Abstract

The inappropriate presence of DNA in the cytosol is a danger signal that alerts the host of potential microbial invasion and triggers innate immune responses including the production of type-I interferons. Under certain pathological conditions, self DNA , which normally reside in the nucleus or mitochondria, could also trigger autoimmune responses from the cytosol, resulting in human diseases such as lupus. Cytosolic DNA induces interferons through a signaling pathway that involves the adaptor protein STING , the kinases IKK and TBK1 , and the transcription factors NF-κB and IRF3 . Through a biochemical approach, we have identified the cytosolic DNA sensor that activates STING and triggers type-I interferon production. This sensor turns out to be a novel enzyme which we name cyclic GMP -AMP synthase (cGAS). cGAS is activated by its binding to DNA and upon activation it catalyzes the synthesis of a unique cyclic GMP -AMP (cGAMP) isomer containing both 2’-5’ and 3’-5’ phosphodiester linkages. This cGAMP isomer, termed 2’3’-cGAMP, functions as a second messenger that binds to and activates STING , leading to the induction of interferons and other cytokines. Genetic experiments show that cGAS is essential for innate immune responses triggered by DNA viruses and retroviruses, including HIV . This work uncovers a cyclic dinucleotide signaling pathway that was previously not known to exist in metazoa, reveals a new signaling mechanism in innate immunity, provides cGAS as a new therapeutic target for the treatment of autoimmune diseases, and offers cGAMP as a new vaccine adjuvant.