Sting1
entrez
498840
canonical
uniprot
F1M391
canonical
ensembl
ENSRNOG00000042137
resolver
ensp
ENSRNOP00000063348
resolver
enst
ENSRNOT00000068386
resolver
genesymbol
Sting1
resolver
genesymbol_syn
Sting
resolver
genesymbol_syn
Tmem173
resolver
uniprot_entry
STING_RAT
resolver
activity_regulation
ACTIVITY REGULATION: Exhibits 2',3' phosphodiester linkage-specific ligand recognition: can bind both 2'-3' linked cGAMP and 3'-3' linked cGAMP but is preferentially activated by 2'-3' linked cGAMP (By similarity). In contrast to mouse protein, not activated by anticancer molecule 5,6-dimethylxanthenone 4-acetic acid (DMXAA) (PubMed:26669264). {ECO:0000250|UniProtKB:Q86WV6, ECO:0000269|PubMed:26669264}.
uniprot
proteins
amino_acid_sequence
MPYSNLHPSIPRPRSYRFKLAAFVLLVGSLMSLWMTGEPPSHTLHYLALHVASQQLGLLLKKLCCLAEELCHVQSRYQGSYWKAVRACVGSPICFMALILLSFYFYCSLENTSDLRLAWHLGILVLSKSLSMTLDLQSLAPAEVSAVCEEKNFNVAHGLAWSYYIGYLKLILPGLQARIRMFNQLHNNMLSGAGSRRLYILFPLDCGVPDDLSVADPNIRFRDMLPQQNTDRAGVKNRAYSNSVYELLENGQPAGACILEYATPLQTLFAMSQDGKAGFSREDRLEQAKLFCRTLEEILADVPESRNHCRLIVYQESEEGNSFSLSQEVLRHIRQEEKEEVTMSGPPTSVAPRPSLLSQEPRLLISGMEQPLPLRTDLI
uniprot
proteins
function
FUNCTION: 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 (PubMed:26669264). 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 (By similarity). 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 (By similarity). May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II) (By similarity). {ECO:0000250|UniProtKB:Q3TBT3, ECO:0000250|UniProtKB:Q86WV6, ECO:0000269|PubMed:26669264}.; FUNCTION: Innate immune signaling adapter that promotes the production of type I interferon (IFN-alpha and IFN-beta) in presence of DNA from bacteria and viruses in the cytosol (PubMed:26669264). Innate immune response is triggered in response to non-CpG double-stranded DNA from viruses and bacteria delivered to the cytoplasm (By similarity). Acts by binding cyclic dinucleotides: 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 virus in the cytosol (By similarity). Upon binding to c-di-GMP, cUAMP 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 antiviral state (PubMed:26669264). 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 (PubMed:26669264). The preference for 2'-3'-cGAMP, compared to other linkage isomers is probably due to the ligand itself, which adopts an organized free-ligand conformation that resembles the STING1-bound conformation and pays low energy costs in changing into the active conformation (By similarity). In addition to promote the production of type I interferons, plays a direct role in autophagy (By similarity). Following cGAMP-binding, STING1 buds from the endoplasmic reticulum into COPII vesicles, which then form the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) (By similarity). 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 (By similarity). Promotes autophagy by acting as a proton channel that directs proton efflux from the Golgi to facilitate MAP1LC3B/LC3B lipidation (By similarity). The autophagy- and interferon-inducing activities can be uncoupled and autophagy induction is independent of TBK1 phosphorylation (By similarity). 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). May be involved in translocon function, the translocon possibly being able to influence the induction of type I interferons (By similarity). May be involved in transduction of apoptotic signals via its association with the major histocompatibility complex class II (MHC-II) (By similarity). Involved in intercellular immune signaling. Cross-activated by 2',3'-cGAMP previously generated in virus-infected cells, triggers type I interferon signaling in macrophages and uninfected neighboring cells to propagate and amplify the antiviral immune response. {ECO:0000250|UniProtKB:Q3TBT3, ECO:0000250|UniProtKB:Q86WV6, ECO:0000269|PubMed:26669264}.
uniprot
proteins
mass_dalton
42655
uniprot
proteins
mutagenesis
MUTAGEN 141; /note="P->A: Abolishes response to 2'-3' linked cGAMP and 3'-3' linked cGAMP and production of interferon IFNB1."; /evidence="ECO:0000269|PubMed:26669264"; MUTAGEN 143; /note="E->A: Abolishes response to 2'-3' linked cGAMP and 3'-3' linked cGAMP and production of interferon IFNB1."; /evidence="ECO:0000269|PubMed:26669264"; MUTAGEN 144; /note="V->A: Decreases response to 2'-3' linked cGAMP and 3'-3' linked cGAMP and production of interferon IFNB1."; /evidence="ECO:0000269|PubMed:26669264"; MUTAGEN 145; /note="S->A: Abolishes response to 2'-3' linked cGAMP and 3'-3' linked cGAMP and production of interferon IFNB1."; /evidence="ECO:0000269|PubMed:26669264"; MUTAGEN 149; /note="E->A,R: Abolishes response to 2'-3' linked cGAMP and 3'-3' linked cGAMP and production of interferon IFNB1."; /evidence="ECO:0000269|PubMed:26669264"; MUTAGEN 150; /note="E->A: Abolishes response to 2'-3' linked cGAMP and 3'-3' linked cGAMP and production of interferon IFNB1."; /evidence="ECO:0000269|PubMed:26669264"; MUTAGEN 151; /note="K->R: Abolishes response to 2'-3' linked cGAMP and 3'-3' linked cGAMP and production of interferon IFNB1."; /evidence="ECO:0000269|PubMed:26669264"; MUTAGEN 230; /note="T->I,L,M,V: No effect on response to 2'-3' linked cGAMP and production of interferon IFNB1. Strongly increases affinity for the synthetic compound 5,6-dimethylxanthenone 4-acetic acid (DMXAA)."; /evidence="ECO:0000269|PubMed:26669264
uniprot
proteins
post_translational_modification
PTM: Formation of an interchain disulfide bond at Cys-148 is essential for stabilizing STING1 dimers into higher-order homooligomers upon activation. {ECO:0000250|UniProtKB:Q86WV6}.; PTM: Phosphorylation by TBK1 leads to activation and production of IFN-beta. Following cyclic nucleotide (c-di-GMP or cGAMP)-binding, activation and translocation from the endoplasmic reticulum, STING1 is phosphorylated by TBK1 at Ser-366 in the pLxIS motif. The phosphorylated pLxIS motif constitutes an IRF3-binding motif, leading to recruitment of the transcription factor IRF3 to induce type-I interferons and other cytokines. Phosphorylation at Ser-366 is also required for association with the AP-1 complex (By similarity). The phosphorylated pLxIS motif facilitates SENP2 recruitment during late phase of viral infection (By similarity). Dephosphorylation by PPP6C leads to inactivation and decreased production of IFN-beta. Phosphorylation at Ser-358 and Ser-366 by IKBKE/IKKE promotes activation of NF-kappa-B signaling. Phosphorylation at Ser-358 is also required to activate IRF3 and may be specific for activation of NF-kappa-B signaling. Phosphorylation at Ser-355 by MAP3K7/TAK1 facilitates its interaction with STEEP1, promoting STING1 translocation to COPII vesicles. Phosphorylation at Tyr-245 by EGFR promotes the activation of the cGAS-STING pathway and induction of type-I interferons, while inhibiting ability to promote autophagy (By similarity). Phosphorylated on tyrosine residues upon MHC-II aggregation (By similarity). {ECO:0000250|UniProtKB:Q3TBT3, ECO:0000250|UniProtKB:Q86WV6}.; PTM: Ubiquitinated (By similarity). Ubiquitinated via 'Lys-63'-linked ubiquitin chains in response to double-stranded DNA treatment, leading to relocalization to autophagosomes and subsequent degradation; this process is dependent on SQSTM1 (By similarity). 'Lys-63'-linked ubiquitination mediated by TRIM56 at Lys-151 promotes homodimerization and recruitment of the antiviral kinase TBK1 and subsequent production of IFN-beta. 'Lys-63'-linked ubiquitination mediated by RNF115 and/or TRIM69 promotes homodimerization and activation. 'Lys-48'-linked polyubiquitination at Lys-151 occurring after viral infection is mediated by RNF5 and leads to proteasomal degradation. 'Lys-11'-linked polyubiquitination at Lys-151 by RNF26 leads to stabilize STING1: it protects STING1 from RNF5-mediated 'Lys-48'-linked polyubiquitination. 'Lys-27'- and 'Lys-29'-linked polyubiquitination at Lys-289 mediated by TRIM10 promotes homooligomerization and activation. 'Lys-33'-linked and 'Lys-48'-linked deubiquitinated by USP20; leading to its stabilization and promotion of innate antiviral response. 'Lys-48'-linked deubiquitinated by USP44; leading to its stabilization and promotion of innate antiviral response. Deubiquitinated by USP13; leading to inhibition of innate antiviral response. 'Lys-63'-linked deubiquitinated by USP49; leading to inhibition of the subsequent recruitment of TBK1 to the signaling complex. 'Lys-63'-linked ubiquitination mediated by RNF39 promotes the activation of the cGAS-STING pathway. MARCHF5-mediated ubiquitination prevents the oxidation-induced polymer formation (By similarity). {ECO:0000250|UniProtKB:Q3TBT3, ECO:0000250|UniProtKB:Q86WV6}.; PTM: Sumoylated at Lys-338 by TRIM38 during the early phase of viral infection, promoting its stability by preventing its relocalization to autophagosomes and subsequent degradation. Desumoylated by SENP2 during the late phase of viral infection. {ECO:0000250|UniProtKB:Q3TBT3}.; PTM: ISGylated by HERC5, preventing ubiquitination and degradation. {ECO:0000250|UniProtKB:Q86WV6}.; PTM: Alkylated via a non-enzymatic covalent modification (By similarity). Itaconate, an anti-inflammatory metabolite generated in response to lipopolysaccharide, alkylates Cys-148, preventing activity (By similarity). {ECO:0000250|UniProtKB:Q3TBT3, ECO:0000250|UniProtKB:Q86WV6}.; PTM: Palmitoylation takes place in the Golgi apparatus and creates a platform for the recruitment of TBK1. Palmitoylation at Cys-64 enables subsequent STING1 oligomerization, ensuring proper conformation and subsequent downstream recruitment of TBK1. Palmitoylation at Cys-64 is also required to prevent inappropriate disulfide formation at Cys-148 in absence of cGAMP. {ECO:0000250|UniProtKB:Q86WV6}.; PTM: Carbonylated at Cys-88, inhibiting palmitoylation and preventing STING1 activation. Carbonylation takes place in the absence of GPX4, generating lipid peroxidation and production of 4-hydroxynonenal. {ECO:0000250|UniProtKB:Q86WV6}.
uniprot
proteins
protein_family
STING family
uniprot
proteins
pubmed
15057822
uniprot
proteins
pubmed
26669264
uniprot
proteins
sequence_length
379
uniprot
proteins
subcellular_location
SUBCELLULAR LOCATION: Endoplasmic reticulum-Golgi intermediate compartment membrane {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein {ECO:0000255}. Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein {ECO:0000255}. Cytoplasm, perinuclear region {ECO:0000250|UniProtKB:Q86WV6}. Golgi apparatus membrane {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein {ECO:0000255}. Golgi apparatus, trans-Golgi network membrane {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein {ECO:0000255}. Cytoplasmic vesicle, autophagosome membrane {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein {ECO:0000255}. Endosome membrane {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein {ECO:0000255}. Lysosome membrane {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein {ECO:0000255}. Mitochondrion outer membrane {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein {ECO:0000255}. Cell membrane {ECO:0000250|UniProtKB:Q3TBT3}; Multi-pass membrane protein {ECO:0000255}. Note=Localizes to the endoplasmic reticulum when inactive. Following activation by cyclic dinucleotides, such as cGAMP, translocates from the endoplasmic reticulum to the endoplasmic reticulum-Golgi intermediate compartment (ERGIC) in a COPII vesicles-dependent process, where the kinase TBK1 is recruited. Translocation to the ERGIC compartment is also dependent on cholesterol and phosphoinositide, such as phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2), which directly bind STING1 at the interface between dimers and promote STING1 homooligomerization. STING1-containing ERGIC serves as a membrane source for LC3 lipidation, which is a key step in autophagosome biogenesis. Activates NF-kappa-B signaling when localized to the endolysosome compartment (By similarity). Localizes in the lysosome membrane in a TMEM203-dependent manner (By similarity). {ECO:0000250|UniProtKB:Q3TBT3, ECO:0000250|UniProtKB:Q86WV6}.
uniprot
proteins
transmembrane_region
TRANSMEM 18..34; /note="Helical; Name=1"; /evidence="ECO:0000250|UniProtKB:Q86WV6"; TRANSMEM 45..69; /note="Helical; Name=2"; /evidence="ECO:0000250|UniProtKB:Q86WV6"; TRANSMEM 92..106; /note="Helical; Name=3"; /evidence="ECO:0000250|UniProtKB:Q86WV6"; TRANSMEM 117..134; /note="Helical; Name=4"; /evidence="ECO:0000250|UniProtKB:Q86WV6
uniprot
proteins