG O SIGHTS TO

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WARD IT OFF EMPLOY SO DNA WAS

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KNOWN TO TIMMULATE IMMUNE

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RESPONSES 40 YEARS BEFORE IT WAS

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KNOWN AS GENETIC MATERIAL BUT WE

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STILL DON'T QUITE UNDERSTAND HOW

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DNA STIMULATE IMMUNE RESPONSES

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UNTIL QUITE RECENTLY.

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SO WHY DO WE WANT AN IMMUNE

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SYSTEM THAT RECOGNIZE D NA?

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FIRST OF ALL THIS WOULD BE

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EXCEPTION ALGORITHMS, FIRST BY

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THE VIRUSES RECOGNIZED BY THE

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[INDISCERNIBLE] PATHWAY THAT I

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WILL TALK ABOUT IN JUST A

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MINUTE, ALL MICROORGANISMS

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INCLUDING VIRUSES, FUNGI AND

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PARASITES THEY ALL HAVE DECKER

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NA AND OR REQUIRE DNA IN THEIR

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LIFE CYCLE AND THAT PROVIES AN

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ALMOST UNIVERSAL MECHANISM TO

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DETECT MICROBIAL INFECTIONS.

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AND SECONDLY, RECOGNITION OF DMA

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OR RNA, IN THIS MICROORGANISMS

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PROVIDE A MECHANISM TO DETECT

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THOSE MICROORGANISMS THAT LIVE

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AND REPLICATE INSIDE OUR CELLS

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EMPLOY WE ALL KNOW PART OF THE

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RECEPTORS ARE IMPORTANT IN

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INNATE IMMUNITY BUT THESE ARE

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PROTEINS WITH A LIGAND BINDING

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INSIDE THE SOILS AND SOME ARE IN

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THE ENDOSTUDIES OF MULTIPLE

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ENDOCRINAL MEMBRANE WITH THE

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LUMEN OF THEEND SOSOME WHICH IS

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EQUIVALENT TO OUTSIDER CELLS.

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SO TOLL RECEPTORS RECOGNIZE THIS

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00:09:17,366 --> 00:09:18,801
OUTSIDE OF THE CELLS BUT THEY

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ARE BLIND TO THIS BOX.

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THEY HAVE SUCCESSFULLY INVADED

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OUR CELLS AND REPLICATED INSIDE

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OUR CELLS.

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AND THE RECOGNITION OF THIS DNA

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OR ROBBER NA FROM THIS BOX, THEN

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PROVIDES A POWERFUL MECHANISM TO

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DETECT THESE REPLICATING

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MICROORGANISMS.

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BUT THIS SYSTEM IS LIABILITY

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BECAUSE OUR CELLS HAVE LOTS OF

225
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DNA AND OUR SOLUTION TO THIS

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PROBLEM IS TO KEEP OUR DNETWORKA

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OUT OF THE CYTOPLASM IN

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EUKARYOTIC CELLS.

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WE KEEP OUR DNA IN THE

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NUCLEOTIDES EUS AND IN THE

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MITOCHONDRIA AND IN THE NUCLEUS

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WE WRAP OUR DNA AROUND HIPPO

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STUDIES OF MULTIPLE ENDOCRINES

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TO CREATE 94 ORGANISMS.

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BUT THIS PERSON IS NOT PERFECT

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AND WHEN IT BREAKS DOWN IT CAN

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LEAD TO A WIDE VARIETY OF CAUSES

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AND IT'S ALSO IMPORTANT IN

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CANCER.

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SO BEFORE I TALK ABOUT A DNA

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SENSING PATHWAY, I WILL BRIEFLY

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TALK ABOUT THE RNA MESSAGING

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PATHWAY WHICH MY GROUP HAS ALSO

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BEEN WORKING ON.

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SO WHEN AN ANTIVIRUS, OR

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SARS-COV-2, INFECT OURSELVES,

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THE VIRAL RNA IS A DETECTED BY

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THESE HELIXES CALLED

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[INDISCERNIBLE], AND THEN THESE

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SENSOR PROTEINS INTACT WITH THIS

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MITOCHONDRIA AUTOMEMBRANE

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PROTEIN THAT WE IDENTIFIED MANY

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YEARS WHICH WE CALL MAVs, IT

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STANDS FOR MITOCHONDRIA

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ANTIVIRAL SIGNALING, WE ALSO

256
00:11:06,842 --> 00:11:09,011
CALL IS MAVs, BECAUSE WE'RE IN

257
00:11:09,011 --> 00:11:10,012
DALLAS, AND WHE WE DISCOVER THIS

258
00:11:10,012 --> 00:11:11,447
MOLECULE IT HAPPENED THAT DALLAS

259
00:11:11,447 --> 00:11:13,516
MAVERICKS WAS PLAYING IN THE NBA

260
00:11:13,516 --> 00:11:15,618
FINAL SO THAT'S HOW WE GOT OUR

261
00:11:15,618 --> 00:11:20,656
NAME EMPLOY --NAME.

262
00:11:20,656 --> 00:11:22,091
SO THIS MITOCHONDRIA SITS ON THE

263
00:11:22,091 --> 00:11:25,494
MEMBRANE AND IT ACTIVATES THESE

264
00:11:25,494 --> 00:11:30,833
KINASES IN THE CYTOSOL, PKP1

265
00:11:30,833 --> 00:11:33,269
WHICH ACTIVATES IL3 AND THESE

266
00:11:33,269 --> 00:11:34,136
TRANSCRIPTION FACTORS MOVE INTO

267
00:11:34,136 --> 00:11:35,438
THE NUCLEUS INTO THE OTHER

268
00:11:35,438 --> 00:11:37,406
CYTOKINES AND THIS IS HOW WE

269
00:11:37,406 --> 00:11:39,375
FIGHT RNA VIRUS INFECTION.

270
00:11:39,375 --> 00:11:44,947
AND AS I MENTIONED EARLIER DNA

271
00:11:44,947 --> 00:11:47,216
FROM BACTERIA OR VIRUSES, THEY

272
00:11:47,216 --> 00:11:49,952
CAN ALSO LEAD TO TYPE 1

273
00:11:49,952 --> 00:11:50,753
INTERFERON PRODUCTION.

274
00:11:50,753 --> 00:11:54,223
BUT A SENSOR OF DNA WAS NOT

275
00:11:54,223 --> 00:11:56,659
KNOWN FOR A LONG TIME AND DOWN

276
00:11:56,659 --> 00:11:59,495
STREAM IN THE SENSOR, THE

277
00:11:59,495 --> 00:12:01,897
REMEMBER PROTEIN CALLED STAIN

278
00:12:01,897 --> 00:12:03,899
WHICH WAS DISCOVERED BY

279
00:12:03,899 --> 00:12:07,069
[INDISCERNIBLE] BARBER IN MIAMI

280
00:12:07,069 --> 00:12:10,539
[INDISCERNIBLE] IN CHINA.

281
00:12:10,539 --> 00:12:15,911
AND STAIN THEN ALSO ACTIVATE THE

282
00:12:15,911 --> 00:12:16,679
IKCASHING AND [INDISCERNIBLE] IN

283
00:12:16,679 --> 00:12:16,979
THE FIELDS.

284
00:12:16,979 --> 00:12:19,014
SO WHAT WAS THE SENSOR IN THERE

285
00:12:19,014 --> 00:12:22,117
WAS A LOT OF INTEREST IN FINDING

286
00:12:22,117 --> 00:12:27,289
THIS DNETWORKA SENSOR ABOUT A

287
00:12:27,289 --> 00:12:29,425
DECADE AGO EMPLOY SO WE TOOK A

288
00:12:29,425 --> 00:12:33,863
BIOCHEMICAL APPROACH TO TRY TO

289
00:12:33,863 --> 00:12:36,098
IDENTIFY THIS DNA SENSOR AND IN

290
00:12:36,098 --> 00:12:38,868
BIOCHEMISTRY, THE MOST IMPORTANT

291
00:12:38,868 --> 00:12:40,970
FIRST STEP IS TO SET UP A CELL

292
00:12:40,970 --> 00:12:42,738
FREE SYSTEM THAT RECAPITULATES

293
00:12:42,738 --> 00:12:43,572
WHAT'S HAPPENING INSIDE CELLS.

294
00:12:43,572 --> 00:12:48,511
SO THIS IS HOW WE DID KNOW ARK

295
00:12:48,511 --> 00:12:50,646
SAY, WE EXTRACTED IT INTO THE

296
00:12:50,646 --> 00:12:55,417
CELL PATHWAY, AND WE USE SHRNA

297
00:12:55,417 --> 00:12:59,388
TO KNOCK DOWN TAIN SUCH THAT WE

298
00:12:59,388 --> 00:13:03,359
CAN TRAP EFFECTOR THAT IS

299
00:13:03,359 --> 00:13:07,196
ACTIVATED BY DNA FUNCTION

300
00:13:07,196 --> 00:13:09,365
UPSTREAM OF STING, SO SUPPOSEDLY

301
00:13:09,365 --> 00:13:11,500
PURE DNA SENSOR WOULD BE

302
00:13:11,500 --> 00:13:14,637
ACTIVATED BY DNA AND IF WE WELL,

303
00:13:14,637 --> 00:13:17,306
YSE THE CELLS, PREPARE THE CELL

304
00:13:17,306 --> 00:13:18,574
LIESATE, THE CELL WILL CONTINUE

305
00:13:18,574 --> 00:13:20,609
TO THE FACTOR THAT IS ACTIVATED

306
00:13:20,609 --> 00:13:21,010
BY DNA.

307
00:13:21,010 --> 00:13:23,746
WE THEN DID A CELL ARK SAY INTO

308
00:13:23,746 --> 00:13:29,051
ANOTHER CELL, IN THIS CASE,

309
00:13:29,051 --> 00:13:29,852
[INDISCERNIBLE] CELLS AND THEY

310
00:13:29,852 --> 00:13:33,322
HAVE A STING PATHWAY AND WE USE

311
00:13:33,322 --> 00:13:34,957
THE TOXIN CALLED [INDISCERNIBLE]

312
00:13:34,957 --> 00:13:35,824
TO PUT IT ON THE MEMORY RESPONSE

313
00:13:35,824 --> 00:13:36,926
BREAN SO WE CAN DELIVER THESE

314
00:13:36,926 --> 00:13:42,064
FACTORS INTO THE CELLS.

315
00:13:42,064 --> 00:13:43,265
STING IS USING ER PROTEINS SO IT

316
00:13:43,265 --> 00:13:44,934
CAN BE THE GET OUT OF THE CELLS,

317
00:13:44,934 --> 00:13:48,437
AND HAD IT'S ACTIVATED IT WILL

318
00:13:48,437 --> 00:13:51,240
SIGNAL A CASICATE IN

319
00:13:51,240 --> 00:13:51,807
DEPHOSPHORYLATION OF

320
00:13:51,807 --> 00:13:52,408
DIMERIZATION OF IREFRESH YOUR

321
00:13:52,408 --> 00:13:54,443
RECOLLECTION REFRESH YOUR

322
00:13:54,443 --> 00:13:55,978
RECOLLECTION F3, SO WE CAN RUN

323
00:13:55,978 --> 00:14:00,316
THIS TO DETECT THE IRF3 DIMER. 

324
00:14:00,316 --> 00:14:02,384
SO THIS ASSAY, EVENTUALLY

325
00:14:02,384 --> 00:14:02,851
WORKED.

326
00:14:02,851 --> 00:14:03,953
IT TOOK ABOUT 2 YEARS TO GET IT

327
00:14:03,953 --> 00:14:09,024
TO WORK AND IT WAS WORKED OUT BY

328
00:14:09,024 --> 00:14:11,093
A VERY TALENTED BIOCHEMIST IN

329
00:14:11,093 --> 00:14:13,829
THE LOB JOSH SUN.

330
00:14:13,829 --> 00:14:15,664
SO, SO FINALLY THIS ASSAY

331
00:14:15,664 --> 00:14:15,898
WORKED.

332
00:14:15,898 --> 00:14:18,500
HERE IF WE USE EXTRACTS FROM DNA

333
00:14:18,500 --> 00:14:20,803
TRANSVECTED CELLS AND DELIVERED

334
00:14:20,803 --> 00:14:21,870
EXTRACT INTOS POLYMERIZED CELLS,

335
00:14:21,870 --> 00:14:23,872
WE CAN SEE THESE IL3 DIMER AND

336
00:14:23,872 --> 00:14:27,042
THESE ARE NEGATIVE CONTROLS.

337
00:14:27,042 --> 00:14:30,012
SO NOW, WE HAVE ASSAY, CELL-FREE

338
00:14:30,012 --> 00:14:34,583
ARK SAY, AND THE PAN WAS TO TART

339
00:14:34,583 --> 00:14:37,987
TO FRACTIONATE A CELL EXTRACTS

340
00:14:37,987 --> 00:14:41,023
TO PURIFY THE ACTIVATOR BUT

341
00:14:41,023 --> 00:14:43,025
BEFORE WE DID A FRACTIONATION,

342
00:14:43,025 --> 00:14:45,227
WE ASK A SIMPLE QUESTION, IS

343
00:14:45,227 --> 00:14:47,997
THIS ACTIVATOR A PROTEIN OR NOT.

344
00:14:47,997 --> 00:14:52,635
SO WE TOOK THE EXTRACTS AND HEAT

345
00:14:52,635 --> 00:14:54,737
IT UP TO 95-DEGREE, WITH THE

346
00:14:54,737 --> 00:14:59,208
PROTEINS, SPUN IT DOWN WITH THE

347
00:14:59,208 --> 00:15:00,275
PROTEINS AND DELIVER THE

348
00:15:00,275 --> 00:15:01,810
SUPERINATENT INTO THE CELLS.

349
00:15:01,810 --> 00:15:05,180
AND TO OUR SURPRISE THIS HEAT

350
00:15:05,180 --> 00:15:06,982
ACTIVATED EXTRACT STILL HAS

351
00:15:06,982 --> 00:15:08,050
ACTIVITY, RESISTANT TO HEAT

352
00:15:08,050 --> 00:15:11,153
TREATMENT, RESIST APT TO PROTEIN

353
00:15:11,153 --> 00:15:12,688
SK, RESISTANT TO NUCLEACES AND

354
00:15:12,688 --> 00:15:16,125
TURNS OUT TO BE A SMALL MOLECULE

355
00:15:16,125 --> 00:15:18,527
EMPLOY AND BASED ON THIS AND

356
00:15:18,527 --> 00:15:20,996
OTHER SPRMS, WE PROPROPOSED THAT

357
00:15:20,996 --> 00:15:22,865
PERHAPS, THE DNA SENSOR IS AN

358
00:15:22,865 --> 00:15:25,167
ENZYME AND THIS ENZYME CAN MAKE

359
00:15:25,167 --> 00:15:28,003
A SMALL MOLECULE THAT THEN

360
00:15:28,003 --> 00:15:29,605
FUNCTIONS AS A SECOND 1 THAT

361
00:15:29,605 --> 00:15:30,939
WOULD BIND AND ACTIVATE TAIN TO

362
00:15:30,939 --> 00:15:33,509
INDUCE IN THE FILMS, AND THIS

363
00:15:33,509 --> 00:15:36,011
MODEL WAS QUITE PROVOCATIVE AT

364
00:15:36,011 --> 00:15:38,480
THE TIME BUT IT TURNED OUT TO BE

365
00:15:38,480 --> 00:15:42,217
CORRECT EMPLOY SO TO MAKE A LONG

366
00:15:42,217 --> 00:15:44,520
STORY SHORT, WE PURIFIED THE

367
00:15:44,520 --> 00:15:50,359
SMALL MOLECULE AND IT TURNS OUT

368
00:15:50,359 --> 00:15:52,861
THAT IT'S A CYCLO DINUCLEOTIDE,

369
00:15:52,861 --> 00:15:55,798
SO THIS IS G-PART, THIS IS AMP

370
00:15:55,798 --> 00:15:57,599
PART, THIS IS 12 IS 5 FRIEM AND

371
00:15:57,599 --> 00:16:01,170
THE OTHER 1 IS 5 PRIME 3 TIME

372
00:16:01,170 --> 00:16:05,007
AMERICA YC EMPLOY SO WE CALL IT

373
00:16:05,007 --> 00:16:08,544
3 PRIME, 2 PRIME CGAMP, SO

374
00:16:08,544 --> 00:16:10,679
THEY--THE KRETICALLY CAN YOU

375
00:16:10,679 --> 00:16:11,246
MAKE 4 ISOMERS.

376
00:16:11,246 --> 00:16:21,190
SO IN ADDITION TO 2 PAM, 2 PAM

377
00:16:21,190 --> 00:16:26,528
CGAMP, OR 3 PAM, 3 PAM, CGAMP

378
00:16:26,528 --> 00:16:28,397
AND WE MAYBE ALL THIS IS MAJOR

379
00:16:28,397 --> 00:16:31,567
TO BYPASSING TO STAIN AND WE

380
00:16:31,567 --> 00:16:37,172
FOUND THAT THIS 2 PAM 3 PAM

381
00:16:37,172 --> 00:16:39,708
CGAMP, THE CANNED WHAT THAT OUR

382
00:16:39,708 --> 00:16:43,011
CELLS MAKE, IT'S ABOUT HIGHER

383
00:16:43,011 --> 00:16:44,546
AFFINITY THAN OTHER CGAMP

384
00:16:44,546 --> 00:16:49,685
ISOMERS AND IF WE DELIVER THESE

385
00:16:49,685 --> 00:16:53,222
2 PAM, 3 PAM CGAMP, IT CAN

386
00:16:53,222 --> 00:16:57,192
INDUCE BETA WITH ABOUT 20 NANO

387
00:16:57,192 --> 00:16:59,261
MOLAR EMPLOY SO CGAMP IS INDEED

388
00:16:59,261 --> 00:17:02,664
A SECURITIZATION. MESSENGER THAT

389
00:17:02,664 --> 00:17:05,300
COMBINE AND ACTIVATE STING TO

390
00:17:05,300 --> 00:17:06,101
INTRODUCE INTERFERON BETA.

391
00:17:06,101 --> 00:17:07,136
NOW THE QUESTION IS WHAT'S THE

392
00:17:07,136 --> 00:17:08,470
ENZYME AND IT TURNS OUT THAT

393
00:17:08,470 --> 00:17:10,739
THIS ENWRIEM WAS VERY DIFFICULT

394
00:17:10,739 --> 00:17:11,440
TO PURIFY.

395
00:17:11,440 --> 00:17:14,543
WE WENT THROUGH MORE THAN 2000

396
00:17:14,543 --> 00:17:16,178
DISHES OF CELLS, THOSE ARE

397
00:17:16,178 --> 00:17:18,413
REALLY LARGE DISHES OF CELLS AND

398
00:17:18,413 --> 00:17:20,482
WE WENT TO DIFFERENT

399
00:17:20,482 --> 00:17:22,151
PURIFICATION STRATEGIES, BUT WE

400
00:17:22,151 --> 00:17:24,586
BEINGN'T PURIFY TO HOW MUCH AN

401
00:17:24,586 --> 00:17:26,855
ENTITY WOULD ACHIEVE ONLY ABOUT

402
00:17:26,855 --> 00:17:28,023
15,000 PURIFICATION AND WE

403
00:17:28,023 --> 00:17:30,993
ESTIMATED THAT WE NEED TO PURIFY

404
00:17:30,993 --> 00:17:34,563
THESE LIKE MEANING TO  ACHIEVE

405
00:17:34,563 --> 00:17:35,531
IMIEWPITY, AND THAT WAS VERY

406
00:17:35,531 --> 00:17:41,904
DIFFICULT, AND SO WE WERE STUCK

407
00:17:41,904 --> 00:17:43,739
THERE WE PUT THIS ON THE

408
00:17:43,739 --> 00:17:44,940
COLLAGEN AND THEN IT WOULD

409
00:17:44,940 --> 00:17:46,074
DISAPPEAR AND THEN WE HAVE TO

410
00:17:46,074 --> 00:17:46,542
START OVER.

411
00:17:46,542 --> 00:17:48,143
SO THEN WE CAME UP WITH A

412
00:17:48,143 --> 00:17:50,846
STRATEGIC PLANEMY, WE REASONED

413
00:17:50,846 --> 00:17:54,850
THAT OKAY IF WE HAVE PURIFIED

414
00:17:54,850 --> 00:17:58,387
THIS BY [INDISCERNIBLE], WE HAVE

415
00:17:58,387 --> 00:18:01,323
MUCH TO GO AND THIS IS ABOUT 1%

416
00:18:01,323 --> 00:18:05,627
PURITY AND IF WE IDENTIFY ALL

417
00:18:05,627 --> 00:18:09,431
PROTEINS OUT, 1 OUT OF 100 WOULD

418
00:18:09,431 --> 00:18:10,599
BE OUR PROTEIN OF INTEREST BUT

419
00:18:10,599 --> 00:18:15,904
WE JUST DIDN'T KNOW WHICH 1.

420
00:18:15,904 --> 00:18:18,807
BUT HOWEVER, IF WE USE MASS

421
00:18:18,807 --> 00:18:20,075
SPEC. TO IDENTIFY ALL THE

422
00:18:20,075 --> 00:18:23,245
PROTEIN ANDS DIFFERENT

423
00:18:23,245 --> 00:18:26,081
FRACTIONS, AND QUANTIFY THE

424
00:18:26,081 --> 00:18:29,484
ABUNDANCE, THE ABUNDANCE OF OUR

425
00:18:29,484 --> 00:18:32,387
PROTEIN SHOULD CO PURIFY WITH

426
00:18:32,387 --> 00:18:39,862
OUR ACTIVITY, AND SO, I RUN THIS

427
00:18:39,862 --> 00:18:43,632
IDEA BY MY STUDENT YIERK AXI,

428
00:18:43,632 --> 00:18:45,467
WU, HE LEARNED HOW TO DO MASS

429
00:18:45,467 --> 00:18:47,002
SPEC. AND BECAME VERY GOOD AT IT

430
00:18:47,002 --> 00:18:49,638
AND HE CUT OUT MORE THAN A

431
00:18:49,638 --> 00:18:50,973
HUNDRED BANDS FROM DIFFERENT

432
00:18:50,973 --> 00:18:52,541
PUREICTION STRATEGY ANDS

433
00:18:52,541 --> 00:18:54,509
IDENTIFY AND QUANT PIE THESE

434
00:18:54,509 --> 00:18:57,112
PROTEINS AND HE FOUND THERE WERE

435
00:18:57,112 --> 00:18:59,114
3 PROTEINS THAT CO PURIFIED WITH

436
00:18:59,114 --> 00:19:01,483
ACTIVITY THROUGH DIFFERENT

437
00:19:01,483 --> 00:19:02,284
PURIFICATION STRATEGIES.

438
00:19:02,284 --> 00:19:06,688
IN 1 OF THESE PROTEINS, WAS A

439
00:19:06,688 --> 00:19:10,993
PROTEIN IN A DATABASE WITH A

440
00:19:10,993 --> 00:19:12,127
CHARACTERIZED FUNCTION AND WE

441
00:19:12,127 --> 00:19:16,765
CALL THIS NOW, WE CALL IT CGAS

442
00:19:16,765 --> 00:19:19,601
AND SEQUENCE ANALYSIS SHOWED

443
00:19:19,601 --> 00:19:22,137
THAT THIS PROTEIN HAS A

444
00:19:22,137 --> 00:19:23,639
NUCLEOTIDE TRANSFER ACE DOMAIN

445
00:19:23,639 --> 00:19:28,076
WHICH IS HOMOLOGOUS TO ANOTHER

446
00:19:28,076 --> 00:19:31,246
ENZYME, OS-1 AND OLIGIO SYNTHASE

447
00:19:31,246 --> 00:19:33,181
1 AND THE HIGHLY [INDISCERNIBLE]

448
00:19:33,181 --> 00:19:34,449
ARE HIGHLY CONSERVED.

449
00:19:34,449 --> 00:19:38,120
SO WE PUBLISH 2 PAPERS THAT YEN

450
00:19:38,120 --> 00:19:39,621
JUST MENTIONED AND FOR THOSE WHO

451
00:19:39,621 --> 00:19:42,357
ARE INTERESTED IN HOW WE

452
00:19:42,357 --> 00:19:45,661
DISCOVERED CGAS AND CGAMP, CAN

453
00:19:45,661 --> 00:19:48,630
YOU SCRUTINIZE THESE PAPERS.

454
00:19:48,630 --> 00:19:50,799
OKAY, SO, THAT'S HOW WE

455
00:19:50,799 --> 00:19:53,302
DISCOVERED CGAZ AND CGAMP.

456
00:19:53,302 --> 00:19:55,837
AND NOW FAST FORWARD MANYIERS

457
00:19:55,837 --> 00:19:58,640
LATER WE HAVE A MORE

458
00:19:58,640 --> 00:19:59,641
UNDERSTANDING OF THE CGAS

459
00:19:59,641 --> 00:20:01,610
STAINING PATHWAY AND I WILL USE

460
00:20:01,610 --> 00:20:03,078
THIS CARTOON TO ILLUSTRATE THIS

461
00:20:03,078 --> 00:20:03,312
PATHWAY.

462
00:20:03,312 --> 00:20:05,580
SO HERE IS A CELL, THERE'S

463
00:20:05,580 --> 00:20:07,516
INFECKED BY A VIRUS, IN THIS

464
00:20:07,516 --> 00:20:10,085
CASE, A DNA VIRUS, THE VIRUS

465
00:20:10,085 --> 00:20:11,954
DELIVERED DNA INTO THE CELLS,

466
00:20:11,954 --> 00:20:14,890
AND THE DNA AND THE CYTOPLASM IS

467
00:20:14,890 --> 00:20:16,191
A DENDRITIC CELL ROUGH ATOM

468
00:20:16,191 --> 00:20:19,828
SIGNAL THAT IS RECOGNIZED BY

469
00:20:19,828 --> 00:20:20,729
THIS ENZYME CGAS.

470
00:20:20,729 --> 00:20:24,399
CGAS BINDS TO THE DNA AND IT

471
00:20:24,399 --> 00:20:25,067
BECOMES ACTIVATED.

472
00:20:25,067 --> 00:20:29,571
SO THIS A STRUCTURAL OF CGAS,

473
00:20:29,571 --> 00:20:35,644
WHEN IT'S BOUND TO DNA, SO DNA

474
00:20:35,644 --> 00:20:36,511
BINDING PUSHES THIS PINK

475
00:20:36,511 --> 00:20:39,047
ACTIVATION LOOP AND INDUCES A

476
00:20:39,047 --> 00:20:40,415
CONFIRMATIONAL CHANGE IN THE

477
00:20:40,415 --> 00:20:42,417
ACTIVE SITE OF THE ENSWROIM AND

478
00:20:42,417 --> 00:20:45,053
THIS DNA BINDING ALSO INDUCES

479
00:20:45,053 --> 00:20:46,288
ACTIVATION OF ENZYME WHICH IS

480
00:20:46,288 --> 00:20:49,825
IMPORTANT FOR ACTIVATION.

481
00:20:49,825 --> 00:20:55,630
SO NOW THIS ENZYME IS ACTIVATED

482
00:20:55,630 --> 00:20:58,567
FROM CTP AND ATP INTO THE C-GAS

483
00:20:58,567 --> 00:21:00,202
MOLECULE WHICH ACTIVATES IMMUNE

484
00:21:00,202 --> 00:21:00,469
RESPONSE.

485
00:21:00,469 --> 00:21:03,839
SO NOW 1 MOLECULE OF ENZYME

486
00:21:03,839 --> 00:21:06,241
MAKING MULTIPLE MOLECULES OF

487
00:21:06,241 --> 00:21:10,379
THIS SECOND MESSENGER, SO THE

488
00:21:10,379 --> 00:21:11,613
SIGNAL IS AMPLIFIED.

489
00:21:11,613 --> 00:21:14,049
AND EACH OF THESE SECOND

490
00:21:14,049 --> 00:21:16,084
MESSENGER COMBINES TO A SKIN

491
00:21:16,084 --> 00:21:17,619
DIMER AND STAIN IS NOW ACTIVATED

492
00:21:17,619 --> 00:21:20,956
AND WHAT LEADS TO ACTIVATION OF

493
00:21:20,956 --> 00:21:23,392
NF-KAPPAB AND IR3 WHICH MOVE

494
00:21:23,392 --> 00:21:25,127
INTO THE NUCLEUS TO TURN ON THE

495
00:21:25,127 --> 00:21:26,428
EXPIRATION OF HUNDREDS OF YEENS

496
00:21:26,428 --> 00:21:33,735
THAT ARE IMPORTANT IN IMMUNE AND

497
00:21:33,735 --> 00:21:34,302
INFLAMMATORY RESPONSES.

498
00:21:34,302 --> 00:21:37,339
THIS IS ANOTHER YOU VIDEO OF THE

499
00:21:37,339 --> 00:21:39,441
PATHWAY WHICH IS CGAS ACTIVATING

500
00:21:39,441 --> 00:21:45,247
THE BINDING DNA WHICH WILL MAKE

501
00:21:45,247 --> 00:21:46,648
THE DISCIPLINARY SULFURIDE

502
00:21:46,648 --> 00:21:51,953
NUCLEOTIDE AND ACTIVATES STING

503
00:21:51,953 --> 00:21:54,456
AND ACTIVATES IPPK, AND IRF3,

504
00:21:54,456 --> 00:21:55,891
WHICH THIS WILL BE SHOWN IN THE

505
00:21:55,891 --> 00:21:56,091
FILMS.

506
00:21:56,091 --> 00:21:58,193
I WILL USE THIS SLIDE TO

507
00:21:58,193 --> 00:21:59,361
HIGHLIGHT 1 IMPORTANT POINT AND

508
00:21:59,361 --> 00:22:01,797
THAT IS THAT CGAS IS ACTIVATED

509
00:22:01,797 --> 00:22:03,398
BY ANY DOUBLE STRANDED DNA

510
00:22:03,398 --> 00:22:07,836
INDEPENDENT OF A DECKER NA

511
00:22:07,836 --> 00:22:08,770
SEQUENCE.

512
00:22:08,770 --> 00:22:13,375
AND THE CRYSTAL STRUCTURE OF THE

513
00:22:13,375 --> 00:22:17,279
CGAS DNA COMPLEX FINDS IT

514
00:22:17,279 --> 00:22:18,914
BEANEDS WITH THE SUGAR COMPOUND

515
00:22:18,914 --> 00:22:21,650
AND THAT EXPLAINS WHERE IT'S DMA

516
00:22:21,650 --> 00:22:22,651
SEQUENCE INDEPENDENT.

517
00:22:22,651 --> 00:22:24,486
AND I REALLY LIKE THESE FOR 2

518
00:22:24,486 --> 00:22:26,088
REASONS, 1 IS THAT, WELL, WE

519
00:22:26,088 --> 00:22:29,391
DON'T HAVE TO DO DNA SEQUENCING

520
00:22:29,391 --> 00:22:32,294
SO THERE'S A LOT OF SEQUENCING,

521
00:22:32,294 --> 00:22:36,832
AND ABOUT SECONDARY AND MORE

522
00:22:36,832 --> 00:22:37,866
IMPORTANTLY, THIS PROBABLY

523
00:22:37,866 --> 00:22:40,502
ALLOWS THE SINGLE PROTEIN TO

524
00:22:40,502 --> 00:22:43,205
DETECT A LARGE VARMIS I HAVEETY

525
00:22:43,205 --> 00:22:45,740
OF PATHOIENS AS LONG AS THEE

526
00:22:45,740 --> 00:22:46,708
PATHOIENS CONTAIN DNA OR REQUIRE

527
00:22:46,708 --> 00:22:48,677
DECKER MA IN THE LIFE CYCLE, SO

528
00:22:48,677 --> 00:22:51,947
WE AND OTHERS HAVE SHOWN THAT

529
00:22:51,947 --> 00:22:54,316
CGAS IS INDEED A DNA SENSOR FOR

530
00:22:54,316 --> 00:22:59,087
DNA VIRUSES SUCH AS HE WERE EASE

531
00:22:59,087 --> 00:23:01,590
VIRUS, [INDISCERNIBLE] VIRUSES

532
00:23:01,590 --> 00:23:05,160
SUCH AS HIV, MDB, AND PARASITES

533
00:23:05,160 --> 00:23:05,727
SUCH AS MALARIA.

534
00:23:05,727 --> 00:23:08,163
ANOTHER 1 THAT CAN ACTIVATE CGAS

535
00:23:08,163 --> 00:23:09,731
AND ACTUALLY OUR OWN DNA.

536
00:23:09,731 --> 00:23:12,167
AS I MENTIONED OUR OWN DNA IS

537
00:23:12,167 --> 00:23:14,169
USUALLY IN THE IN YOU KLF-TWOYUS

538
00:23:14,169 --> 00:23:16,505
AND IN THE MITOCHONDRIA BUT

539
00:23:16,505 --> 00:23:17,672
UNDER SOME PATHOLOGICAL CONDIGS,

540
00:23:17,672 --> 00:23:21,243
IF OUR OWN DNA GETS IN THE

541
00:23:21,243 --> 00:23:23,145
CYTOSOL, IT CAN LEAD TO A

542
00:23:23,145 --> 00:23:25,647
VARIETY OF AUTOIMMUNE AND

543
00:23:25,647 --> 00:23:25,914
DISEASES.

544
00:23:25,914 --> 00:23:28,617
AND 1 EXAMPLE OF AUTOIMMUNE

545
00:23:28,617 --> 00:23:30,118
DISEASE IS CALLED

546
00:23:30,118 --> 00:23:30,752
[INDISCERNIBLE] OR IEE, AUDIENCE

547
00:23:30,752 --> 00:23:33,321
GS AND THESE ARE THE CHOSEN WITH

548
00:23:33,321 --> 00:23:37,292
THE DISEASE, THEY HAVE SEVERE

549
00:23:37,292 --> 00:23:38,994
CALCESKS IN THE BRAIN AND THAT'S

550
00:23:38,994 --> 00:23:41,730
BECAUSE WHEN THESE KIDS WERE

551
00:23:41,730 --> 00:23:43,431
BOARN THEY PRODUCE THIS TYPE 1

552
00:23:43,431 --> 00:23:44,966
INTERFERON THAT DAMAGE THE BRAIN

553
00:23:44,966 --> 00:23:47,536
IN THE ABSENCE OF APPEARING

554
00:23:47,536 --> 00:23:48,837
INFECTION ANDS THESE ARE

555
00:23:48,837 --> 00:23:50,005
MONOGENIC DISEASES AND MANY OF

556
00:23:50,005 --> 00:23:52,107
THESE YEENS HAVE BEEN IESHES

557
00:23:52,107 --> 00:23:56,611
DENTIFIED BY [INDISCERNIBLE] AND

558
00:23:56,611 --> 00:23:58,713
OTHERS AND MOST OF THESE GENE

559
00:23:58,713 --> 00:24:01,016
MUTATIONS LEAD TOACIVATION OF

560
00:24:01,016 --> 00:24:02,417
THE CGAS STAINING PATHWAY.

561
00:24:02,417 --> 00:24:05,053
SO FOR EXAMPLE, 25% OF THESE

562
00:24:05,053 --> 00:24:07,489
PATIENTS HAVE MUTATIONS IN THIS

563
00:24:07,489 --> 00:24:10,025
GENE CALLED TRX1 WHOSE ENCODE

564
00:24:10,025 --> 00:24:12,894
NUCLEUS THAT DIGESTS DNA IN THE

565
00:24:12,894 --> 00:24:13,228
CYTOPLASM.

566
00:24:13,228 --> 00:24:15,964
AND SO LOSS OF FUNCTION

567
00:24:15,964 --> 00:24:17,265
MUTATIONS OF THIS GENE CRIPPLE

568
00:24:17,265 --> 00:24:23,505
ACTIVITY OF THE ENZYME AND THIS

569
00:24:23,505 --> 00:24:24,105
ALLOWS CYTOPLASMIC DNA

570
00:24:24,105 --> 00:24:25,874
ACCUMULATE ASK THAT TRIGGERS THE

571
00:24:25,874 --> 00:24:26,174
PRODUCTION.

572
00:24:26,174 --> 00:24:27,709
THE QUESTION IS WHETHER THE KIDS

573
00:24:27,709 --> 00:24:29,244
HAVE THE DISEASE BECAUSE THEY

574
00:24:29,244 --> 00:24:30,745
HAVE HYPER ACTIVATION OF THE

575
00:24:30,745 --> 00:24:31,379
CGAS PATHWAY.

576
00:24:31,379 --> 00:24:36,585
SO TO TEST THESE, WE USE

577
00:24:36,585 --> 00:24:37,719
[INDISCERNIBLE] DEFICIENT MICE.

578
00:24:37,719 --> 00:24:41,423
AND THESE MICE DIE WITHIN A FEW

579
00:24:41,423 --> 00:24:43,391
WEEKS AFTER BIRTH BECAUSE THEY

580
00:24:43,391 --> 00:24:45,160
HAVE VERY SEVERE INFLAMMATION IN

581
00:24:45,160 --> 00:24:48,063
MANY ORGANS AND WE ASKED IF WE

582
00:24:48,063 --> 00:24:51,399
REMOVE CGAS FROM TREX1, KNOCKOUT

583
00:24:51,399 --> 00:24:53,034
MICE, CAN WE RESCUE THE DISEASE

584
00:24:53,034 --> 00:24:58,740
IN SO WE GENERATED TREX1 CGAS

585
00:24:58,740 --> 00:25:00,075
DOUBLE KNOCKOUT MICE AND NOW A

586
00:25:00,075 --> 00:25:01,543
HUNDRED PERCENT OF THE MICE

587
00:25:01,543 --> 00:25:09,084
SURVIVE AND THEY DIDN'T HAVE ANY

588
00:25:09,084 --> 00:25:10,752
SYMPTOMS OF DISEASE EMPLOY

589
00:25:10,752 --> 00:25:13,288
INTERESTINGLY IF WE JUST REMOVE

590
00:25:13,288 --> 00:25:16,124
1 CGAS, WE CAN LARGELY RESCUE

591
00:25:16,124 --> 00:25:17,225
SURVIVAL AS YOU CAN SEE HERE.

592
00:25:17,225 --> 00:25:20,495
SOPHISTICATEDY WE THINK THAT

593
00:25:20,495 --> 00:25:22,430
THIS HAPLOINSUFFICIENCY OF CGAS

594
00:25:22,430 --> 00:25:24,866
IS DUE TO THIS PHENOMENON THAT

595
00:25:24,866 --> 00:25:27,469
WE DISCOVERED RECENTLY CALLED

596
00:25:27,469 --> 00:25:31,706
BASICALLY IT'S A DNA INDUCED

597
00:25:31,706 --> 00:25:33,408
[INDISCERNIBLE] SEPARATION OR

598
00:25:33,408 --> 00:25:33,742
CGAS.

599
00:25:33,742 --> 00:25:37,912
SO BASICALLY CGAS HAS MULTIPLE

600
00:25:37,912 --> 00:25:39,114
DNA BINDING DOMAINS AND THEY

601
00:25:39,114 --> 00:25:41,182
COMBINE TO DECKER NA TO

602
00:25:41,182 --> 00:25:44,252
MULTIVARIANT INTERACTIONS AND

603
00:25:44,252 --> 00:25:45,820
THIS MULTIVARIANT INTERACTIONS

604
00:25:45,820 --> 00:25:49,824
BETWEEN DNA AND CGAS, DRIVE THE

605
00:25:49,824 --> 00:25:51,326
SEPARATION THAT LEAD TO

606
00:25:51,326 --> 00:25:54,496
FORMATION OF THESE BASE IN WHICH

607
00:25:54,496 --> 00:25:57,966
CGAS IS CONCENTRATED AND

608
00:25:57,966 --> 00:25:58,233
ACTIVATED.

609
00:25:58,233 --> 00:26:03,104
AND WE THINK THAT THIS LIQUID

610
00:26:03,104 --> 00:26:05,206
PHASE SEPARATION OF CGAS RENDERS

611
00:26:05,206 --> 00:26:07,609
THIS ENZYME HIGHLY SENSITIVE TO

612
00:26:07,609 --> 00:26:09,377
THE CYTOPLASMIC CONCENTRATION OF

613
00:26:09,377 --> 00:26:13,648
BOG DNA AND CGAS.

614
00:26:13,648 --> 00:26:18,353
SO, FOR EXAMPLE, IN TREX 1

615
00:26:18,353 --> 00:26:19,521
DEFICIENCY CELLS, CYTOPLASMIC

616
00:26:19,521 --> 00:26:23,458
DNA IS ELEVATED BUT STILL QUITE

617
00:26:23,458 --> 00:26:23,725
LOW.

618
00:26:23,725 --> 00:26:27,195
SO THESE THEN, IF WE BRING THE

619
00:26:27,195 --> 00:26:32,033
CGAS CONCENTRATION DOWN BY 50%,

620
00:26:32,033 --> 00:26:34,869
THAT BRINGS IT DOWN FOR THE

621
00:26:34,869 --> 00:26:36,538
SEPARATION AND SO CGAS, IF YOU

622
00:26:36,538 --> 00:26:43,278
HAVE 50% OF CGAS, IT CANNOT

623
00:26:43,278 --> 00:26:45,246
SEPARATE AND CANNOT SEPARATE TO

624
00:26:45,246 --> 00:26:48,316
STOP THE DISEASE SO WE THINK

625
00:26:48,316 --> 00:26:49,084
THIS CONTAINS

626
00:26:49,084 --> 00:26:49,517
HAPLOINSUFFICIENCY.

627
00:26:49,517 --> 00:26:50,785
WE THIS IS VERY EXCITING BECAUSE

628
00:26:50,785 --> 00:26:51,853
THIS RESULT AND OTHER RESULTS

629
00:26:51,853 --> 00:26:53,955
THAT I DON'T HAVE TIME TO SHOW

630
00:26:53,955 --> 00:26:55,523
HERE, BASICALLY PROVIDE THE

631
00:26:55,523 --> 00:26:58,193
PROOF OF CONCEPT FOR TARGETING

632
00:26:58,193 --> 00:26:59,060
CGAS.

633
00:26:59,060 --> 00:27:02,664
SO IF WE CAN FOR INHIBITOR OF

634
00:27:02,664 --> 00:27:03,231
CGAS.

635
00:27:03,231 --> 00:27:06,000
THAT EVEN PARTIAL INHIBITION OF

636
00:27:06,000 --> 00:27:09,304
CGAS MAY PROVIDE BENEFITS TO

637
00:27:09,304 --> 00:27:11,139
PASHTS WITH AUTOIMMUNITY

638
00:27:11,139 --> 00:27:13,108
DISEASES SUCH AS ATS, SO MANY

639
00:27:13,108 --> 00:27:15,310
MAPS AND COMPANIES ARE LOOKING

640
00:27:15,310 --> 00:27:20,949
ON THE CGAS INHIBITORS.

641
00:27:20,949 --> 00:27:23,518
SO IN THE PAST 20 YEARS OR SO,

642
00:27:23,518 --> 00:27:25,120
WORK FROM MANY LABS THROUGHOUT

643
00:27:25,120 --> 00:27:27,856
OUR WORK HAS SHOWN THAT THIS

644
00:27:27,856 --> 00:27:29,557
CGAS THIN PATHWAY PLAYS A

645
00:27:29,557 --> 00:27:34,863
CENTRAL ROLE IN MANY

646
00:27:34,863 --> 00:27:35,730
PHYSIOLOGICAL PATHOLOGICAL

647
00:27:35,730 --> 00:27:36,231
PROCESSES.

648
00:27:36,231 --> 00:27:38,400
AND THERE ARE TOO MANY PAPERS IN

649
00:27:38,400 --> 00:27:41,002
IN SPACE, YESTERDAY, I CHECKED

650
00:27:41,002 --> 00:27:45,740
PUB MED, DID A SEARCH WITH CGAS

651
00:27:45,740 --> 00:27:48,843
AND STING AS KEY WORDS AND IT

652
00:27:48,843 --> 00:27:54,716
RETURNED MORE THAN 2000 PAPERS

653
00:27:54,716 --> 00:27:56,718
SINCE 2013 AND THIS YEAR SO FAR,

654
00:27:56,718 --> 00:28:01,022
THERE WERE 480 PAPERS WHICH

655
00:28:01,022 --> 00:28:02,857
MEANS EVERY DAY, YOU HAVE ALMOST

656
00:28:02,857 --> 00:28:05,960
2 PAPERS ON THIS PATHWAY WHICH

657
00:28:05,960 --> 00:28:07,495
IS DIFFICULT TO CATCH UP, SO

658
00:28:07,495 --> 00:28:12,567
HERE I WANT TO SUMMARIZE, YOU

659
00:28:12,567 --> 00:28:13,768
KNOW TRY MY BEST TO SUMMARIZE

660
00:28:13,768 --> 00:28:24,245
THIS WORK AND IN THIS SLIDE.

661
00:28:26,948 --> 00:28:29,350
SO ACTIVATION IMPOSES VIRUSES,

662
00:28:29,350 --> 00:28:30,718
PARASITES, ACTIVATION ON THIS

663
00:28:30,718 --> 00:28:33,388
PATHWAY CAN LEAD TO A VARIETY OF

664
00:28:33,388 --> 00:28:36,357
AUTOIMMUNE AND INFAMOUS DISEASES

665
00:28:36,357 --> 00:28:46,868
SUCH AS AGS, SAVI, AS YOU KNOW

666
00:28:47,902 --> 00:28:51,539
FROM DR. ELA'S WORK THIS HAS

667
00:28:51,539 --> 00:28:53,408
BEEN SHOWN TO LEAD TO

668
00:28:53,408 --> 00:28:56,778
NEURODEGENERATION VERY NICE WORK

669
00:28:56,778 --> 00:29:07,322
FROM HITCH ARD YU HAS SHOWN HERE

670
00:29:14,229 --> 00:29:16,965
THAT AND PATH THIS PATHWAY CAN

671
00:29:16,965 --> 00:29:19,767
LEAD TO NONKAN--KANA CANONICAL

672
00:29:19,767 --> 00:29:21,636
FORM OF AUTOPHAGY AND WE AS MANY

673
00:29:21,636 --> 00:29:22,837
AS OTHER LABS HAVE SHOWN THAT

674
00:29:22,837 --> 00:29:25,673
ACTIVATION ON THIS PATHWAY CAN

675
00:29:25,673 --> 00:29:26,841
LEAD TO CELLULAR SENESCENSEL ASK

676
00:29:26,841 --> 00:29:28,443
THIS PATHWAY IS ALSO VERY

677
00:29:28,443 --> 00:29:36,618
IMPORTANT FOR IMPACT HUMAN

678
00:29:36,618 --> 00:29:37,085
IMMUNITY.

679
00:29:37,085 --> 00:29:37,719
SO THAT'S OUR INTRODUCTION AND

680
00:29:37,719 --> 00:29:40,121
NOW I WILL TALK ABOUT THE

681
00:29:40,121 --> 00:29:48,062
REGULATION OF CGAS SIGNALING IN

682
00:29:48,062 --> 00:29:50,732
ANIMAL CELLS EMPLOY SO TO THIS

683
00:29:50,732 --> 00:29:56,404
SLIDE, SO CGAS IS PRODUCED BY

684
00:29:56,404 --> 00:29:57,572
CGAS, THE QUESTION IS HOW DID

685
00:29:57,572 --> 00:29:59,173
THAT ACTIVATE THE PATHWAY

686
00:29:59,173 --> 00:30:01,009
THROUGH STING AND SPECIFICALLY

687
00:30:01,009 --> 00:30:07,482
WE ASK HOW DOES CGAS ACTIVATE

688
00:30:07,482 --> 00:30:11,252
STING, HOW DOES STINTH ACTIVATE

689
00:30:11,252 --> 00:30:12,787
CP1, AND WE STARTED THIS FIRST

690
00:30:12,787 --> 00:30:21,229
BECAUSE OF THE EXPERIMENT WE DID

691
00:30:21,229 --> 00:30:21,763
MANY YEARS AGO.

692
00:30:21,763 --> 00:30:23,498
SO HERE WE CAN SEE

693
00:30:23,498 --> 00:30:25,833
PHOSPHORYLATION AS WELL AS

694
00:30:25,833 --> 00:30:28,636
PHOSPHORYLATION OF 3, AND THAT

695
00:30:28,636 --> 00:30:31,406
IS EXPECTED BECAUSE THE TPK1 IS

696
00:30:31,406 --> 00:30:34,075
THE KINASE PHOSPHOR IL3, IF WE

697
00:30:34,075 --> 00:30:43,217
STIMULATE CELLS WITH DNA OR THE

698
00:30:43,217 --> 00:30:46,421
GENOMIC PATHWAY, WE CAN ALSO SEE

699
00:30:46,421 --> 00:30:51,593
TBK ACTIVATION AS WELL AS WELL

700
00:30:51,593 --> 00:30:54,729
AS PHOSPHORYLATION OF IRF3.

701
00:30:54,729 --> 00:30:57,131
NOW WE CAN SEE TPK 1 ACTIVATION,

702
00:30:57,131 --> 00:30:58,766
BUT WE COULDN'T SEE IERK L3

703
00:30:58,766 --> 00:31:01,369
PHOSPHORYLATION EMPLOY AND

704
00:31:01,369 --> 00:31:02,503
THAT'S SOMEWHAT STRANGE BECAUSE

705
00:31:02,503 --> 00:31:06,074
IT IS VERY WELL KNOWN THAT TPK1

706
00:31:06,074 --> 00:31:07,842
IS THE KINASE, AND SO WHY IT

707
00:31:07,842 --> 00:31:10,244
THAT WE CAN SEE ACTIVATIONOT

708
00:31:10,244 --> 00:31:12,180
KINASE BUT NOT FORFORALATION OF

709
00:31:12,180 --> 00:31:13,114
THE SUBSTRATE.

710
00:31:13,114 --> 00:31:14,749
AND THE SIMPLEST MODEL THAT

711
00:31:14,749 --> 00:31:17,418
COULD EXPLAIN THIS RESULT IS

712
00:31:17,418 --> 00:31:19,220
THAT TPK1 IS NECESSARY BUT NOT

713
00:31:19,220 --> 00:31:20,521
SUFFICIENT TO ACTIVATE IL3.

714
00:31:20,521 --> 00:31:22,190
SO HERE WITHY IF WE LOOK AT 3

715
00:31:22,190 --> 00:31:24,225
DIFFERENT PATHWAYS THAT CAN LEAD

716
00:31:24,225 --> 00:31:26,828
TO THE ACTIVATION OF TPK1 AND

717
00:31:26,828 --> 00:31:30,264
ICASHING K, SO THIS IS THE RNA

718
00:31:30,264 --> 00:31:31,332
PATHWAY THAT ACTIVATE THESE IN

719
00:31:31,332 --> 00:31:33,935
MAPS, THIS IS THE DNA PATHWAY TO

720
00:31:33,935 --> 00:31:36,204
ACTIVATE STAIN AND THIS IS IERK

721
00:31:36,204 --> 00:31:41,709
L1 PATHWAY THAT ACTIVATE THIS

722
00:31:41,709 --> 00:31:42,377
PROTEIN CALLED [INDISCERNIBLE] 6

723
00:31:42,377 --> 00:31:45,613
AND WE SHOWED THAT IT IS

724
00:31:45,613 --> 00:31:47,915
UBIQUITIN E3 LIGASE THAT

725
00:31:47,915 --> 00:31:48,516
CHARACTERIZE THE POLYUCIBOL

726
00:31:48,516 --> 00:31:53,988
WINNATION THAT LEADS TO

727
00:31:53,988 --> 00:31:55,223
ACTIVATION OF IKK.

728
00:31:55,223 --> 00:32:00,361
AND TARE, AF6 CAN ALSO ACTIVATE

729
00:32:00,361 --> 00:32:02,463
TBK1, IN CONTRAST, TBK IS

730
00:32:02,463 --> 00:32:07,669
ACTIVATED BY STING OR MAVS, SO

731
00:32:07,669 --> 00:32:09,504
THERE MUST BE SOMETHING SPECIAL

732
00:32:09,504 --> 00:32:10,338
ABOUT MAVs ANDS STING AND

733
00:32:10,338 --> 00:32:13,608
THEIR ABILITY TO NOT ONLY

734
00:32:13,608 --> 00:32:22,650
ACTIVATE TPK1 BUT ALSO TBK1 TO

735
00:32:22,650 --> 00:32:23,451
MAKE IERK RF3.

736
00:32:23,451 --> 00:32:24,819
AND THIS WAS PERFOR THE PURPOSED

737
00:32:24,819 --> 00:32:26,888
BY A POST DOC STUDENT AND AT THE

738
00:32:26,888 --> 00:32:28,156
TIME THIS OPPORTUNITY WAS

739
00:32:28,156 --> 00:32:30,391
WORKING ON REGULATION OF MAVS BY

740
00:32:30,391 --> 00:32:33,194
RNA RIEROUS INFECTION AND SHE

741
00:32:33,194 --> 00:32:36,998
FOUND THAT MAVS IS

742
00:32:36,998 --> 00:32:41,903
PHOSPHORYLATED SHOWN HERE IN

743
00:32:41,903 --> 00:32:43,771
RESPONSE TO THE ACTIVATION, SO

744
00:32:43,771 --> 00:32:45,373
SHE FOUND THIS SHORT SEQUENCE

745
00:32:45,373 --> 00:32:47,475
MOTIF THAT IS HIGHLY CONSERVED

746
00:32:47,475 --> 00:32:50,878
NOT ONLY IN MAVS BUT ALSO IN IL3

747
00:32:50,878 --> 00:32:51,612
AND STING.

748
00:32:51,612 --> 00:32:55,049
SO THE PHOSPHORYLATION OF IL3 OF

749
00:32:55,049 --> 00:32:57,385
THIS RESIDUE DUE TO DIMERIZATION

750
00:32:57,385 --> 00:32:59,921
AND ACTIVATION, AND SO SHE ALSO

751
00:32:59,921 --> 00:33:03,091
SHOWED THAT STING IS INDEED

752
00:33:03,091 --> 00:33:03,825
PHOSPHORYLATED AND

753
00:33:03,825 --> 00:33:05,727
[INDISCERNIBLE] AT THE

754
00:33:05,727 --> 00:33:08,529
C-TERMINAL TAIL OF STING.

755
00:33:08,529 --> 00:33:11,599
AND SHE BASICALLY USE HER EYES,

756
00:33:11,599 --> 00:33:13,601
NOT COMPUTER TO IDENTIFY AND

757
00:33:13,601 --> 00:33:16,003
SHOW SEQUENCE MOTIFS WHICH WAS

758
00:33:16,003 --> 00:33:19,474
REMARKABLE AND THIS SEQUENCE

759
00:33:19,474 --> 00:33:21,008
MOTIF ACTUALLY CONSERVING OTHER

760
00:33:21,008 --> 00:33:22,410
PROTEINS INROFULLED IN INNATE

761
00:33:22,410 --> 00:33:24,846
IMMUNITY FOR EXAMPLE IS ALSO

762
00:33:24,846 --> 00:33:27,749
FOUND IN THIS ASH DATA

763
00:33:27,749 --> 00:33:29,851
PROTECTIONER PROTEIN CALLED TRIP

764
00:33:29,851 --> 00:33:38,926
WHICH IS INVOLVED IN TLR4

765
00:33:38,926 --> 00:33:39,293
SIGNALING.

766
00:33:39,293 --> 00:33:41,529
SO WHEN IS COMMON AMONG ALL

767
00:33:41,529 --> 00:33:43,865
PATHWAYS CAN LEAD TO INDUCTION

768
00:33:43,865 --> 00:33:46,667
FOR ALL INTERFERONS, SO MAVS,

769
00:33:46,667 --> 00:33:48,302
STING AND TRF, THEY CALL WHAT WE

770
00:33:48,302 --> 00:33:52,273
CALL A CANNED WHAT MOTIF, AND SO

771
00:33:52,273 --> 00:33:55,309
WHEN EACH OF THESE RECEPTORS IS

772
00:33:55,309 --> 00:33:57,245
ENGAGED BY AN UPSTREAM LIGAND,

773
00:33:57,245 --> 00:34:01,215
IT WOULD LEAD TOACIVATION OF THE

774
00:34:01,215 --> 00:34:02,583
KINASE IPK AND ITISSUING T1,

775
00:34:02,583 --> 00:34:03,785
WHICH WOULD SEQUENCE THE MOTIF,

776
00:34:03,785 --> 00:34:06,888
SO NOW THE ADAPTER PROTEIN IS

777
00:34:06,888 --> 00:34:09,657
PHOSPHORYLATED AND THE IL3,

778
00:34:09,657 --> 00:34:12,426
BECAUSE IL3 CONTAINS THIS

779
00:34:12,426 --> 00:34:15,096
POSITIVELY CHARGED SURFACE, THAT

780
00:34:15,096 --> 00:34:18,166
CAN BIND TO THIS PHOSPHORYLATED

781
00:34:18,166 --> 00:34:20,935
MOTIF, THEN THIS, FOR THE

782
00:34:20,935 --> 00:34:23,604
PHOSPHORYLATION BY TPK1, NOW

783
00:34:23,604 --> 00:34:25,106
IL3, IS PHOSPHORYLATED, IT FORMS

784
00:34:25,106 --> 00:34:28,576
A DIMER AND MOVES INTO A NUCLEUS

785
00:34:28,576 --> 00:34:29,477
TO INDUCE TYPE 1 INTERFERONS SO

786
00:34:29,477 --> 00:34:31,479
WHAT WE'RE ROUGH ATOM POSING

787
00:34:31,479 --> 00:34:33,881
HERE IS THAT FORFORALATION OF

788
00:34:33,881 --> 00:34:36,751
THIS ADAPTER PROTEINS, SEQUENCE

789
00:34:36,751 --> 00:34:37,418
MOTIFS, PRORIDES LICENSING

790
00:34:37,418 --> 00:34:40,087
MECHANISM THAT ARK LOWS THE

791
00:34:40,087 --> 00:34:41,489
KINASE TO PHOSPHORYLATE THE

792
00:34:41,489 --> 00:34:43,457
SUBSTRATE AND FOR IRPT LUKEIN 1

793
00:34:43,457 --> 00:34:45,359
AND TNF, THAT DON'T ENGAGE ANY

794
00:34:45,359 --> 00:34:48,062
OF THESE ADAPTIVE PROTEINS, AND

795
00:34:48,062 --> 00:34:50,231
THAT'S WHY THEY CAN LEAD TO IL3

796
00:34:50,231 --> 00:34:53,434
ACTIVATION WAS FOR THIS OTHER

797
00:34:53,434 --> 00:34:58,039
PATHWAYS THAT ENGAGE THESE

798
00:34:58,039 --> 00:35:01,442
ADAPTER POLINGS THAT CONDUCT THE

799
00:35:01,442 --> 00:35:04,312
IL3 AND WE THINK PROVIES A

800
00:35:04,312 --> 00:35:05,379
UNIFIED MECHANISM THAT EXPLAINS

801
00:35:05,379 --> 00:35:07,815
WHY THESE PATHWAYS THAT WE

802
00:35:07,815 --> 00:35:09,817
PRESENT VIRUS INFECTION AND

803
00:35:09,817 --> 00:35:11,152
OTHER INFECTION CAN LEAD TO TYPE

804
00:35:11,152 --> 00:35:16,190
1 INTERFERON PRODUCTION. 

805
00:35:16,190 --> 00:35:21,329
HOWEVER FOR EXPERTS IN INNATE

806
00:35:21,329 --> 00:35:22,563
IMMUNITY HERE, WHAT SAY OKAY,

807
00:35:22,563 --> 00:35:24,699
WHAT ABOUT A MECHANISM?

808
00:35:24,699 --> 00:35:26,634
WHAT ABOUT A TOLL-LIKE RECEPTOR

809
00:35:26,634 --> 00:35:30,404
7, 8, AND 9 WHICH CAN ALSO

810
00:35:30,404 --> 00:35:34,041
INDUCE TYPE 1 INTERFERONS?

811
00:35:34,041 --> 00:35:37,511
AND THIS QUESTION WAS ADDRESSED

812
00:35:37,511 --> 00:35:42,516
BY THIS VERY NICE PAPER FROM

813
00:35:42,516 --> 00:35:45,853
JULIA [INDISCERNIBLE] ABOUT 3

814
00:35:45,853 --> 00:35:47,922
YEARS AGO AND THEY IESHES

815
00:35:47,922 --> 00:35:50,691
DENTIFY A PROTEIN CALLED TESLA

816
00:35:50,691 --> 00:35:52,460
AND A FUNCTION IN THE

817
00:35:52,460 --> 00:35:54,462
ENDOSTUDIES OF MULTIPLE

818
00:35:54,462 --> 00:35:58,366
ENDOCRINAL RECEPTOR PATHWAYS SO

819
00:35:58,366 --> 00:36:00,067
FOR THESE RECEPTORS, TLR7, 8,

820
00:36:00,067 --> 00:36:03,404
AND 9 THEY DID TECT RNA OR DMA

821
00:36:03,404 --> 00:36:05,806
LIGANDS AND THEN, THEY WERE

822
00:36:05,806 --> 00:36:08,009
ACTIVATED AT THE MYD88 PATHWAY

823
00:36:08,009 --> 00:36:11,746
AND ACTIVATION OF IKKBETTA IN

824
00:36:11,746 --> 00:36:15,283
THIS CASE WERE PHOSPHORYLATE

825
00:36:15,283 --> 00:36:16,550
THIS TRANSLATION FACTOR IRF5

826
00:36:16,550 --> 00:36:18,519
WHICH WOULD LEAD TO INDUCTION OF

827
00:36:18,519 --> 00:36:21,088
TYPE 1 ISHT FERON AND OTHER

828
00:36:21,088 --> 00:36:21,956
INFLAMMATORY CYTOKINES.

829
00:36:21,956 --> 00:36:23,357
HOWEVER, THE KEY POINT HERE IS

830
00:36:23,357 --> 00:36:27,929
THAT IN ORDER FOR IKKF BETA TO

831
00:36:27,929 --> 00:36:30,598
PHOSPHORYLATE IL5, IT MUST FIRST

832
00:36:30,598 --> 00:36:33,301
PHOSPHORYLATE THE PROTEIN THAT

833
00:36:33,301 --> 00:36:36,037
ALSO HAS THIS PLACE MOTIF THAT

834
00:36:36,037 --> 00:36:38,306
WE IDENTIFY SO ONLY AFTER THIS

835
00:36:38,306 --> 00:36:40,308
PLACE MOTIF IS CO REG IEWLGTED

836
00:36:40,308 --> 00:36:42,310
CAN WE GET IKKB BETA SO THE

837
00:36:42,310 --> 00:36:45,146
MECHANISM IS SIM ARRA TO CGAS

838
00:36:45,146 --> 00:36:46,847
STAIN PATHWAY.

839
00:36:46,847 --> 00:36:49,717
THE MAVS AND STING PATHWAY.

840
00:36:49,717 --> 00:36:51,218
SO NOW BACK TO THE STING

841
00:36:51,218 --> 00:36:51,452
PATHWAY.

842
00:36:51,452 --> 00:36:53,788
SO NOW WE HAVE A BETTER

843
00:36:53,788 --> 00:36:55,756
UNDERSTANDING OF HOW TPK1

844
00:36:55,756 --> 00:36:56,524
ACTIVATE IL3, SO THE BOTTOM LINE

845
00:36:56,524 --> 00:37:00,428
HERE IS THAT IN ORDER FOR TPK1

846
00:37:00,428 --> 00:37:03,931
TO PHOSPHORYLATE 3, IT MUST

847
00:37:03,931 --> 00:37:05,933
FIRST PHOSPHORYLATE THE ADAPTING

848
00:37:05,933 --> 00:37:06,167
STAIN.

849
00:37:06,167 --> 00:37:08,436
SO WE JUST ADD ANOTHER QUESTION

850
00:37:08,436 --> 00:37:10,304
TO THE LIST AND TO BE ABLE TO

851
00:37:10,304 --> 00:37:15,576
ANSWER ALL THESE QUESTIONS WE

852
00:37:15,576 --> 00:37:18,446
FEEL THAT WE NEED TO SOLVE THE

853
00:37:18,446 --> 00:37:20,081
STRUCTURE OF THE FOOD AND STAIN

854
00:37:20,081 --> 00:37:21,749
PROTEIN.

855
00:37:21,749 --> 00:37:24,251
SO STAIN IS A SMALL

856
00:37:24,251 --> 00:37:25,553
TRANSMEMBRANE PROTEIN, IT'S

857
00:37:25,553 --> 00:37:26,587
ABOUT 40 KILODALT OPEN MEETING

858
00:37:26,587 --> 00:37:28,322
AND A 4 TRANSMEMBRANE DOMAINS

859
00:37:28,322 --> 00:37:30,658
AND THE ER MEMBRANE AND HAS THE

860
00:37:30,658 --> 00:37:34,562
LIGAND BINDING DOMAIN THAT BIENS

861
00:37:34,562 --> 00:37:37,665
TO CGAMP AND IT CONTAINS THIS

862
00:37:37,665 --> 00:37:38,232
RESDUE THAT GERONTOLOGYSTSS

863
00:37:38,232 --> 00:37:39,533
FOSTER NURSED FOCUSED ON

864
00:37:39,533 --> 00:37:39,800
FORALATED.

865
00:37:39,800 --> 00:37:41,135
AND PRIOR TO THIS WORK THE

866
00:37:41,135 --> 00:37:45,006
BINDING STRUCTURE OF THE LIGAND

867
00:37:45,006 --> 00:37:46,407
DOMAIN STAINING BUT WE DIDN'T

868
00:37:46,407 --> 00:37:47,575
HAVE THE STRUCTURAL INFORMATION

869
00:37:47,575 --> 00:37:49,477
FOR THE REST OF THE MOLECULES.

870
00:37:49,477 --> 00:37:54,515
SO WE ASSEMBLE A TEAM TO TRY TO

871
00:37:54,515 --> 00:37:57,151
SOLVE A STRUCKURE OF THE FOOD

872
00:37:57,151 --> 00:37:59,353
AND STAIN, THIS A POST DOC IN

873
00:37:59,353 --> 00:38:02,957
THE PROFESSOR'S LAB AND WE'RE

874
00:38:02,957 --> 00:38:04,859
FORTUNATE TO COLLABORATE WITH A

875
00:38:04,859 --> 00:38:06,427
CRYOEM EXPERT [INDISCERNIBLE]

876
00:38:06,427 --> 00:38:09,964
AND TOGETHER THEY SOLVE THE

877
00:38:09,964 --> 00:38:10,965
STRUCTURE OF FULL LENGTH STING

878
00:38:10,965 --> 00:38:13,167
WHICH I THINK IS QUITE

879
00:38:13,167 --> 00:38:16,570
REMARKABLE BECAUSE STING IS A

880
00:38:16,570 --> 00:38:18,906
SMALL MEMBRANE PROTEIN, EVEN A

881
00:38:18,906 --> 00:38:20,741
SKIN DIMER IS ONLY 80 DILL O

882
00:38:20,741 --> 00:38:22,977
DALTON WHICH IS SMALL FOR CRYO

883
00:38:22,977 --> 00:38:23,144
EM.

884
00:38:23,144 --> 00:38:29,650
SO IN ANY CASE, SOPHISTICATED

885
00:38:29,650 --> 00:38:32,686
SOLVE THE STRUCTURAL OF FOOD AND

886
00:38:32,686 --> 00:38:34,188
STING PROTEIN, SO STING FORMS

887
00:38:34,188 --> 00:38:38,959
THE SUBDIMER AND THE MONOMERHAS

888
00:38:38,959 --> 00:38:39,527
4 TRANSMEMBRANE HELICS AND

889
00:38:39,527 --> 00:38:40,895
CONNECKS TO THE DISCIPLINARY

890
00:38:40,895 --> 00:38:42,963
LAND BINDING DOMAIN AND THIS

891
00:38:42,963 --> 00:38:45,066
BINDING DOMAIN FORMS THIS CGAMP

892
00:38:45,066 --> 00:38:45,433
BINDING POCKET.

893
00:38:45,433 --> 00:38:49,603
SO THIS IS THE STRUCTURE OF

894
00:38:49,603 --> 00:38:56,644
STING IN THE  ABSENCE OF THE

895
00:38:56,644 --> 00:38:57,344
LIGAND TO PERFORM THE STING.

896
00:38:57,344 --> 00:39:00,347
SO WHAT HAPPENS IF YOU ADD

897
00:39:00,347 --> 00:39:01,949
LIGAND TO THE STING, SO STING

898
00:39:01,949 --> 00:39:04,218
WILL COME IN HERE AND BIND HERE

899
00:39:04,218 --> 00:39:05,886
AND INDUCES 1 ACHE DEGREE

900
00:39:05,886 --> 00:39:07,555
ROTATION OF THE LIGAND BINDING

901
00:39:07,555 --> 00:39:09,390
DOMAIN RELATIVE TO THE

902
00:39:09,390 --> 00:39:13,260
TRANSMEMBRANE DOMAIN AND THE

903
00:39:13,260 --> 00:39:14,195
CGAMP INDUCES CONFIRMATIONAL

904
00:39:14,195 --> 00:39:15,096
CHANGE SUCH THAT STRUCTURAL COME

905
00:39:15,096 --> 00:39:16,897
CLOSER TO EACH OTHER AND NOW WE

906
00:39:16,897 --> 00:39:19,533
CAN SEE THIS NEW STRUCTURE.

907
00:39:19,533 --> 00:39:23,070
SO NOW IF WE LOOK AT THE

908
00:39:23,070 --> 00:39:24,705
STRUCTURE OF STING, AND THE

909
00:39:24,705 --> 00:39:27,475
PRESENCE OF THE LIGAND OR IN THE

910
00:39:27,475 --> 00:39:30,344
ABSENCE OF LIGAND AND COMPARE

911
00:39:30,344 --> 00:39:34,949
THIS STRUCTURES CAN WE NOTICE

912
00:39:34,949 --> 00:39:36,117
SOME INTERESTING FEATURES, SO

913
00:39:36,117 --> 00:39:41,522
NOW IF WE ZOOM IN TO THIS

914
00:39:41,522 --> 00:39:45,192
REGION, AND SO THIS--THIS IS A

915
00:39:45,192 --> 00:39:47,228
STRUCTURAL OF STING BOUND TO

916
00:39:47,228 --> 00:39:50,231
CGAMP AND YOU CAN SEE THAT THE

917
00:39:50,231 --> 00:39:53,300
PROHELIXES ARE FALLING APART AS

918
00:39:53,300 --> 00:39:55,603
COMPARED TO THE [INDISCERNIBLE]

919
00:39:55,603 --> 00:39:59,306
PERFORM OF STING.

920
00:39:59,306 --> 00:40:00,841
SO THIS THESE 2 HELIXES ARE SO

921
00:40:00,841 --> 00:40:02,776
CLOSE TO EACH OTHER THAT THEY

922
00:40:02,776 --> 00:40:04,578
CAN ACCOMMODATE ONLY A SMALL

923
00:40:04,578 --> 00:40:08,015
AMINO ACIDS SUCH AS A

924
00:40:08,015 --> 00:40:08,382
[INDISCERNIBLE].

925
00:40:08,382 --> 00:40:09,283
SO A PREDICTION IS THAT IF YOU

926
00:40:09,283 --> 00:40:12,820
CHANGE THIS TO A LARGER RESIDUE,

927
00:40:12,820 --> 00:40:14,121
IT MIGHT INDUCE SPONTANEOUS

928
00:40:14,121 --> 00:40:15,489
ACTIVATION WITH STING.

929
00:40:15,489 --> 00:40:21,962
AND THAT'S INDEED THE CASE, SO

930
00:40:21,962 --> 00:40:24,298
HERE IF WE CHANGE THIS TO AMINO

931
00:40:24,298 --> 00:40:26,267
ARK SIGNIFYS WE CAN SEE

932
00:40:26,267 --> 00:40:28,969
INDUCTION OF BETA, IN ABSENCE OF

933
00:40:28,969 --> 00:40:31,805
STING, WHERE THE WILD-TYPE STING

934
00:40:31,805 --> 00:40:33,474
ACTIVATION, INDUCTION OF

935
00:40:33,474 --> 00:40:34,942
INTERFERON ABOUTETTA DEPENDS ON

936
00:40:34,942 --> 00:40:35,176
CGAMP.

937
00:40:35,176 --> 00:40:36,744
AND WE CAN ALSO SEE THIS BY

938
00:40:36,744 --> 00:40:40,814
LOOKING AT THE SIGNALING CASCADE

939
00:40:40,814 --> 00:40:45,719
AND SEE ACTIVATION OF TBK IL13,

940
00:40:45,719 --> 00:40:50,157
FOR THIS IN THE CELLS THAT CAN

941
00:40:50,157 --> 00:40:52,927
BE THE MUTANTS, EVEN IN THE

942
00:40:52,927 --> 00:40:55,462
ABSENCE OF CGAMP, WHEREAS FOR

943
00:40:55,462 --> 00:40:56,830
THE WILD-TYPE STING THAT IT

944
00:40:56,830 --> 00:41:00,134
REQUIRES THE PRESENCE OF CGAMP.

945
00:41:00,134 --> 00:41:04,471
THIS IS VERY INTERESTING BECAUSE

946
00:41:04,471 --> 00:41:06,774
MUTATIONS OF THESE RESIDUES HAVE

947
00:41:06,774 --> 00:41:10,811
BEEN FOUND IN HUMAN PATIENTS

948
00:41:10,811 --> 00:41:13,113
WITH THIS AUTOINPOLICEMANNATORY

949
00:41:13,113 --> 00:41:15,916
DISEASE CALLED SAVI, OR SUSTAIN

950
00:41:15,916 --> 00:41:17,551
[INDISCERNIBLE] VASC LOP ALGTY

951
00:41:17,551 --> 00:41:19,520
ALMOST IN EARLY INFANCY AND THE

952
00:41:19,520 --> 00:41:22,256
SARI DISEASE WAS NICELY

953
00:41:22,256 --> 00:41:23,424
CHARACTERIZED BY RAFAEL

954
00:41:23,424 --> 00:41:29,496
[INDISCERNIBLE] HERE AT NIH.

955
00:41:29,496 --> 00:41:30,397
SO SPONTANEOUS ACTIVATION OF

956
00:41:30,397 --> 00:41:32,566
STING WITH LEAD TO SEVERE CASES.

957
00:41:32,566 --> 00:41:34,702
OKAY, AND SO WE ALSO SOLVE THE

958
00:41:34,702 --> 00:41:36,570
STRUCTURAL STING BOUND TO TPK1

959
00:41:36,570 --> 00:41:37,871
WHICH WAS PUBLISH INDEED 1 OR

960
00:41:37,871 --> 00:41:40,107
WOPAPERS AND HERE I WOULD JUST

961
00:41:40,107 --> 00:41:42,610
SUMMARIZE THE MODEL BASED ON

962
00:41:42,610 --> 00:41:43,310
THESE STUDIES.

963
00:41:43,310 --> 00:41:45,412
SO HERE IS A STING DIMER THAT IS

964
00:41:45,412 --> 00:41:48,616
ON THE ER MEMBRANE AND THIS IS

965
00:41:48,616 --> 00:41:51,151
THE CGAMP MOLECULE IN RESPONSE

966
00:41:51,151 --> 00:41:53,687
TO DNA, SO THIS CGAMP MOLECULE

967
00:41:53,687 --> 00:41:56,390
BINDS TO STAIN DIMER AND INDUCES

968
00:41:56,390 --> 00:41:58,158
180-DEGREE ROTATION, OR THE

969
00:41:58,158 --> 00:41:59,560
LIGAND BINDING DOMAIN, WITH THE

970
00:41:59,560 --> 00:42:02,096
TRANSPLANT, RELATIVE TO THE

971
00:42:02,096 --> 00:42:04,265
TRANSMEMBRANE DOMAIN, AND THIS

972
00:42:04,265 --> 00:42:06,400
CGAMP BINDING INUS DOOS

973
00:42:06,400 --> 00:42:07,868
CONFIRMATIONAL CHANGE SUCH THAT

974
00:42:07,868 --> 00:42:10,070
IT CAN FORM THE OLIGMER.

975
00:42:10,070 --> 00:42:12,273
AND THIS USES THE C-TERMINAL

976
00:42:12,273 --> 00:42:14,708
CARE TO RECRUIT THE KINASE TPK1

977
00:42:14,708 --> 00:42:17,811
AND AS A RESULT OF THIS

978
00:42:17,811 --> 00:42:21,148
AUTOMATIZATION, IT BRINGS THE

979
00:42:21,148 --> 00:42:22,316
TP1 KINASE CLOSE TO EACH OTHER

980
00:42:22,316 --> 00:42:24,051
SO THEY COME CLOSE TO

981
00:42:24,051 --> 00:42:25,886
PHOSPHORYLATE ITSELF AND THAT'S

982
00:42:25,886 --> 00:42:28,389
FOR THE TPK1 ACTIVATION.

983
00:42:28,389 --> 00:42:33,494
NOW THAT THIS ACTIVATED KINASE

984
00:42:33,494 --> 00:42:35,462
WILL INVOLVE THE TAIL THAT IS

985
00:42:35,462 --> 00:42:38,465
NOT USED FOR RECRUITMENT, SO

986
00:42:38,465 --> 00:42:40,768
THIS STAINED CTL, IS

987
00:42:40,768 --> 00:42:41,769
PHOSPHORYLATED AND ANOTHER STING

988
00:42:41,769 --> 00:42:45,039
TAIL IS RECRUITED AND

989
00:42:45,039 --> 00:42:46,307
PHOSPHORYLATED AND THE

990
00:42:46,307 --> 00:42:48,509
FORFORALATED SEE THE TERMINUS

991
00:42:48,509 --> 00:42:51,211
TAIL CAN THEN RECRUIT THIS

992
00:42:51,211 --> 00:42:53,814
TRANSCRIPTION FACTOR IL3 IN

993
00:42:53,814 --> 00:42:57,584
POSITION, THE RESIDUE OF IR3 FOR

994
00:42:57,584 --> 00:43:00,054
TPK1 AND SO NOW IL3 AND

995
00:43:00,054 --> 00:43:02,589
PHOSPHORYLATED AND ANOTHER IL3

996
00:43:02,589 --> 00:43:03,891
AND RECRUITED, AND

997
00:43:03,891 --> 00:43:04,625
PHOSPHORYLATED AND

998
00:43:04,625 --> 00:43:05,859
PHOSPHORYLATED IL3 FORMS A

999
00:43:05,859 --> 00:43:07,294
DIMER, MOVE INTO THE MUSEUM

1000
00:43:07,294 --> 00:43:11,498
CLEUS TO INDUCE TYPE 1

1001
00:43:11,498 --> 00:43:11,799
INTERFERONS.

1002
00:43:11,799 --> 00:43:14,101
SO THIS IS A MODEL BASED ON

1003
00:43:14,101 --> 00:43:14,735
STRUCTURE AND BIOCHEMICAL DATA

1004
00:43:14,735 --> 00:43:18,138
AND THE QUESTION IS WHETHER IT'S

1005
00:43:18,138 --> 00:43:24,978
TRUE IN VIVO, AND SO WE

1006
00:43:24,978 --> 00:43:30,517
DPENERATED STAINED KNOCK-IN MICE

1007
00:43:30,517 --> 00:43:32,586
USING CRSPR, TO MAKE MORE MUSEUM

1008
00:43:32,586 --> 00:43:35,089
TAIGS WITH THE STAINED TAIL THAT

1009
00:43:35,089 --> 00:43:37,758
ABROGATE AND BINDING TO TPK1 OR

1010
00:43:37,758 --> 00:43:43,897
BINDING TO IL3 AND WE SHOW THAT

1011
00:43:43,897 --> 00:43:44,765
BASICALLY THIS MODEL AND

1012
00:43:44,765 --> 00:43:46,867
SPECIFICALLY WE FOUND THAT TPK1

1013
00:43:46,867 --> 00:43:49,803
RECRUITMENT TO STAIN IS VERY

1014
00:43:49,803 --> 00:43:51,271
IMPORTANT FOR ACTIVATION OF BOTH

1015
00:43:51,271 --> 00:43:54,742
IERK L3 AND THE NFCAPPA AND

1016
00:43:54,742 --> 00:43:58,212
THAT'S IMPORTANT FOR ANTITUMOR

1017
00:43:58,212 --> 00:43:59,480
IMMUNITIASMUNE DEFENSE AGAINST

1018
00:43:59,480 --> 00:44:02,182
VIRAL INFECTION, IN THIS TPK1

1019
00:44:02,182 --> 00:44:03,083
RECRUITMENT FOR STAIN SUGGEST

1020
00:44:03,083 --> 00:44:05,185
ALSO VERY IMPORTANT FOR

1021
00:44:05,185 --> 00:44:11,658
AUTOIMMUNE DISEASES CAUSED BY

1022
00:44:11,658 --> 00:44:13,260
DNA EMPLOY OKAY, SO IN THE

1023
00:44:13,260 --> 00:44:15,195
REMAINING FEW MINUTES, I WILL

1024
00:44:15,195 --> 00:44:19,133
TURN THE CLOCK BACK BY

1025
00:44:19,133 --> 00:44:21,001
[INDISCERNIBLE] AND TALK ABOUT

1026
00:44:21,001 --> 00:44:25,539
BACTERIAL CGAS AND IMPACT FOR

1027
00:44:25,539 --> 00:44:26,006
IMMUNE DEFENSE.

1028
00:44:26,006 --> 00:44:29,510
SO THROUGHOUT BILLIONS OF YEARS

1029
00:44:29,510 --> 00:44:33,347
OF EVOLUTION, BASICALLY THIS

1030
00:44:33,347 --> 00:44:36,784
CONSTANT ARMS RACE BETWEEN

1031
00:44:36,784 --> 00:44:38,719
BACTERIA AND BACTERIAL PHAGES

1032
00:44:38,719 --> 00:44:41,255
AND THAT GIVES ENORMOUS

1033
00:44:41,255 --> 00:44:45,759
DIVERSITY AND COMP A XATOXITY

1034
00:44:45,759 --> 00:44:46,660
FOR BACTERIAL PHAGES.

1035
00:44:46,660 --> 00:44:49,730
IT IS ESTIMATED THAT THERE ARE

1036
00:44:49,730 --> 00:44:51,064
10-30 FAINLS ON A PANEL AND THAT

1037
00:44:51,064 --> 00:44:55,869
IS MORE THAN OTHER ORGANISMS

1038
00:44:55,869 --> 00:44:58,071
COMBINED INCLUDING BACTERIA.

1039
00:44:58,071 --> 00:45:00,207
LIKE ANY VIRUSES, BACTERIAL

1040
00:45:00,207 --> 00:45:04,311
PHAGES THAT HAVE DNA OR RNA

1041
00:45:04,311 --> 00:45:05,779
DENOAMS WOULD A DOUBLE STRANDED

1042
00:45:05,779 --> 00:45:07,848
DNA GERONTOLOGYSTS NEMS COMPRISE

1043
00:45:07,848 --> 00:45:10,184
IN MORE THAN 95% OF BACTERIAL

1044
00:45:10,184 --> 00:45:14,188
PHAGES AND AS I MENTIONED

1045
00:45:14,188 --> 00:45:16,156
EARLIER BACTERIAL HAS POWERFUL

1046
00:45:16,156 --> 00:45:18,225
AND SOPHISTICATED IMMUNE SYSTEMS

1047
00:45:18,225 --> 00:45:21,295
SUCH AS RESTRICTIONS USING

1048
00:45:21,295 --> 00:45:24,364
CRSPR, AND 1 IMPORTANT

1049
00:45:24,364 --> 00:45:25,532
DEVELOPMENT IN THE CGAS STAIN

1050
00:45:25,532 --> 00:45:29,803
FIELD IS THE DORPHY OF A LARGE

1051
00:45:29,803 --> 00:45:34,508
FAMILY OF CGAS LIKE ENZYMES IN

1052
00:45:34,508 --> 00:45:35,142
BACTERIA.

1053
00:45:35,142 --> 00:45:36,877
SO PHILLIP'S [INDISCERNIBLE] LAB

1054
00:45:36,877 --> 00:45:38,512
AT HARVARD MEDICAL SCHOOL IERK

1055
00:45:38,512 --> 00:45:42,516
DENTIFY ABOUT 6000 BACTERIA WILL

1056
00:45:42,516 --> 00:45:49,156
CGAS LIKE PROTEINS IN VARIOUS

1057
00:45:49,156 --> 00:45:49,723
BACTERIAL.

1058
00:45:49,723 --> 00:45:52,793
WORK FROM [INDISCERNIBLE] ISRAEL

1059
00:45:52,793 --> 00:45:53,961
AND PHILLIP [INDISCERNIBLE] HAS

1060
00:45:53,961 --> 00:45:56,697
SHOWN THAT THE MAJOR FUNCTION OF

1061
00:45:56,697 --> 00:45:58,966
THIS BACTERIAL CEMBASSY LIKE

1062
00:45:58,966 --> 00:46:00,467
ENZYMES IS FOR IMMUNE

1063
00:46:00,467 --> 00:46:02,936
DIFFERENCE, FOR EXAMPLE IN THIS

1064
00:46:02,936 --> 00:46:06,373
PAPER, FROM THE LAB ISSUE THEY

1065
00:46:06,373 --> 00:46:10,444
SHOW THAT THIS BACTERIAL CGAS

1066
00:46:10,444 --> 00:46:12,513
ENZYME IS ACTIVATED BY PHAGE

1067
00:46:12,513 --> 00:46:14,414
INFECTION TO AN UNKNOWN

1068
00:46:14,414 --> 00:46:16,884
MECHANISM AND THIS ENZYME THEN

1069
00:46:16,884 --> 00:46:19,620
CONVERTS TO GTP AND ATP TO THE

1070
00:46:19,620 --> 00:46:25,692
MOLECULE WHICH IN THIS CASE WERE

1071
00:46:25,692 --> 00:46:28,028
BACTERIAL [INDISCERNIBLE] AND

1072
00:46:28,028 --> 00:46:29,563
THIS LIPASE HAS THE MEMBRANE

1073
00:46:29,563 --> 00:46:33,166
LIPID AND CAUSES THE VIRUS

1074
00:46:33,166 --> 00:46:34,468
INFECTOR CELLS TO COMMIT SUICIDE

1075
00:46:34,468 --> 00:46:37,437
AND THIS IS THE MECHANISM TO

1076
00:46:37,437 --> 00:46:40,073
LIMIT THE VIRUS PREDOMINANTLY TO

1077
00:46:40,073 --> 00:46:41,909
PROTECT THE BACTERIAL COMMUNITY.

1078
00:46:41,909 --> 00:46:47,347
SO THIS CGAS NEW DEFENSE SIZE IS

1079
00:46:47,347 --> 00:46:52,819
ALSO CALLED CBASS, OR CYCLIC

1080
00:46:52,819 --> 00:46:53,987
OLIGONUCLEOTIDE-BASED ANTIPAGE

1081
00:46:53,987 --> 00:46:56,690
SIGNALING SYSTEMS, SO THIS CGAS

1082
00:46:56,690 --> 00:46:59,059
IS THE GENE IS QUITE OFTEN NEXT

1083
00:46:59,059 --> 00:47:00,427
TO THE GENE ENCODING THE

1084
00:47:00,427 --> 00:47:03,830
EFFECTOR PROTEIN SUCH AS A

1085
00:47:03,830 --> 00:47:06,400
PHOSPHOR LIPASE.

1086
00:47:06,400 --> 00:47:09,403
AND INTERESTINGLY, ABOUT 40% OF

1087
00:47:09,403 --> 00:47:12,940
THIS CBASS SYSTEM WHICH MORE

1088
00:47:12,940 --> 00:47:15,642
THAN 2000 CBASS SYSTEM HAVE

1089
00:47:15,642 --> 00:47:17,878
GENES THAT ENCODE ENZYMATIC

1090
00:47:17,878 --> 00:47:21,081
DOMAINS THAT UBIQUITIN E1 OR E2

1091
00:47:21,081 --> 00:47:24,551
ENZYME DOMAINS AS WELL AS

1092
00:47:24,551 --> 00:47:25,552
[INDISCERNIBLE] ENZYME DOMAINS.

1093
00:47:25,552 --> 00:47:28,388
I WAS REALLY INTRIGUED BY THESE

1094
00:47:28,388 --> 00:47:29,590
FINDINGS BECAUSE AS I MENTIONED

1095
00:47:29,590 --> 00:47:31,792
IN MY PREVENTIVUOUS LIFE I WAS

1096
00:47:31,792 --> 00:47:33,860
WORKING ON UBIQUITIN SYSTEM.

1097
00:47:33,860 --> 00:47:40,500
SO AT THIS TIME, POST DOC JOINS

1098
00:47:40,500 --> 00:47:41,902
THE LAB AND 1 OF THE FIRST

1099
00:47:41,902 --> 00:47:45,439
QUESTIONS THAT JUSTIN ASKED IS

1100
00:47:45,439 --> 00:47:52,879
WHETHER THE BACTERIAL E1, E2

1101
00:47:52,879 --> 00:47:54,481
PROTEINS CONFIRM WITH A

1102
00:47:54,481 --> 00:47:56,650
BACTERIAL PROTEIN MUCH LIKE

1103
00:47:56,650 --> 00:47:59,052
UBIQUITIN IN THE MAMMALIAN

1104
00:47:59,052 --> 00:48:00,220
SYSTEM.

1105
00:48:00,220 --> 00:48:02,589
SO HE FOCUSED ON THIS SO CALLED

1106
00:48:02,589 --> 00:48:04,925
CAP 2 PROTEIN WHICH IS AN FUSION

1107
00:48:04,925 --> 00:48:08,495
PROTEIN EMPLOY SO HE TOOK THIS

1108
00:48:08,495 --> 00:48:10,397
CGAS FROM THIS STRAIN OF E.COLI

1109
00:48:10,397 --> 00:48:14,067
AND TRANSFERRED IT TO THE

1110
00:48:14,067 --> 00:48:16,003
LABRATORY TRAIN OF E.COLI WHICH

1111
00:48:16,003 --> 00:48:22,242
DOESN'T HAVE THE CBASS SYSTEM

1112
00:48:22,242 --> 00:48:24,711
AND HE EPITOPE CAP 2 TO SEE IF

1113
00:48:24,711 --> 00:48:26,213
THIS WOULD [INDISCERNIBLE] WITH

1114
00:48:26,213 --> 00:48:28,915
THE BACTERIAL PROTEIN AND INDEED

1115
00:48:28,915 --> 00:48:31,918
HE FOUND THIS [INDISCERNIBLE]

1116
00:48:31,918 --> 00:48:33,720
WITH 50 KILODALTON PROTEIN AND

1117
00:48:33,720 --> 00:48:35,188
THIS IS [INDISCERNIBLE] BECAUSE

1118
00:48:35,188 --> 00:48:38,392
IT'S SENSITIVE TO DTISSUING

1119
00:48:38,392 --> 00:48:40,594
T AND HYDROXYL AMIN THAT IS

1120
00:48:40,594 --> 00:48:41,962
INDICATING IT'S CANNED WHAT.

1121
00:48:41,962 --> 00:48:43,764
HE THEN CUT OUT THE BAND FOR

1122
00:48:43,764 --> 00:48:47,668
MASS SPEC AND TURNS OUT TO BE

1123
00:48:47,668 --> 00:48:50,203
BACTERIAL CGAS OR DNCB, IN OTHER

1124
00:48:50,203 --> 00:48:54,641
WORDS IF BEHAVIOR YELL CGAS

1125
00:48:54,641 --> 00:48:56,977
BEHAVES LIKE UBIQUITIN WHICH IS

1126
00:48:56,977 --> 00:48:58,478
VERY STRANGE.

1127
00:48:58,478 --> 00:49:03,150
SO TO TEST IF CGAS CONYUIGATES

1128
00:49:03,150 --> 00:49:04,117
LIKE UBIQUITIN, JUSTIN DID A

1129
00:49:04,117 --> 00:49:05,285
WEST OTHER THAN BLOCK AND HE

1130
00:49:05,285 --> 00:49:07,587
FOUND THAT CGAS IN A WILD-TYPE

1131
00:49:07,587 --> 00:49:10,257
THAT THE CBASS SYSTEM THAT IT

1132
00:49:10,257 --> 00:49:12,192
CONFORMED THIS CONYUIGATE AND

1133
00:49:12,192 --> 00:49:14,027
THE FORMATION OF THESE

1134
00:49:14,027 --> 00:49:17,130
CONJUGATES DEPENDS ON THE E1 E2

1135
00:49:17,130 --> 00:49:19,199
ACTIVITY OF THIS CAP 2 BECAUSE

1136
00:49:19,199 --> 00:49:20,600
IF HE MUTATED THE ACTIVE SYSTEM

1137
00:49:20,600 --> 00:49:23,537
OF E1 OR E2, THEN WE DON'T SEE

1138
00:49:23,537 --> 00:49:26,006
THIS CONYUIGATE ANYMORE.

1139
00:49:26,006 --> 00:49:27,674
AND IMPORTANTLY, THE CONJUGATE

1140
00:49:27,674 --> 00:49:32,045
FORMATION ALSO DEPENDS ON THE

1141
00:49:32,045 --> 00:49:33,280
C-TERMINAL [INDISCERNIBLE] OF

1142
00:49:33,280 --> 00:49:35,415
CGAS IF WE CHANGE

1143
00:49:35,415 --> 00:49:36,416
[INDISCERNIBLE] TO ALA19 WE

1144
00:49:36,416 --> 00:49:39,052
DON'T SHE THE CHAIMPLE THIS THE

1145
00:49:39,052 --> 00:49:39,352
CONJUGATES.

1146
00:49:39,352 --> 00:49:43,223
AND THE MUTATION OF THIS SITE

1147
00:49:43,223 --> 00:49:44,858
RESDUE, THESE 2 ARE SLIGHT

1148
00:49:44,858 --> 00:49:47,394
INCREASE OF THESE CONYUIGATES.

1149
00:49:47,394 --> 00:49:50,130
SO THE BACTERIAL CGAS INDEED

1150
00:49:50,130 --> 00:49:51,965
BEHAVES LIKE UBIQUITIN IN THAT

1151
00:49:51,965 --> 00:49:55,569
IT CAN BE ACTIVATED BY E1 AND

1152
00:49:55,569 --> 00:49:57,204
EWOAND CONJUGATED TO OTHER

1153
00:49:57,204 --> 00:49:57,604
PROTEINS.

1154
00:49:57,604 --> 00:49:59,873
THIS IS QUITE STRANGE BECAUSE

1155
00:49:59,873 --> 00:50:02,743
THE BACTERIAL CGAS DOES NOT DO

1156
00:50:02,743 --> 00:50:04,211
UBIQUITIN AT ALL.

1157
00:50:04,211 --> 00:50:06,413
IN PARTICULAR, UBIQUITIN HAS

1158
00:50:06,413 --> 00:50:09,850
ALLY CONSERVED HELP THAT HAS 2

1159
00:50:09,850 --> 00:50:11,384
[INDISCERNIBLE] TUBES.

1160
00:50:11,384 --> 00:50:13,954
FOR BACTERIAL CGAS THEY DON'T

1161
00:50:13,954 --> 00:50:16,923
HAVE THESE RESIDUES AND INSTEAD

1162
00:50:16,923 --> 00:50:18,091
FOR THOSE CGAS [INDISCERNIBLE]

1163
00:50:18,091 --> 00:50:21,728
THEY HAVE THE E1, E2 AND THE

1164
00:50:21,728 --> 00:50:22,996
[INDISCERNIBLE] DOMAIN, THEY'RE

1165
00:50:22,996 --> 00:50:25,432
HIGHLY [INDISCERNIBLE] IN THE

1166
00:50:25,432 --> 00:50:26,566
ALA19, AND FOR THIS PROBLEM THEY

1167
00:50:26,566 --> 00:50:28,401
DON'T HAVE THE E1, E2

1168
00:50:28,401 --> 00:50:32,439
STRUCTURES, THAT IS NOT

1169
00:50:32,439 --> 00:50:34,875
CONSERVED EMPLOY SO JUSTIN

1170
00:50:34,875 --> 00:50:36,443
MUTATED THE C-TERMINAL

1171
00:50:36,443 --> 00:50:37,911
[INDISCERNIBLE] OF THESE

1172
00:50:37,911 --> 00:50:39,212
BACTERIAL CGAS INTO OTHER AMINO

1173
00:50:39,212 --> 00:50:41,748
ARK SIDES AND LOOK AT CONJUGATE

1174
00:50:41,748 --> 00:50:46,253
FORMATION WITH THE ACCEPTION OR

1175
00:50:46,253 --> 00:50:48,088
THIS TO ALA19 SUBTUITION WHICH

1176
00:50:48,088 --> 00:50:52,425
CAN STILL FORM CONYUIGATES OR

1177
00:50:52,425 --> 00:50:53,660
OTHER AMINO SUBSTITUTION UPON

1178
00:50:53,660 --> 00:50:55,629
THE FORMULATION OF THESE

1179
00:50:55,629 --> 00:50:56,196
CONJUGATES.

1180
00:50:56,196 --> 00:50:59,666
SO CGAS FORMS THIS CONJUGATES TO

1181
00:50:59,666 --> 00:51:00,367
CONSERVE THE RESDUE.

1182
00:51:00,367 --> 00:51:03,737
NOW THE IMPORTANT QUESTION IS

1183
00:51:03,737 --> 00:51:05,572
WHETHER THIS UBIQUITIN CONYU

1184
00:51:05,572 --> 00:51:07,941
IMAIGZ IS IMPORTANT FOR IMPACT

1185
00:51:07,941 --> 00:51:14,948
PAGE IMMUNE DEFENSE, SO HERE THE

1186
00:51:14,948 --> 00:51:17,918
NUMBER OF PHAGE INFECTION,

1187
00:51:17,918 --> 00:51:20,887
E.COLI STRAINS, THAT EITHER HAVE

1188
00:51:20,887 --> 00:51:21,955
FUNCTIONAL CBASS OR EMPTY

1189
00:51:21,955 --> 00:51:23,023
[INDISCERNIBLE].

1190
00:51:23,023 --> 00:51:24,691
AND THE FUNCTIONAL CBASS SYSTEM,

1191
00:51:24,691 --> 00:51:27,260
REGIEWS THE VIRAL TIGHTER BY

1192
00:51:27,260 --> 00:51:32,032
MORE THAN 10,000 FOLD AND THIS

1193
00:51:32,032 --> 00:51:37,204
ACTIVITY DEPENDS ON THE PHOSPHOR

1194
00:51:37,204 --> 00:51:37,871
LIPASE ACTIVITY OF THE

1195
00:51:37,871 --> 00:51:39,773
[INDISCERNIBLE] AND DEPENDS ON

1196
00:51:39,773 --> 00:51:42,008
CGAS, DEPENDS ON E1 E2 ACTIVITY

1197
00:51:42,008 --> 00:51:46,646
OF CAP 2 AND IMPORTANTLY REMOVAL

1198
00:51:46,646 --> 00:51:48,582
OF THE C-TERMINAL GUISEIN AND

1199
00:51:48,582 --> 00:51:51,117
C-GAS AND THE EFFECTOR OF THE E1

1200
00:51:51,117 --> 00:51:53,687
AND 2 MUTATION AND DISGUISING TO

1201
00:51:53,687 --> 00:51:55,755
THIS MUTATION HAS A PARTIAL

1202
00:51:55,755 --> 00:51:57,490
PHENOTYPE BECAUSE THIS MUTANT

1203
00:51:57,490 --> 00:52:02,529
CAN STILL FORM SOME CONYUIGATES.

1204
00:52:02,529 --> 00:52:05,632
SO, SIMILARLY, THE C-TERMINAL

1205
00:52:05,632 --> 00:52:09,169
GUISEIN OF C-GAS, PHENOCAPY, E2

1206
00:52:09,169 --> 00:52:12,539
E1 MUTATION IN THE CBASS SYSTEM.

1207
00:52:12,539 --> 00:52:16,409
SO THIS CGAS CONJUGATION IS VERY

1208
00:52:16,409 --> 00:52:17,344
IMPORTANT FOR ANTIPHAGE IMMUNE

1209
00:52:17,344 --> 00:52:18,778
DEFENSE.

1210
00:52:18,778 --> 00:52:20,380
AND THE QUESTION IS HOW DOES IT

1211
00:52:20,380 --> 00:52:21,548
DO THAT?

1212
00:52:21,548 --> 00:52:27,053
SO IN THIS EXPERIMENT, JUSTIN

1213
00:52:27,053 --> 00:52:29,356
TOOK E.COLI STRAINS THAT HAVE

1214
00:52:29,356 --> 00:52:32,626
THE WILD-TYPE CBASS SYSTEM OR

1215
00:52:32,626 --> 00:52:36,529
CBASS SYSTEM IN WHICH CGAS

1216
00:52:36,529 --> 00:52:37,564
CANNOT BE CONJUGATED.

1217
00:52:37,564 --> 00:52:39,766
HE INFECTED THE E.COLI WITH

1218
00:52:39,766 --> 00:52:46,406
BACTERIAL PHAGE AND TO MAJOR

1219
00:52:46,406 --> 00:52:48,341
CGAMP PRODUCTION, SECOND MEASURE

1220
00:52:48,341 --> 00:52:49,342
IN E.COLI AFTER PHAGE INFECTION,

1221
00:52:49,342 --> 00:52:51,378
SO CAN YOU SEE THAT FOR THE

1222
00:52:51,378 --> 00:52:53,647
WILD-TYPE CBASS SYSTEM, SHOWN IN

1223
00:52:53,647 --> 00:52:56,082
RED HERE THEY CAN PRODUCE A LOT

1224
00:52:56,082 --> 00:52:58,518
OF CGAMP AND THE CGAMP

1225
00:52:58,518 --> 00:53:01,221
PRODUCTION IS REDUCED IN THE

1226
00:53:01,221 --> 00:53:05,225
E.COLI STRAIN THAT CANNOT MAKE

1227
00:53:05,225 --> 00:53:05,659
OR CONYUIGATE CGAS.

1228
00:53:05,659 --> 00:53:09,863
SO MAJOR EECT OF THIS

1229
00:53:09,863 --> 00:53:11,865
CONJUGATION WITH CGAS IS TO

1230
00:53:11,865 --> 00:53:14,801
GREATLY ENHANCE THIS ACTIVITY

1231
00:53:14,801 --> 00:53:15,201
PRODUCE CGAMP.

1232
00:53:15,201 --> 00:53:17,170
NOW THE OBVIOUS QUESTION IS WHAT

1233
00:53:17,170 --> 00:53:21,574
ARE THE TARGETS OF THIS

1234
00:53:21,574 --> 00:53:32,118
UBIQUITIN CONYUIGATION BY CGAS,

1235
00:53:47,200 --> 00:53:49,102
SO THEN JUSTIN DID AN

1236
00:53:49,102 --> 00:53:51,004
ALTERNATIVE OPROACH WHICH IS THE

1237
00:53:51,004 --> 00:53:53,773
FORWARD GENETIC SCREEN FOR THE

1238
00:53:53,773 --> 00:53:54,841
ANTAGONISTS OF CGAS CONJUGATION,

1239
00:53:54,841 --> 00:53:58,311
SO HERE IF WE INFECT E.COLI WITH

1240
00:53:58,311 --> 00:54:00,580
T4 PHAGE, THOSE E.COLI THAT

1241
00:54:00,580 --> 00:54:01,548
DON'T HAVE CBASS SYSTEM, THEY

1242
00:54:01,548 --> 00:54:07,420
WILL BE INFEBBED BY THE PHAGE,

1243
00:54:07,420 --> 00:54:10,156
AND FOR THOSE E.COLI THAT HAVE

1244
00:54:10,156 --> 00:54:14,094
THE CBASS SYSTEM THERE WILL BE

1245
00:54:14,094 --> 00:54:14,794
ADDITIONAL INFECTION AND FOR

1246
00:54:14,794 --> 00:54:16,429
THOSE THAT HAVE THE CBASS SYSTEM

1247
00:54:16,429 --> 00:54:26,973
THAT HAVE MUTATIONS IN THE E1 E2

1248
00:54:26,973 --> 00:54:29,642
ACTIVITY THEN THEY LOST THE

1249
00:54:29,642 --> 00:54:33,179
PROTECTION AGAINST INFEC.

1250
00:54:33,179 --> 00:54:37,083
SO JUSTIN MUSEUM TANNIZED THOSE

1251
00:54:37,083 --> 00:54:41,021
TO INFECT MUTANTS AND NOW WE CAN

1252
00:54:41,021 --> 00:54:43,456
INFECT THE MUTANT CBASS AND SO

1253
00:54:43,456 --> 00:54:45,058
PRESUMABLY THERE ARE MUTATIONS

1254
00:54:45,058 --> 00:54:48,862
IN THIS T4 PAGES AND SOME OF

1255
00:54:48,862 --> 00:54:51,231
THOSE MUTANTS MOOIT ENCODAN

1256
00:54:51,231 --> 00:54:54,401
TAGANIST OR CGAS CONJUGATION, SO

1257
00:54:54,401 --> 00:54:56,636
THIS SCREEN IDENTIFY AND

1258
00:54:56,636 --> 00:55:07,247
CHARACTERIZE 10 KILODALTOR

1259
00:55:07,247 --> 00:55:07,947
CALLED BS4.

1260
00:55:07,947 --> 00:55:09,616
AND INTERESTINGLY THIS COMBINED

1261
00:55:09,616 --> 00:55:10,650
WITH ABOUT 30 NANO MOLAR AND HE

1262
00:55:10,650 --> 00:55:13,420
WEPT ON TO SOLVE THE CRYSTAL

1263
00:55:13,420 --> 00:55:15,588
STRUCTURE OF BS4 BOUND TO CGAMP

1264
00:55:15,588 --> 00:55:18,792
AND HE FOUND THAT BSFORM,

1265
00:55:18,792 --> 00:55:23,363
HORMONE LEVELSS A HEXAMERTHAT

1266
00:55:23,363 --> 00:55:26,066
BIENS TO 3 MONITOR MERS OF

1267
00:55:26,066 --> 00:55:32,439
CGAMP, AND IT'S COMPOSED OF 2

1268
00:55:32,439 --> 00:55:40,380
BVS4 MONITOR MERS, SO THESE ARE

1269
00:55:40,380 --> 00:55:41,781
THE MODELS.

1270
00:55:41,781 --> 00:55:44,284
SO TO VALIDATE THE MODEL JUSTIN

1271
00:55:44,284 --> 00:55:47,954
DID INVIF ROW CAP B ACTIVITY, SO

1272
00:55:47,954 --> 00:55:50,690
THIS IS A LIGASE ACTIVATED BY

1273
00:55:50,690 --> 00:55:55,462
CGAMP AND IF YOU USE THE

1274
00:55:55,462 --> 00:55:58,131
WILD-TYPE VIRAL PROTEIN VS4, YOU

1275
00:55:58,131 --> 00:56:00,767
IT CAN INHIBIT ACTIVATION BY

1276
00:56:00,767 --> 00:56:03,670
CGAMP, AND IF YOU ACTIVATE THE

1277
00:56:03,670 --> 00:56:05,972
RESDUES ARE INVOLVED IN THE

1278
00:56:05,972 --> 00:56:10,710
OPTIMIZATION OF BS4, THEN THEY

1279
00:56:10,710 --> 00:56:12,245
THEY LOST INHIBITING CAP B ISSUE

1280
00:56:12,245 --> 00:56:14,848
AND JUSTIN ALSO DID A

1281
00:56:14,848 --> 00:56:15,982
BIOINFORMATIC ANALYSIS TO

1282
00:56:15,982 --> 00:56:22,522
IDENTIFY VS4 LIKE PROTEINS IN

1283
00:56:22,522 --> 00:56:24,491
THE BACTERIAL PHAGE WOULD AND HE

1284
00:56:24,491 --> 00:56:26,559
FOUND ABOUT 200 VS4 FLIEK O

1285
00:56:26,559 --> 00:56:31,197
PROTEINS AND VARIOUS TYPES OF

1286
00:56:31,197 --> 00:56:32,532
PHAGES AND IMPORTANTLY, THE

1287
00:56:32,532 --> 00:56:34,467
RESIDUES THAT ARE INVOLVED IN

1288
00:56:34,467 --> 00:56:39,472
CGASM BINDING ARE HIGHLY

1289
00:56:39,472 --> 00:56:39,739
CONSERVED.

1290
00:56:39,739 --> 00:56:43,643
SO BASED ON THESE AND OTHER

1291
00:56:43,643 --> 00:56:54,087
RESULTS SO IN RESPONSE TO

1292
00:57:09,802 --> 00:57:11,471
INFECTION, FOR THE BACTERIAL

1293
00:57:11,471 --> 00:57:12,405
COMMUNITY.

1294
00:57:12,405 --> 00:57:13,439
HOWEVER SOME BACTERIAL PHAGES

1295
00:57:13,439 --> 00:57:21,047
WILL FIGHT BACK BY ENCODING THIS

1296
00:57:21,047 --> 00:57:23,449
VS 4 PROTEIN FUNCTIONS LIKE A

1297
00:57:23,449 --> 00:57:27,654
SPONGE, TO SOAK UP THIS CGAMP

1298
00:57:27,654 --> 00:57:29,422
MOLECULE AND THAT CAN PREVENT

1299
00:57:29,422 --> 00:57:31,791
ACTIVATION AND THAT ALLOWS THE

1300
00:57:31,791 --> 00:57:35,428
VIRUS TO CONTINUE TO FINISH THE

1301
00:57:35,428 --> 00:57:38,831
VIRAL REPLICATION CYCLE AND

1302
00:57:38,831 --> 00:57:39,799
ALLOWS THE VIRUS TO SPRAY.

1303
00:57:39,799 --> 00:57:50,310
SO IN IN CASE, THE VIRUS WON.

1304
00:57:58,351 --> 00:58:04,691
AND THAT PRODUCES SO MUCH CGAMP

1305
00:58:04,691 --> 00:58:06,092
THAT OVERWHELM THE VIRUS AND

1306
00:58:06,092 --> 00:58:07,860
THAT WILL ATACT AND KILL THE

1307
00:58:07,860 --> 00:58:10,463
VIRUS CELLS, SO THIS IS LIKE A

1308
00:58:10,463 --> 00:58:13,666
TYPICAL ARMS RACE IS LIKE A ROCK

1309
00:58:13,666 --> 00:58:16,736
PAPER, SCISSOR TYPE OF ARMS RACE

1310
00:58:16,736 --> 00:58:21,374
BETWEEN BACTERIA AND PHAGES AND

1311
00:58:21,374 --> 00:58:22,642
WE THINK THAT AND WE THINK THAT

1312
00:58:22,642 --> 00:58:28,047
THE SYSTEM MIGHT EVOLVE AS A

1313
00:58:28,047 --> 00:58:31,618
RESULT OF THIS ARMS RACE BETWEEN

1314
00:58:31,618 --> 00:58:32,218
BACTERIA AND PHAGES.

1315
00:58:32,218 --> 00:58:34,053
SO WE PUBLISH THIS WORK AND WE

1316
00:58:34,053 --> 00:58:38,291
FOUND NOT A GROUP.

1317
00:58:38,291 --> 00:58:42,996
THAT AARON WILY, BASICALLY

1318
00:58:42,996 --> 00:58:45,832
REACHES THE SAME CONCLUSION FOR

1319
00:58:45,832 --> 00:58:49,669
THIS BY CGAS IS IMPORTANT FOR

1320
00:58:49,669 --> 00:58:55,808
IMMUNE DEFENSE AND SO ANOTHER

1321
00:58:55,808 --> 00:58:59,212
GROUP THAT BY AT UCSF, THEY

1322
00:58:59,212 --> 00:59:01,648
IDENTIFY THE SAME RIERALLAN

1323
00:59:01,648 --> 00:59:03,883
TAGANIST, FOR THIS, WHICH THEY

1324
00:59:03,883 --> 00:59:06,286
CALL ACB 2 THAT FUNCTIONS

1325
00:59:06,286 --> 00:59:07,920
THROUGH THIS SPONGE LIKE

1326
00:59:07,920 --> 00:59:17,196
MECHANISM TO SOAK UP CGAMP.

1327
00:59:17,196 --> 00:59:18,598
SO THIS IS STILL A WORK IN

1328
00:59:18,598 --> 00:59:27,473
PROGRESS, FOR EXAMPLE, HOW DOES

1329
00:59:27,473 --> 00:59:28,374
CGAS INHIBIT'MUNE FUNCTION

1330
00:59:28,374 --> 00:59:29,809
THERE'S NO EVIDENT THAT THE

1331
00:59:29,809 --> 00:59:31,611
BACTERIAL CGAS CAN BE ACTIVATE

1332
00:59:31,611 --> 00:59:33,112
BIDE DNA ALONE, SO EXACTLY HUGH

1333
00:59:33,112 --> 00:59:35,915
IT IS ACTIVATE SIDE STILL NOT

1334
00:59:35,915 --> 00:59:36,115
CLEAR.

1335
00:59:36,115 --> 00:59:38,785
WHAT ARE THE TARGETS OF CGAS

1336
00:59:38,785 --> 00:59:40,386
CONJUGATION, THESE TARGETS COULD

1337
00:59:40,386 --> 00:59:43,189
BE PROTEINS, COULD BE LIPIDS

1338
00:59:43,189 --> 00:59:47,126
MUCH LIKE AUTOPHAGE EXPE STILL

1339
00:59:47,126 --> 00:59:50,663
DO REMAINS TO BE DETERMINED.

1340
00:59:50,663 --> 00:59:53,433
HOW DOES CGAS CONYUIGATION

1341
00:59:53,433 --> 00:59:54,167
ACTIVATE THE ANTIPHAGE IMMUNITY

1342
00:59:54,167 --> 00:59:57,136
AND THE OTHER TARGETS OF THAT

1343
00:59:57,136 --> 00:59:58,037
CONJUGATION ENSWROIMS IN

1344
00:59:58,037 --> 00:59:58,304
BACTERIA.

1345
00:59:58,304 --> 00:59:59,906
SO THERE ARE STILL MANY

1346
00:59:59,906 --> 01:00:02,642
QUESTIONS TO ANSWER AND I THINK

1347
01:00:02,642 --> 01:00:05,778
THIS IS A RAPIDLY ADVANCING

1348
01:00:05,778 --> 01:00:05,978
FIELD.

1349
01:00:05,978 --> 01:00:11,551
OKAY, SO IN CLOSING, I JUST WANT

1350
01:00:11,551 --> 01:00:14,954
TO HIGHLIGHT THE FACT THAT CGAS

1351
01:00:14,954 --> 01:00:17,256
JOINS ENZYMES AND CRSPR AS

1352
01:00:17,256 --> 01:00:20,193
IMPORTANT IMMUNE DEFENSE

1353
01:00:20,193 --> 01:00:20,460
MECHANISM.

1354
01:00:20,460 --> 01:00:26,632
IN BACTERIA AGAINST INFECTION,

1355
01:00:26,632 --> 01:00:28,801
SO CONSIDER CRSPR IN BACTERIA

1356
01:00:28,801 --> 01:00:30,870
AND CGAS IS 1 OF THE INNATE

1357
01:00:30,870 --> 01:00:32,572
IMMUNE SYSTEM IN BACTERIA AND

1358
01:00:32,572 --> 01:00:35,641
INTERESTINGLY IN HUMANS WE NO

1359
01:00:35,641 --> 01:00:37,710
LONGER USE CRSPR ISSUE, OR

1360
01:00:37,710 --> 01:00:38,778
ENZYMES TO PROTECT US AGAINST

1361
01:00:38,778 --> 01:00:40,646
VIRUS INFEC, ABOUT YOU WE STILL

1362
01:00:40,646 --> 01:00:43,049
RELY ON CGAS TO PROTECT US

1363
01:00:43,049 --> 01:00:44,917
AGAINST VIRUS INFECTIONS SO THIS

1364
01:00:44,917 --> 01:00:47,353
IMMUNE DEFENSE AGAINST VIRUS

1365
01:00:47,353 --> 01:00:50,223
INFECTION FUNCTION OF CGAS HAS

1366
01:00:50,223 --> 01:00:52,291
BEEN CONSERVED THROUGH EVOLUTION

1367
01:00:52,291 --> 01:00:57,563
FROM BACTERIAL TO HUMAN, SO IT'S

1368
01:00:57,563 --> 01:01:00,266
HUMAN, THERE'S [INDISCERNIBLE]

1369
01:01:00,266 --> 01:01:02,201
CGAS, [INDISCERNIBLE] CGAS,

1370
01:01:02,201 --> 01:01:03,703
THERE'S SINGLE CELL EUKARYOTE,

1371
01:01:03,703 --> 01:01:06,105
THAT ALSO HAVE CGAS,

1372
01:01:06,105 --> 01:01:07,840
[INDISCERNIBLE] AS CGAS AND OF

1373
01:01:07,840 --> 01:01:10,009
COURSE BACTERIA THAT THERE ARE

1374
01:01:10,009 --> 01:01:12,211
MANY, MANY CGAS OR CGAS

1375
01:01:12,211 --> 01:01:13,212
ORIGINATE INDEED BACTERIAER RAW

1376
01:01:13,212 --> 01:01:18,684
DATA AND HAS BEEN CONSERVED FOR

1377
01:01:18,684 --> 01:01:19,519
BILLIONS OF YEARS.

1378
01:01:19,519 --> 01:01:21,254
OKAY SO I THINK I HAVE

1379
01:01:21,254 --> 01:01:22,321
ACKNOWLEDGED KEY PEOPLE WHO DID

1380
01:01:22,321 --> 01:01:23,556
THE WORK DURING MIRROR IMAGE

1381
01:01:23,556 --> 01:01:26,325
TALK AND MORE RECENT WORK ON

1382
01:01:26,325 --> 01:01:27,427
BACTERIAL CGAS WAS DONE BY

1383
01:01:27,427 --> 01:01:27,660
JUSTIN.

1384
01:01:27,660 --> 01:01:30,897
THANK YOU VERY MUCH.

1385
01:01:30,897 --> 01:01:35,368
[ APPLAUSE ]

1386
01:01:35,368 --> 01:01:38,104
NTHANK YOU ANYONE IS FREE TOO

1387
01:01:38,104 --> 01:01:39,338
USE THE MICs, 2 QUICK THINGS

1388
01:01:39,338 --> 01:01:40,540
ISSUES THE CME CODE WAS 5 WHERE

1389
01:01:40,540 --> 01:01:46,279
ARE  500 NIEF

1390
01:01:46,279 --> 01:01:46,479
FINE.

1391
01:01:46,479 --> 01:01:48,748
AND TO GET THE LIVE FEEDBACK

1392
01:01:48,748 --> 01:01:50,750
FORM, IT YOU HAVE TO REFRESH,

1393
01:01:50,750 --> 01:01:51,818
CAN YOU FIRST STARTED WATCHING

1394
01:01:51,818 --> 01:01:54,620
OR CAN YOU E-MAIL QUESTIONS

1395
01:01:54,620 --> 01:01:55,288
DIRECTLY.

1396
01:01:55,288 --> 01:01:56,222
NBEAUTIFUL WORK AND I HOPE I

1397
01:01:56,222 --> 01:01:59,959
DIDN'T MISS IT ON YOUR SLIDE,

1398
01:01:59,959 --> 01:02:04,897
THE LAST PART ABOUT THE CGAS

1399
01:02:04,897 --> 01:02:07,867
REGULATION, YOU ALSO HAD A

1400
01:02:07,867 --> 01:02:08,668
[INDISCERNIBLE] CGAS, I WANT TO

1401
01:02:08,668 --> 01:02:10,136
CALL IT DO YOU NEED THAT FOR THE

1402
01:02:10,136 --> 01:02:13,206
REDUCTION OR DO YOU NEED THE

1403
01:02:13,206 --> 01:02:13,840
REVERSIBLE CONJUGATION FOR WHAT

1404
01:02:13,840 --> 01:02:15,708
YOU SEE, DO YOU KNOW THAT

1405
01:02:15,708 --> 01:02:16,075
ALREADY?

1406
01:02:16,075 --> 01:02:20,580
NYEAH, THAT'S INTERESTING, SO

1407
01:02:20,580 --> 01:02:21,514
ABOUT [INDISCERNIBLE] ENZYME,

1408
01:02:21,514 --> 01:02:25,651
THIS IS THE CAP 3 PROTEIN, AND 1

1409
01:02:25,651 --> 01:02:26,552
WOULD EXPECT THAT, YOU KNOW THAT

1410
01:02:26,552 --> 01:02:31,858
THIS 1 IF YOU REMOVE THIS

1411
01:02:31,858 --> 01:02:33,326
UBIQUITIN CONYUIGATION, IT WOULD

1412
01:02:33,326 --> 01:02:36,496
HAVE AN OPPORTUNITY FOR FAT AND

1413
01:02:36,496 --> 01:02:38,130
IN SOME--IN SOME OF THESE

1414
01:02:38,130 --> 01:02:40,433
ACTUALLY HAD HAS A POSITIVE

1415
01:02:40,433 --> 01:02:42,602
EFFECT, IT ACTUALLY BEHAVES WHY

1416
01:02:42,602 --> 01:02:43,436
UOF THE LIKE CONJUSTICE ACCESS

1417
01:02:43,436 --> 01:02:44,904
GAGE, SO MAYBE IT REQUIRE A

1418
01:02:44,904 --> 01:02:48,007
CYCLE IN ORDER TO STIMULATE

1419
01:02:48,007 --> 01:02:52,245
ENZYME ACTIVITY, AND SO THAT'S

1420
01:02:52,245 --> 01:02:53,746
THE CAP 3, ENZYME IT'S VERY

1421
01:02:53,746 --> 01:02:56,282
INTERESTING BUT IT'S ALSO

1422
01:02:56,282 --> 01:02:57,083
ENIGMA.

1423
01:02:57,083 --> 01:02:57,283
YEAH.

1424
01:02:57,283 --> 01:02:57,950
>> THANK YOU.

1425
01:02:57,950 --> 01:02:59,385
THERE IS AT LEAST 1 ONLINE

1426
01:02:59,385 --> 01:03:09,195
BECAUSE WE'RE PAST TIME. 

1427
01:03:09,195 --> 01:03:13,733
>> THE QUESTION IS--
HELLO?

1428
01:03:13,733 --> 01:03:14,033
>> YES,.

1429
01:03:14,033 --> 01:03:16,402
>> THE QUESTION IS MOST OF
THE

1430
01:03:16,402 --> 01:03:18,070
NUCLEIC ARK SIDS ARE

1431
01:03:18,070 --> 01:03:21,774
INFLAMMATORY SO 1 WAY TO REDUCE

1432
01:03:21,774 --> 01:03:28,614
INFLAMMATION AND IS THE REASON

1433
01:03:28,614 --> 01:03:34,186
THE [INDISCERNIBLE]  CHANGING

1434
01:03:34,186 --> 01:03:35,388
[INDISCERNIBLE] THAT ENDED UP

1435
01:03:35,388 --> 01:03:36,455
MAKING THE VACCINE THAT SAVED

1436
01:03:36,455 --> 01:03:38,090
LIVES ALL OVER THE WORLD NOW SO

1437
01:03:38,090 --> 01:03:40,760
DO WE HAVE A SIMILAR SYSTEM IN

1438
01:03:40,760 --> 01:03:43,262
THE MAMMALIAN SYSTEM WITH

1439
01:03:43,262 --> 01:03:43,996
MULTICELLULAR ORGANISM WHERE

1440
01:03:43,996 --> 01:03:46,265
THIS KIND OF REACTION MIGHT

1441
01:03:46,265 --> 01:03:48,734
HAPPEN BECAUSE WHENEVER YOU HAVE

1442
01:03:48,734 --> 01:03:51,370
A HIGH CELL DEATH AND ASCHEMIC

1443
01:03:51,370 --> 01:03:53,773
DEATH IN A STROKE OR HEART

1444
01:03:53,773 --> 01:03:58,544
ATTACK THAT IS A HUGE NUMBER OF

1445
01:03:58,544 --> 01:04:00,880
CELLS, HUGE NUMBER OF NEGLIG

1446
01:04:00,880 --> 01:04:04,317
ENSEL IS RELEASED, HOW DO THE

1447
01:04:04,317 --> 01:04:09,555
CELLS COMPARTMENTALIZE WITH THE

1448
01:04:09,555 --> 01:04:10,990
IN[INDISCERNIBLE] FRAGMENTS IN

1449
01:04:10,990 --> 01:04:15,394
THE MAMMALIAN SYSTEM.

1450
01:04:15,394 --> 01:04:15,695
>> RIGHT.

1451
01:04:15,695 --> 01:04:17,463
SO, YOU KNOW IT'S A VERY

1452
01:04:17,463 --> 01:04:22,635
IMPORTANT QUESTIONS AND SO I

1453
01:04:22,635 --> 01:04:23,836
TEND, MANY TIMES WE HAVE MANY

1454
01:04:23,836 --> 01:04:26,739
WAYS TO DEAL WITH DNA AND THE

1455
01:04:26,739 --> 01:04:29,375
CYTOPLASM, YOU DON'T WANT DNA TO

1456
01:04:29,375 --> 01:04:31,577
GET INTO THE CYTOPLASM SO CAN

1457
01:04:31,577 --> 01:04:35,348
YOU USE NUCLEACES TO DEGRADE DNA

1458
01:04:35,348 --> 01:04:44,557
AND THAT'S WHAT TRAX1 DOES.

1459
01:04:44,557 --> 01:04:47,760
AND THEN, YOU ALSO USE THIS

1460
01:04:47,760 --> 01:04:48,394
COMFORTMENTALLIZATION WITHIN THE

1461
01:04:48,394 --> 01:04:51,230
CELLS TO KEEP THE DNA IN THE

1462
01:04:51,230 --> 01:04:52,865
NUCLEUS OR IN THE MITOCHONDRIA

1463
01:04:52,865 --> 01:04:55,635
BUT IF THERE'S DAMAGE IN THE

1464
01:04:55,635 --> 01:04:58,838
MITOCHONDRIA, AND ALL OF HAVE

1465
01:04:58,838 --> 01:05:01,807
YOU DEFECTIVE AUTOPHAGY ISSUE BY

1466
01:05:01,807 --> 01:05:04,577
RICHARD YU, THEN THE ACTIVATED

1467
01:05:04,577 --> 01:05:08,481
PATHWAY CAN TRIGGER DECS SUCH AS

1468
01:05:08,481 --> 01:05:11,217
PARKINSON'S DISEASE, SIMILARLY,

1469
01:05:11,217 --> 01:05:12,118
[INDISCERNIBLE] IS COMPROMISED

1470
01:05:12,118 --> 01:05:13,319
SOMEHOW THAT CAN ALSO LEAD TO

1471
01:05:13,319 --> 01:05:15,421
ACTIVATION OF THESE PATHWAY,

1472
01:05:15,421 --> 01:05:17,623
GENOMIC INSTABILITY CAN LEAD TO

1473
01:05:17,623 --> 01:05:19,258
THE FORMATION OF MICROMUSEUM CLE

1474
01:05:19,258 --> 01:05:21,727
I, AND CGAS WOULD IMEAN TO THE

1475
01:05:21,727 --> 01:05:22,595
MICRONUCLEI AND GETS ACTIVATED

1476
01:05:22,595 --> 01:05:26,966
AND THAT CAN LEAD TO SENESCENSEL

1477
01:05:26,966 --> 01:05:34,674
AND SO, I THINK THAT WE USE THE

1478
01:05:34,674 --> 01:05:38,344
CGAS TO DETECTION VIRUSES ON

1479
01:05:38,344 --> 01:05:40,413
BACTERIA AND CERTAINLY THAT'S

1480
01:05:40,413 --> 01:05:45,117
IMPORTANT FOR HOST DEFENSE BUT

1481
01:05:45,117 --> 01:05:48,454
THIS PATHWAY ACTIVATION CAN HAVE

1482
01:05:48,454 --> 01:05:53,325
ADVERSE CONSEQUENCES AS SHOWN IN

1483
01:05:53,325 --> 01:05:54,760
MANY INFLAMMATORY DISEASES, A

1484
01:05:54,760 --> 01:05:56,128
LOT OF THESE DISEASES ARE CALLED

1485
01:05:56,128 --> 01:06:01,367
BY THE SO CALLED STERILE

1486
01:06:01,367 --> 01:06:03,069
INFLAMMATION AND WE THINK THAT

1487
01:06:03,069 --> 01:06:05,171
DNA IS AN IMPORTANT TRIGGER OF

1488
01:06:05,171 --> 01:06:06,572
THIS STERILE INFLAMM EGG EMPLOY

1489
01:06:06,572 --> 01:06:09,875
NIS THERE A MEASURE OFMENT CGAS

1490
01:06:09,875 --> 01:06:13,412
IN SOME OF THE AREAS OF ESCHEMIC

1491
01:06:13,412 --> 01:06:15,014
STROKE OR SOME OF THE OTHER

1492
01:06:15,014 --> 01:06:20,319
DISEASE IN LARGE ANIMALS?

1493
01:06:20,319 --> 01:06:24,557
ANY EVIDENCE OF CGAS RELEASE OR

1494
01:06:24,557 --> 01:06:27,126
ACTIVATION IN MAMMALIAN SYSTEMS?

1495
01:06:27,126 --> 01:06:31,530
ANY EVIDENCE?

1496
01:06:31,530 --> 01:06:33,399
>> YEAH, SO YEAH, CGAS

1497
01:06:33,399 --> 01:06:36,702
ACTIVATION AND YOU KNOW HUMAN

1498
01:06:36,702 --> 01:06:42,842
CELLS AND MOUSE MODELS AND MANY

1499
01:06:42,842 --> 01:06:45,644
DIFFERENT MODEL ORGANISMS.

1500
01:06:45,644 --> 01:06:48,614
YES, I'M NOT SURE IF I GET THE

1501
01:06:48,614 --> 01:06:51,083
QUESTION CORRECTLY BUT CERTAINLY

1502
01:06:51,083 --> 01:06:52,485
CGAS--CGAS ITSELF IS NOT

1503
01:06:52,485 --> 01:06:53,786
RELEASED OUTSIDE OF CELLS SO

1504
01:06:53,786 --> 01:06:56,322
IT'S ACTIVATED WITHIN A

1505
01:06:56,322 --> 01:06:57,923
CYTOPLASM BUT I SHOULD ALSO

1506
01:06:57,923 --> 01:07:00,926
POINT OUT IT'S ALSO CGAS IN THE

1507
01:07:00,926 --> 01:07:03,562
NUCLEUS, AND IN THE NUCLEUS,

1508
01:07:03,562 --> 01:07:06,999
CGAS IS BOUND TO HISTONES AND

1509
01:07:06,999 --> 01:07:08,534
THAT HISTONE BINDING PREVENTS

1510
01:07:08,534 --> 01:07:11,537
CGAS FROM GETTING ACTIVATED BY

1511
01:07:11,537 --> 01:07:17,176
GENOMIC DECKER NA. DNA.

1512
01:07:17,176 --> 01:07:18,677
>> THIS WAS BEAUTIFUL,
IT'S

1513
01:07:18,677 --> 01:07:20,513
ALWAYS EXCITING FOR THE

1514
01:07:20,513 --> 01:07:22,882
BACTERIAL PHAGE STUFF IS REALLY

1515
01:07:22,882 --> 01:07:23,182
FASCINATING.

1516
01:07:23,182 --> 01:07:24,316
I HAVE 2 QUESTIONS, WOKNOW IS

1517
01:07:24,316 --> 01:07:26,318
THERE IS A REPORT--I MEAN

1518
01:07:26,318 --> 01:07:27,453
RECENTLY STING IS ACTUALLY

1519
01:07:27,453 --> 01:07:30,790
REPORTED TO ACTUALLY FORM A PORE

1520
01:07:30,790 --> 01:07:32,625
AS WELL, YOU DIDN'T MENTION THAT

1521
01:07:32,625 --> 01:07:34,760
BUT HOW MUCH DO YOU THINK IT

1522
01:07:34,760 --> 01:07:37,630
KRIEWBS, I THINK IT WAS CLAIMED

1523
01:07:37,630 --> 01:07:39,365
TO CONTROL AUTOPHAGE EXPE ALLOW

1524
01:07:39,365 --> 01:07:40,132
P3 ACTIVATION, DID YOU SEE THAT

1525
01:07:40,132 --> 01:07:45,471
AS WELL IN THE CONFIRMATIONAL

1526
01:07:45,471 --> 01:07:48,107
CHANGES HAVE YOU SEEN OR

1527
01:07:48,107 --> 01:07:48,674
ACTUALLY OPEN IT?

1528
01:07:48,674 --> 01:07:53,045
IT WOULD BE INTERESTING IN THOSE

1529
01:07:53,045 --> 01:07:55,247
PATIENTS THAT CONSTITTIVELY

1530
01:07:55,247 --> 01:07:56,615
ACTIVE STING WHAT WOULD BE THE

1531
01:07:56,615 --> 01:07:56,882
CORRELATE.

1532
01:07:56,882 --> 01:07:58,417
THE SECOND QUESTION IS MORE IN

1533
01:07:58,417 --> 01:08:00,052
REGARDS TO THE ACCOUNTERIAL

1534
01:08:00,052 --> 01:08:01,020
PHAGE MECHANISM WHICH IS

1535
01:08:01,020 --> 01:08:01,821
FASCINATING.

1536
01:08:01,821 --> 01:08:06,358
IS THERE A HUMAN CORRELATE

1537
01:08:06,358 --> 01:08:08,394
PARTICULARLY SENGS CGAS IS QUITE

1538
01:08:08,394 --> 01:08:13,132
ACTIVATED, IS THERE A SPONGE FOR

1539
01:08:13,132 --> 01:08:14,733
A HUMAN HOMOLOG OR OF THE V4

1540
01:08:14,733 --> 01:08:18,103
PROTEIN THAT HAVE YOU SEEN AND

1541
01:08:18,103 --> 01:08:19,939
IS ACTUALLY UBIQUITYALATION OF

1542
01:08:19,939 --> 01:08:22,842
CGAS A WAY IN WHICH HUMANS CAN

1543
01:08:22,842 --> 01:08:24,276
ACTIVATE AND MODIFY THAT PATHWAY

1544
01:08:24,276 --> 01:08:31,283
AS WELL.

1545
01:08:31,283 --> 01:08:32,952
>> OKAY, THANK YOU.

1546
01:08:32,952 --> 01:08:34,320
>> YEAH, OKAY, GREAT.

1547
01:08:34,320 --> 01:08:35,487
>> ALL RIGHT, FITTER FIRST

1548
01:08:35,487 --> 01:08:38,624
QUESTION IS BIOTAINED AND REASON

1549
01:08:38,624 --> 01:08:40,893
PAPER FROM [INDISCERNIBLE] LAB

1550
01:08:40,893 --> 01:08:45,531
AT MIT SHOWING THAT STING CAN

1551
01:08:45,531 --> 01:08:47,600
FORM PROTEOME CHANNEL AND I KNOW

1552
01:08:47,600 --> 01:08:51,904
IT'S A NICE PAPER, YOU KNOW AND

1553
01:08:51,904 --> 01:09:02,081
THE STRUCTURE OF STING WE DID

1554
01:09:02,081 --> 01:09:03,949
SEE A PAW AND WE DON'T KNOW WHAT

1555
01:09:03,949 --> 01:09:07,119
IT DOES AND WE ALSO KNOW THAT

1556
01:09:07,119 --> 01:09:08,020
WITH STING TRAFFICKING FROM

1557
01:09:08,020 --> 01:09:08,921
[INDISCERNIBLE], IT WOULD LEAD

1558
01:09:08,921 --> 01:09:14,126
TO WHAT WE CALL THE NONCAN

1559
01:09:14,126 --> 01:09:17,162
NONEICAL FORM OF AUTOPHAGY IT

1560
01:09:17,162 --> 01:09:20,733
WOULD LEAD TO LC3 DEGRADATION IS

1561
01:09:20,733 --> 01:09:22,368
IT IS CAUSE BIDE ENDOSTUDIES OF

1562
01:09:22,368 --> 01:09:23,869
MULTIPLE ENDOCRINAL MEMBRANE

1563
01:09:23,869 --> 01:09:24,703
DAMAGE OR LYSOSOMAL MEMORY

1564
01:09:24,703 --> 01:09:28,607
RESPONSE BREAN DAMAGE.

1565
01:09:28,607 --> 01:09:31,510
AND SO, I THINK THAT STAIN CAN

1566
01:09:31,510 --> 01:09:34,847
FORM A POL OR CHANNEL AND IT CAN

1567
01:09:34,847 --> 01:09:37,182
LEAK PROTON, AND THAT COULD BE A

1568
01:09:37,182 --> 01:09:39,485
MECHANISM TO ACTIVATE DATP S

1569
01:09:39,485 --> 01:09:40,352
THAT LEADS TO AUTOPHAGE

1570
01:09:40,352 --> 01:09:42,288
COMPETENT INDUCTION CAN THAT'S

1571
01:09:42,288 --> 01:09:44,857
AUTOSOMAL DAMAGE THAT COULD

1572
01:09:44,857 --> 01:09:46,825
ACTIVATE NRP 3 AND MACROPHAGES

1573
01:09:46,825 --> 01:09:49,495
BUT NOT IN OTHER CELLS.

1574
01:09:49,495 --> 01:09:50,729
NTHAT WOULD BE CONSTITTATIVELY

1575
01:09:50,729 --> 01:09:51,997
ACTIVATED IN THE PATIENT WHO IS

1576
01:09:51,997 --> 01:09:55,234
HAVE MUTATIONS RIGHT?

1577
01:09:55,234 --> 01:09:55,534
>> RIGHT.

1578
01:09:55,534 --> 01:09:58,837
SO I THINK IN TERMS OF THE POL

1579
01:09:58,837 --> 01:10:00,072
FORMATION, THEN THE QUESTION,

1580
01:10:00,072 --> 01:10:02,474
THIS DEPENDS ON THE EXTENT OF

1581
01:10:02,474 --> 01:10:04,610
STAIN ACCOUNTIVATION, I THINK IF

1582
01:10:04,610 --> 01:10:06,111
YOU ACTIVATE STING VERY

1583
01:10:06,111 --> 01:10:09,949
STRONGLY, THEN THEY CAN LEAD TO

1584
01:10:09,949 --> 01:10:11,684
CELL DEATH, BUT IF IT'S

1585
01:10:11,684 --> 01:10:14,687
WEAKACIVATION AND SOME OF THOSE

1586
01:10:14,687 --> 01:10:16,422
POLs CAN BE REPAIRED BY

1587
01:10:16,422 --> 01:10:17,456
[INDISCERNIBLE] CONTACTS SO I

1588
01:10:17,456 --> 01:10:20,259
DON'T KNOW WITH THOSE PATES IF

1589
01:10:20,259 --> 01:10:22,261
THOSE POLs ARE REPAIRED BY

1590
01:10:22,261 --> 01:10:24,830
[INDISCERNIBLE] COMPLEX OR THEY

1591
01:10:24,830 --> 01:10:29,702
LEADS TO CELL DEATH, IT'S NOT

1592
01:10:29,702 --> 01:10:30,369
CLEAR.

1593
01:10:30,369 --> 01:10:34,073
AND SO, YEAH, I THINK THAT IN

1594
01:10:34,073 --> 01:10:35,941
MACROPHAGES, THE FORMATION OF

1595
01:10:35,941 --> 01:10:38,677
THESE POLs CAN LEAD TO NFCAP B

1596
01:10:38,677 --> 01:10:43,549
FORMATION AND THAT CAN ALSO

1597
01:10:43,549 --> 01:10:45,050
TRIGGER THIS NONCANONICLE FORM

1598
01:10:45,050 --> 01:10:45,951
OF AUTOPHAGY.

1599
01:10:45,951 --> 01:10:51,056
THE SECOND QUESTION IS WHETHER

1600
01:10:51,056 --> 01:10:52,758
IN MAMMALIAN CELLS, CGAS USE A

1601
01:10:52,758 --> 01:10:54,093
URK CIBOL WITTEN LIKE MECHANISM

1602
01:10:54,093 --> 01:10:56,028
TO GET ACTIVATED AND THE ANSWER

1603
01:10:56,028 --> 01:10:58,330
I THINK IS PROBABLY NOT BECAUSE

1604
01:10:58,330 --> 01:10:59,732
THE TERMINAL [INDISCERNIBLE] IS

1605
01:10:59,732 --> 01:11:02,901
NOT CONSERVED IN HUMAN CGAS.

1606
01:11:02,901 --> 01:11:05,270
AND AND SO WE THINK, YOU KNOW IN

1607
01:11:05,270 --> 01:11:07,339
BACTERIA, I MENTION THEY ARE

1608
01:11:07,339 --> 01:11:10,642
LIKE 6000 BACTERIA LIKE CGAS

1609
01:11:10,642 --> 01:11:14,880
ENZYMES, THE CGAS, SOMEHOW GETS

1610
01:11:14,880 --> 01:11:17,182
INTO EUKARYOTIC CELLS, THROUGH

1611
01:11:17,182 --> 01:11:21,320
THESE SYMBIOSIS, YOU KNOW THEY

1612
01:11:21,320 --> 01:11:24,857
MAY NOT USE THIS MECHANISM, SO,

1613
01:11:24,857 --> 01:11:26,625
SO IT WILL BE A DIFFERENT

1614
01:11:26,625 --> 01:11:29,161
MECHANISM, SO I THINK THAT IN

1615
01:11:29,161 --> 01:11:29,795
BACTERIAL BECAUSE

1616
01:11:29,795 --> 01:11:31,130
THEY'RE--THERE'S SUCH A

1617
01:11:31,130 --> 01:11:34,299
DIVERSITY OF THIS CGAS LIKE

1618
01:11:34,299 --> 01:11:35,901
ENZYMES, THE MECHANISM OF

1619
01:11:35,901 --> 01:11:37,703
ACTIVATION COULD BE QUITE

1620
01:11:37,703 --> 01:11:42,875
DIFFERENT BETWEEN DIFFERENT

1621
01:11:42,875 --> 01:11:44,076
BACTERIAL SPECIES AND SO THE

1622
01:11:44,076 --> 01:11:47,479
SHORT ANSWER IS THAT FOR HUMAN

1623
01:11:47,479 --> 01:11:49,148
CGAS, THE ACTIVATION BASKLY IS

1624
01:11:49,148 --> 01:11:51,050
VERY SIMPLE, BY BINDING TO DNA,

1625
01:11:51,050 --> 01:11:53,185
THAT'S A MEASURE MECHANISM.

1626
01:11:53,185 --> 01:11:54,653
THERE MAY BE SOME

1627
01:11:54,653 --> 01:11:55,454
[INDISCERNIBLE] MECHANISM BUT

1628
01:11:55,454 --> 01:11:56,789
THE MEASURE MECHANISM IS DNA

1629
01:11:56,789 --> 01:12:04,196
BINDING AND THEN THE QUESTION

1630
01:12:04,196 --> 01:12:09,034
THE OTHER QUESTION IS WHERE DO

1631
01:12:09,034 --> 01:12:14,873
THE MAMMALIAN  CELLS SPONGE UP

1632
01:12:14,873 --> 01:12:15,841
THESE CGAS?

1633
01:12:15,841 --> 01:12:21,246
SO SOME VIRAL PROTEINS THEY WILL

1634
01:12:21,246 --> 01:12:22,581
COMPETE WITH CGAS COMBINE TO DNA

1635
01:12:22,581 --> 01:12:26,385
AND SO FOR EXAMPLE IN K, SV,

1636
01:12:26,385 --> 01:12:31,023
THERE'S A VIRAL PROTEIN THAT CAN

1637
01:12:31,023 --> 01:12:33,225
BIND TO DNA AND MUCH MOREENTIOUS

1638
01:12:33,225 --> 01:12:35,327
FICIENTLY THAN CGAS AND IT

1639
01:12:35,327 --> 01:12:36,361
INHIBITS CGAS ACTIVATION,

1640
01:12:36,361 --> 01:12:38,697
THERE'S A P.O. BOX VIRUS HA CAN

1641
01:12:38,697 --> 01:12:41,400
ENCODE A ENZYME THAT, CAN

1642
01:12:41,400 --> 01:12:44,636
DEGRADE THESE 2 PRIME 3 PRIME

1643
01:12:44,636 --> 01:12:48,640
CGAS, SO THERE'S A POX VIRUS

1644
01:12:48,640 --> 01:12:50,075
PATHWAY AND THERE ARE OTHER

1645
01:12:50,075 --> 01:12:51,276
PROTEINS THAT COMBINE TO STING

1646
01:12:51,276 --> 01:12:52,444
AND INHIBIT THIS PATHWAY.

1647
01:12:52,444 --> 01:12:55,047
SO THE SHORT ANSWER IS THAT,

1648
01:12:55,047 --> 01:12:56,181
ANIMAL VIRUSES THAT USE A

1649
01:12:56,181 --> 01:13:01,954
VARIETY OF MECHANISMS TO INHIBIT

1650
01:13:01,954 --> 01:13:02,754
THE CGAS PATHWAY.

1651
01:13:02,754 --> 01:13:09,428
>> GREAT TALK YAIMS 
JAMES, HOWU

1652
01:13:09,428 --> 01:13:10,963
SEE THE INFLAMMATORY MODELS, IN

1653
01:13:10,963 --> 01:13:15,501
MOST CELLS IT'S ACTIVATED

1654
01:13:15,501 --> 01:13:17,536
ALONGSIDE CGAS ARE THERE CERTAIN

1655
01:13:17,536 --> 01:13:18,537
CIRCUMSTANCES IN WHICH THE

1656
01:13:18,537 --> 01:13:23,709
RESPONSE IS MORE IMPORTANT?

1657
01:13:23,709 --> 01:13:27,012
>> RIGHT, SO WITH M2 IT'S
A VERY

1658
01:13:27,012 --> 01:13:27,479
INTERESTING QUESTION.

1659
01:13:27,479 --> 01:13:34,319
SO YOU KNOW I SHOW THAT IN

1660
01:13:34,319 --> 01:13:35,621
TRUCKS 1 DEFICIENT CELLS AND

1661
01:13:35,621 --> 01:13:38,423
MICE, IF YOU KNOCK OUT CGAS, YOU

1662
01:13:38,423 --> 01:13:39,258
COMPLETELY RESCUE THE PHENOTYPE

1663
01:13:39,258 --> 01:13:43,662
AND WE ALSO HAVE ANOTHER MODEL

1664
01:13:43,662 --> 01:13:45,297
THAT'S DNAS2 KNOCKOUT MICE,

1665
01:13:45,297 --> 01:13:49,768
THOSE MICE THEY HAVE EVEN MOSTLY

1666
01:13:49,768 --> 01:13:51,003
BEEN PHENOTYPE IS EMBRYONIC

1667
01:13:51,003 --> 01:13:53,205
LETHAL AND THAT CAN ALSO BE

1668
01:13:53,205 --> 01:14:00,946
RESCUE BY KNOCKING OUT CGAS OR

1669
01:14:00,946 --> 01:14:01,146
STING.

1670
01:14:01,146 --> 01:14:02,314
AND SO THAT IF YOU THINK ABOUT

1671
01:14:02,314 --> 01:14:04,883
IT, YOU MAY NOT PREDICT SUCH A

1672
01:14:04,883 --> 01:14:06,952
RESULT BECAUSE IN DNS 2 KNOCK

1673
01:14:06,952 --> 01:14:09,388
OUT CELLS YOUR CLERLY IN THE DNA

1674
01:14:09,388 --> 01:14:11,823
OF THE CYTOPLASM AND IF YOU TAKE

1675
01:14:11,823 --> 01:14:14,026
AWAY CGAS, IF THOSE CAN ACTIVATE

1676
01:14:14,026 --> 01:14:14,626
INFLAMMA STUDIES OF MULTIPLE

1677
01:14:14,626 --> 01:14:16,595
ENDOCRINE, YOU WILL HAVE TO HAVE

1678
01:14:16,595 --> 01:14:17,663
DISEASE, THE RESULT IS THAT ALL

1679
01:14:17,663 --> 01:14:20,632
WE NEED TO DO IS TO TAKE OUR

1680
01:14:20,632 --> 01:14:23,268
CGAS OR STING AND THEN WE CAN

1681
01:14:23,268 --> 01:14:25,137
RESCUE THE PHENOTYPE AND THAT

1682
01:14:25,137 --> 01:14:26,705
SUGGESTS THAT THOSE DNA IT THEY

1683
01:14:26,705 --> 01:14:29,007
GET INTO THE CYTOPLASM, THEY

1684
01:14:29,007 --> 01:14:30,909
DON'T ACTIVATE M2, THERE'S 1

1685
01:14:30,909 --> 01:14:32,644
POSSIBILITY OR THEY DON'T

1686
01:14:32,644 --> 01:14:34,513
ACTIVATE TLR 9 AND THIS 1

1687
01:14:34,513 --> 01:14:36,114
POSSIBILITY, NOT A POSSIBILITY,

1688
01:14:36,114 --> 01:14:39,418
SOMEHOW IN THOSE CELLS THE DMA

1689
01:14:39,418 --> 01:14:40,319
THEREYA ANOTHER MECHANISM TO GET

1690
01:14:40,319 --> 01:14:42,421
RID OF THE DNA.

1691
01:14:42,421 --> 01:14:43,789
NSO I COMPLETELY DIFFERENT

1692
01:14:43,789 --> 01:14:45,390
QUESTION, IN YOUR ORIGINAL

1693
01:14:45,390 --> 01:14:47,192
SCREEN WITH THE MASS SPEC, YOU

1694
01:14:47,192 --> 01:14:48,594
FOUND 3 PROTEINS, ARE THE OTHER

1695
01:14:48,594 --> 01:14:59,137
2 RELATED TO CGASES IN ANY WAY.

1696
01:15:21,793 --> 01:15:22,828
>> YEAH, YEAH.

1697
01:15:22,828 --> 01:15:25,597
--WE HAVE NOT GONE BACK IN WITH

1698
01:15:25,597 --> 01:15:25,931
THE PROTEINS.

1699
01:15:25,931 --> 01:15:27,499
INCOME OKAY, I'M SORRY--THERE

1700
01:15:27,499 --> 01:15:28,667
WAS ANOTHER QUESTION BUT I HAVE

1701
01:15:28,667 --> 01:15:29,735
TO CUT IT OFF NOW.

1702
01:15:29,735 --> 01:15:31,303
WE HAVE ANOTHER LECTURE COMING

1703
01:15:31,303 --> 01:15:31,603
IN.

1704
01:15:31,603 --> 01:15:33,472
BUT THERE WILL BE A RECEPTION,

1705
01:15:33,472 --> 01:15:34,873
SO PERHAPS PEOPLE CAN TALK TO

1706
01:15:34,873 --> 01:15:38,844
YOU A LITTLE MORE DURING THE

1707
01:15:38,844 --> 01:15:39,978
RECEPTION AND MAYBE I CAN

1708
01:15:39,978 --> 01:15:41,647
FORWARD A LOT OF QUESTIONS FROM

1709
01:15:41,647 --> 01:15:43,382
ONLINE, MAYBE I CAN FORWARD THEM

1710
01:15:43,382 --> 01:15:46,585
TO YOU.

1711
01:15:46,585 --> 01:15:48,553
NOKAY, APOLOGIZE TO THE PEOPLE

1712
01:15:48,553 --> 01:15:51,089
ONLINE, ANY CLOSING REMARKS

1713
01:15:51,089 --> 01:15:51,323
DOCTOR?

1714
01:15:51,323 --> 01:15:52,491
ALL RIGHT, THANK YOU VERY

1715
01:15:52,491 --> 01:15:52,691
MUCH.

1716
01:15:52,691 --> 01:15:55,794
THANK YOU VERY MUCH.

1717
01:15:55,794 --> 01:16:06,104
[ APPLAUSE ]