Protein: Stimulator of interferon genes protein (hSTING) (Endoplasmic reticulum interferon stimulator) (ERIS) (Mediator of IRF3 activation) (hMITA) (Transmembrane protein 173) (Q86WV6)
Organism: Homo sapiens (Human)
Function: 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, STING1 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, STING1 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 (By similarity). 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 STING1-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) (By similarity).
Subcellular location: Endoplasmic reticulum membrane {ECO:0000269|PubMed:18724357, ECO:0000269|PubMed:19285439, ECO:0000269|PubMed:19433799, ECO:0000269|PubMed:19776740, ECO:0000269|PubMed:25254379, ECO:0000269|PubMed:29694889, ECO:0000269|PubMed:30842653, ECO:0000269|PubMed:30842659, ECO:0000269|PubMed:32690950, ECO:0000269|PubMed:37832545}; Multi-pass membrane protein {ECO:0000255, ECO:0000269|PubMed:30842659, ECO:0000269|PubMed:32690950}. Cytoplasm, perinuclear region {ECO:0000269|PubMed:19433799, ECO:0000269|PubMed:29694889, ECO:0000269|PubMed:30842653}. Endoplasmic reticulum-Golgi intermediate compartment membrane {ECO:0000269|PubMed:30842662, ECO:0000269|PubMed:32690950, ECO:0000269|PubMed:37832545}; Multi-pass membrane protein {ECO:0000255, ECO:0000269|PubMed:32690950}. Golgi apparatus membrane {ECO:0000269|PubMed:30842653, ECO:0000269|PubMed:34903048, ECO:0000269|PubMed:36808561, ECO:0000269|PubMed:37535724}; Multi-pass membrane protein {ECO:0000255}. Cytoplasmic vesicle, autophagosome membrane {ECO:0000269|PubMed:30842662}; Multi-pass membrane protein {ECO:0000255}. Mitochondrion outer membrane {ECO:0000269|PubMed:18724357, ECO:0000269|PubMed:19285439, ECO:0000269|PubMed:19433799, ECO:0000269|PubMed:19776740}; Multi-pass membrane protein {ECO:0000255}. Cell membrane {ECO:0000250|UniProtKB:Q3TBT3}; Multi-pass membrane protein {ECO:0000255}. Note=In response to double-stranded DNA stimulation, translocates from the endoplasmic reticulum through the endoplasmic reticulum-Golgi intermediate compartment and Golgi to post-Golgi vesicles, where the kinase TBK1 is recruited (PubMed:19433799, PubMed:29694889, PubMed:30842653, PubMed:30842659). Upon cGAMP-binding, translocates to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) in a process that is dependent on COPII vesicles; STING1-containing ERGIC serves as a membrane source for LC3 lipidation, which is a key step in autophagosome biogenesis (PubMed:30842662, PubMed:37832545). Localizes in the lysosome membrane in a TMEM203-dependent manner (By similarity). {ECO:0000250|UniProtKB:Q3TBT3, ECO:0000269|PubMed:19433799, ECO:0000269|PubMed:29694889, ECO:0000269|PubMed:30842653, ECO:0000269|PubMed:30842659, ECO:0000269|PubMed:30842662, ECO:0000269|PubMed:32690950, ECO:0000269|PubMed:37832545}.
Interaction partners:
- Mitochondrial antiviral-signaling protein
- Serine/threonine-protein kinase TBK1
- Interferon regulatory factor 3
- Cyclic GMP-AMP synthase
- Inhibitor of nuclear factor kappa-B kinase subunit epsilon
- Gamma-interferon-inducible protein 16
- Antiviral innate immune response receptor RIG-I
- E3 ubiquitin-protein ligase TRIM56
- ADP-ribosylation factor 1
- E3 ubiquitin-protein ligase RNF5
Sequence:
MPHSSLHPSIPCPRGHGAQKAALVLLSACLVTLWGLGEPPEHTLRYLVLHLASLQLGLLLNGVCSLAEELRHIHSRYRGSYWRTVRACLGCPLRRGALLLLSIYFYYSLPNAVGPPFTWMLALLGLSQALNILLGLKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPELQARIRTYNQHYNNLLRGAVSQRLYILLPLDCGVPDNLSMADPNIRFLDKLPQQTGDHAGIKDRVYSNSIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSREDRLEQAKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRHLRQEEKEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS