STING
Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm. Acts by binding cyclic dinucleotides: recognizes and binds cyclic di-GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger produced by CGAS in response to DNA virus in the cytosol. Upon binding of c-di-GMP or cGAMP, TMEM173/STING oligomerizes, translocates from the endoplasmic reticulum and is 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 anti-viral state. In addition to promote the production of type I interferons, plays a direct role in autophagy. Following cGAMP-binding, TMEM173/STING buds from the endoplasmic reticulum into COPII vesicles, which then form the endoplasmic reticulum-Golgi intermediate compartment (ERGIC). 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. 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. Exhibits 2',3' phosphodiester linkage-specific ligand recognition: can bind both 2'-3' linked cGAMP (2'-3'-cGAMP) and 3'-3' linked cGAMP but is preferentially activated by 2'-3' linked cGAMP. The preference for 2'-3'-cGAMP, compared to other linkage isomers is probably due to the ligand itself, whichs adopts an organized free-ligand conformation that resembles the TMEM173/STING-bound conformation and pays low energy costs in changing into the active conformation. May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons. May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II). (Microbial infection) Antiviral activity is antagonized by oncoproteins, such as papillomavirus (HPV) protein E7 and adenovirus early E1A protein. Such oncoproteins prevent the ability to sense cytosolic DNA. Belongs to the TMEM173 family. Ubiquitously expressed. Expressed in skin endothelial cells, alveolar type 2 pneumocytes, bronchial epithelium and alveolar macrophages. Note: This description may include information from UniProtKB.
Molecular Function: 2',3'-cyclic GMP-AMP binding; cyclic-di-GMP binding; identical protein binding; protein binding; protein homodimerization activity; protein kinase binding; RNA polymerase II-specific DNA-binding transcription factor binding; signaling adaptor activity; ubiquitin protein ligase binding
Biological Process: activation of innate immune response; antiviral innate immune response; autophagosome assembly; cellular response to exogenous dsRNA; cellular response to interferon-beta; cellular response to organic cyclic compound; cytosolic pattern recognition receptor signaling pathway; defense response to virus; innate immune response; pattern recognition receptor signaling pathway; positive regulation of defense response to virus by host; positive regulation of DNA-binding transcription factor activity; positive regulation of interferon-beta production; positive regulation of macroautophagy; positive regulation of protein binding; positive regulation of transcription by RNA polymerase II; positive regulation of type I interferon production; positive regulation of type I interferon-mediated signaling pathway; protein complex oligomerization; regulation of inflammatory response; reticulophagy
