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SUMMARY:Innate Immune Sensing and Signaling of Cytosolic DNA and RNA - Zhi
 jan 'James' Chen\, University of Texas Southwestern Medical Center
DTSTART:20130924T151500Z
DTEND:20130924T170000Z
UID:TALK46284@talks.cam.ac.uk
CONTACT:Scientific Meetings Co-ordinator
DESCRIPTION:The inappropriate presence of DNA in the cytosol is a danger s
 ignal that alerts the host of potential microbial invasion and triggers in
 nate immune responses including the production of type-I interferons. Unde
 r certain pathological conditions\, self DNA\, which normally reside in th
 e nucleus or mitochondria\, could also trigger autoimmune responses from t
 he cytosol\, resulting in human diseases such as lupus. Cytosolic DNA indu
 ces interferons through a signaling pathway that involves the adaptor prot
 ein STING\, the kinases IKK and TBK1\, and the transcription factors NF-κ
 B and IRF3. Through a biochemical approach\, we have identified the cytoso
 lic DNA sensor that activates STING and triggers type-I interferon product
 ion. This sensor turns out to be a novel enzyme which we name cyclic GMP-A
 MP synthase (cGAS). cGAS is activated by its binding to DNA and upon activ
 ation it catalyzes the synthesis of a unique cyclic GMP-AMP (cGAMP) isomer
  containing both 2’-5’ and 3’-5’ phosphodiester linkages. This cGA
 MP isomer\, termed 2’3’-cGAMP\, functions as a second messenger that b
 inds to and activates STING\, leading to the induction of interferons and 
 other cytokines. Genetic experiments show that cGAS is essential for innat
 e immune responses triggered by DNA viruses and retroviruses\, including H
 IV. This work uncovers a cyclic dinucleotide signaling pathway that was pr
 eviously not known to exist in metazoa\, reveals a new signaling mechanism
  in innate immunity\, provides cGAS as a new therapeutic target for the tr
 eatment of autoimmune diseases\, and offers cGAMP as a new vaccine adjuvan
 t.  
LOCATION:Max Perutz Lecture Theatre\, Medical Research Council (MRC) (MRC 
 Laboratory of Molecular Biol
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