STING1

Key innate immune signaling adapter that promotes the production of type I interferon (IFN-alpha and IFN-beta) in response to the presence of DNA from bacteria and viruses in the cytosol. Innate immune response is triggered by non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm, which induces production of cyclic dinucleotides that bind and activate STING1: STING1 recognizes and binds cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, cyclic UMP-AMP (2',3'-cUAMP), and cyclic GMP-AMP (cGAMP), a messenger produced by CGAS in response to DNA in the cytosol. Upon binding to c-di-GMP, cUAMP or cGAMP, STING1 oligomerizes and buds from the endoplasmic reticulum into COPII vesicles, which then form the endoplasmic reticulum-Golgi intermediate compartment (ERGIC). It is then phosphorylated by TBK1 on the pLxIS motif, leading to recruitment and subsequent activation of the transcription factor IRF3 to induce expression of type I interferon and exert a potent antiviral state. Also involved in intercellular immune signaling: cross-activated by 2',3'-cGAMP previously generated in virus-infected cells, triggering type I interferon signaling in macrophages and uninfected neighboring cells to propagate and amplify the antiviral immune response. In addition to promote the production of type I interferon, cGAS-STING signaling also activates the NF-kappa-B signaling: mechanistically, STING1 recruits TRAF6, leading to degradation of the NF-kappa-B inhibitor and subsequent translocation of NF-kappa-B into the nucleus. Activation of NF-kappa-B signaling takes place in the endolysosome and is independent of type I interferon response via direct activation by RNA viruses. Independently of type I interferon production, plays a direct role in autophagy. The ERGIC serves as the membrane source for WIPI2 recruitment and LC3 lipidation, leading to formation of autophagosomes that target cytosolic DNA or DNA viruses for degradation by the lysosome. Promotes autophagy by acting as a proton channel that directs proton efflux from the Golgi to facilitate MAP1LC3B/LC3B lipidation. The autophagy- and interferon-inducing activities can be uncoupled and autophagy induction is independent of TBK1 phosphorylation. Autophagy is also triggered upon infection by bacteria: following c-di-GMP-binding, which is produced by live Gram-positive bacteria, promotes reticulophagy (By similarity). The proton channel activity also regulates lysosome biogenesis by activating transcription factors TFEB and TFE3, driving the expression of lysosome-related genes: activated STING1 in post-Golgi vesicles induces proton efflux and lipidation of GABARAP, sequestering the FLCN-FNIP complex and blocking mTORC1-dependent inhibition of TFEB and TFE3. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II) (By similarity)..