B8XX90 · STING_PIG
- ProteinStimulator of interferon genes protein
- GeneSTING1
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids378 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
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) (PubMed:35584187).
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 anti-viral state (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 (PubMed:31167783).
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 (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).
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 anti-viral state (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 (PubMed:31167783).
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 (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).
Catalytic activity
- H+(in) = H+(out)
Features
Showing features for binding site.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Binding site | 162 | 2',3'-cGAMP (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 162 | 3',3'-c-di-GMP (UniProtKB | ChEBI) | ||||
Sequence: S | ||||||
Binding site | 167 | 2',3'-cGAMP (UniProtKB | ChEBI) | ||||
Sequence: Y | ||||||
Binding site | 167 | 2',3'-cUAMP (UniProtKB | ChEBI) | ||||
Sequence: Y | ||||||
Binding site | 167 | 3',3'-c-di-GMP (UniProtKB | ChEBI) | ||||
Sequence: Y | ||||||
Binding site | 238 | 2',3'-cGAMP (UniProtKB | ChEBI) | ||||
Sequence: R | ||||||
Binding site | 238 | 2',3'-cUAMP (UniProtKB | ChEBI) | ||||
Sequence: R | ||||||
Binding site | 238-241 | 3',3'-c-di-GMP (UniProtKB | ChEBI) | ||||
Sequence: RVYT | ||||||
Binding site | 263 | 2',3'-cGAMP (UniProtKB | ChEBI) | ||||
Sequence: T | ||||||
Binding site | 263 | 2',3'-cUAMP (UniProtKB | ChEBI) | ||||
Sequence: T | ||||||
Binding site | 263 | 3',3'-c-di-GMP (UniProtKB | ChEBI) | ||||
Sequence: T |
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Names & Taxonomy
Protein names
- Recommended nameStimulator of interferon genes protein
- Short namespoSTING
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Laurasiatheria > Artiodactyla > Suina > Suidae > Sus
Accessions
- Primary accessionB8XX90
Proteomes
Subcellular Location
UniProt Annotation
GO Annotation
Endoplasmic reticulum membrane ; Multi-pass membrane protein
Endoplasmic reticulum-Golgi intermediate compartment membrane ; Multi-pass membrane protein
Golgi apparatus membrane ; Multi-pass membrane protein
Cytoplasmic vesicle, autophagosome membrane ; Multi-pass membrane protein
Mitochondrion outer membrane ; Multi-pass membrane protein
Cell membrane ; Multi-pass membrane protein
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. 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. Localizes in the lysosome membrane in a TMEM203-dependent manner.
Features
Showing features for topological domain, transmembrane.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Topological domain | 1-17 | Cytoplasmic | ||||
Sequence: MPYSSLHPSIPQPRGLR | ||||||
Transmembrane | 18-34 | Helical; Name=1 | ||||
Sequence: AQVAALVLLGACLVALW | ||||||
Topological domain | 35-44 | Lumenal | ||||
Sequence: GLGELPEYTL | ||||||
Transmembrane | 45-69 | Helical; Name=2 | ||||
Sequence: RWLVLHLASQQIGLLVKGLCSLAEE | ||||||
Topological domain | 70-91 | Cytoplasmic | ||||
Sequence: LCHVHSRYQSSYWRAARACLGC | ||||||
Transmembrane | 92-106 | Helical; Name=3 | ||||
Sequence: PIRCGALLLLSCYFY | ||||||
Topological domain | 107-116 | Lumenal | ||||
Sequence: FSIRDKAGLP | ||||||
Transmembrane | 117-134 | Helical; Name=4 | ||||
Sequence: LPWMLALLGLSQALNILL | ||||||
Topological domain | 135-378 | Cytoplasmic | ||||
Sequence: GLQHLAPAEVSAICEKRNFNVAHGLAWSYYIGYLRLILPGLRARIQAYNQRHKNVLGGIGNHRLHILFPLDCGVPDDLSVADPNIRFLHELPQQSADRAGIKGRVYTNSIYELLENGQPAGVCVLGYATPLQTLFAMSQDGRAGFSREDRLEQAKLFCRTLEDILADAPEAQNNCRLIVYQEPTEGGSFSLSQEILRHLRQEEREVTMGSAETSVVPTSSTLSQEPELLISGMEQPLPLRSDIF |
Keywords
- Cellular component
PTM/Processing
Features
Showing features for chain, lipidation, cross-link, modified residue.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Chain | PRO_0000404587 | 1-378 | Stimulator of interferon genes protein | |||
Sequence: MPYSSLHPSIPQPRGLRAQVAALVLLGACLVALWGLGELPEYTLRWLVLHLASQQIGLLVKGLCSLAEELCHVHSRYQSSYWRAARACLGCPIRCGALLLLSCYFYFSIRDKAGLPLPWMLALLGLSQALNILLGLQHLAPAEVSAICEKRNFNVAHGLAWSYYIGYLRLILPGLRARIQAYNQRHKNVLGGIGNHRLHILFPLDCGVPDDLSVADPNIRFLHELPQQSADRAGIKGRVYTNSIYELLENGQPAGVCVLGYATPLQTLFAMSQDGRAGFSREDRLEQAKLFCRTLEDILADAPEAQNNCRLIVYQEPTEGGSFSLSQEILRHLRQEEREVTMGSAETSVVPTSSTLSQEPELLISGMEQPLPLRSDIF | ||||||
Lipidation | 88 | S-palmitoyl cysteine | ||||
Sequence: C | ||||||
Lipidation | 91 | S-palmitoyl cysteine | ||||
Sequence: C | ||||||
Cross-link | 150 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Cross-link | 236 | Glycyl lysine isopeptide (Lys-Gly) (interchain with G-Cter in ubiquitin) | ||||
Sequence: K | ||||||
Modified residue | 354 | Phosphoserine | ||||
Sequence: S | ||||||
Modified residue | 355 | Phosphothreonine | ||||
Sequence: T | ||||||
Modified residue | 357 | Phosphoserine; by TBK1 | ||||
Sequence: S | ||||||
Modified residue | 365 | Phosphoserine; by TBK1 | ||||
Sequence: S |
Post-translational modification
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-365 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 (By similarity).
Phosphorylated on tyrosine residues upon MHC-II aggregation (By similarity).
Dephosphorylation by PPP6C leads to inactivation and decreased production of IFN-beta (By similarity).
Phosphorylation at Ser-357 is also required to activate IRF3 (By similarity).
Phosphorylation at Ser-354 by MAP3K7/TAK1 facilitates its interaction with STEEP1, promoting STING1 translocation to COPII vesicles (By similarity).
Phosphorylated on tyrosine residues upon MHC-II aggregation (By similarity).
Dephosphorylation by PPP6C leads to inactivation and decreased production of IFN-beta (By similarity).
Phosphorylation at Ser-357 is also required to activate IRF3 (By similarity).
Phosphorylation at Ser-354 by MAP3K7/TAK1 facilitates its interaction with STEEP1, promoting STING1 translocation to COPII vesicles (By similarity).
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-150 promotes homodimerization and recruitment of the antiviral kinase TBK1 and subsequent production of IFN-beta. 'Lys-48'-linked polyubiquitination at Lys-150 occurring after viral infection is mediated by RNF5 and leads to proteasomal degradation. 'Lys-11'-linked polyubiquitination at Lys-150 by RNF26 leads to stabilize STING1: it protects STING1 from RNF5-mediated 'Lys-48'-linked polyubiquitination (By similarity).
'Lys-33'-linked and 'Lys-48'-linked deubiquitinated by USP20; leading to its stabilization and promotion of innate antiviral response (By similarity).
'Lys-48'-linked deubiquitinated by USP44; leading to its stabilization and promotion of innate antiviral response (By similarity).
Deubiquitinated by USP13; leading to inhibition of innate antiviral response (By similarity).
'Lys-63'-linked deubiquitinated by USP49; leading to inhibition of the subsequent recruitment of TBK1 to the signaling complex (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-150 promotes homodimerization and recruitment of the antiviral kinase TBK1 and subsequent production of IFN-beta. 'Lys-48'-linked polyubiquitination at Lys-150 occurring after viral infection is mediated by RNF5 and leads to proteasomal degradation. 'Lys-11'-linked polyubiquitination at Lys-150 by RNF26 leads to stabilize STING1: it protects STING1 from RNF5-mediated 'Lys-48'-linked polyubiquitination (By similarity).
'Lys-33'-linked and 'Lys-48'-linked deubiquitinated by USP20; leading to its stabilization and promotion of innate antiviral response (By similarity).
'Lys-48'-linked deubiquitinated by USP44; leading to its stabilization and promotion of innate antiviral response (By similarity).
Deubiquitinated by USP13; leading to inhibition of innate antiviral response (By similarity).
'Lys-63'-linked deubiquitinated by USP49; leading to inhibition of the subsequent recruitment of TBK1 to the signaling complex (By similarity).
Palmitoylation takes place in the Golgi apparatus and creates a platform for the recruitment of TBK1.
Keywords
- PTM
Proteomic databases
Expression
Tissue specificity
Expressed at higher level in the spleen, lymph node, lung and bone marrow, followed by the small intestine, heart, liver and brain, and to a lesser extent in the stomach and kidney.
Interaction
Subunit
Homodimer; forms a homodimer in absence of cyclic nucleotide (c-di-GMP or cGAMP); 'Lys-63'-linked ubiquitination at Lys-150 is required for homodimerization (By similarity).
Homotetramer; in presence of cyclic nucleotide (c-di-GMP or cGAMP), forms tetramers and higher-order oligomers through side-by-side packing (By similarity).
Interacts (when phosphorylated) with IRF3; following activation and phosphorylation on the pLxIS motif by TBK1, recruits IRF3 (By similarity).
Interacts with DDX58/RIG-I, MAVS and SSR2 (By similarity).
Interacts with RNF5 and TRIM56 (By similarity).
Interacts with TBK1; when homodimer, leading to subsequent production of IFN-beta (By similarity).
Interacts with IFIT1 and IFIT2 (By similarity).
Interacts with TRIM29; this interaction induces STING1 ubiquitination and subsequent degradation (By similarity).
Associates with the MHC-II complex (By similarity).
Interacts with STEEP1; interaction takes place upon cGAMP-activation and STING1 phosphorylation by MAP3K7/TAK1 and promotes STING1 translocation to COPII vesicles (By similarity).
Interacts with SEC24A, SEC24B and SEC24C; promoting translocation to COPII vesicles (By similarity).
Interacts (when ubiquitinated) with SQSTM1; leading to relocalization to autophagosomes (By similarity).
Interacts with SURF4 (By similarity).
Interacts with HNRNPA2B1 (By similarity).
Interacts with ZDHHC1; ZDHHC1 constitutively interacts with STING1 and in presence of DNA viruses activates it by promoting its cGAMP-induced oligomerization and the recruitment of downstream signaling components (By similarity).
Interacts with ZDHHC11; in presence of DNA viruses promotes the recruitment of IRF3 to STING1 (By similarity).
Interacts with TOMM70 (By similarity).
Interacts with TAB1; promoting recruitment of TAB1 to the endoplasmic reticulum membrane and subsequent activation of MAP3K7/TAK1 (By similarity).
Interacts (via transmembrane domain) with TMEM203 (By similarity).
Homotetramer; in presence of cyclic nucleotide (c-di-GMP or cGAMP), forms tetramers and higher-order oligomers through side-by-side packing (By similarity).
Interacts (when phosphorylated) with IRF3; following activation and phosphorylation on the pLxIS motif by TBK1, recruits IRF3 (By similarity).
Interacts with DDX58/RIG-I, MAVS and SSR2 (By similarity).
Interacts with RNF5 and TRIM56 (By similarity).
Interacts with TBK1; when homodimer, leading to subsequent production of IFN-beta (By similarity).
Interacts with IFIT1 and IFIT2 (By similarity).
Interacts with TRIM29; this interaction induces STING1 ubiquitination and subsequent degradation (By similarity).
Associates with the MHC-II complex (By similarity).
Interacts with STEEP1; interaction takes place upon cGAMP-activation and STING1 phosphorylation by MAP3K7/TAK1 and promotes STING1 translocation to COPII vesicles (By similarity).
Interacts with SEC24A, SEC24B and SEC24C; promoting translocation to COPII vesicles (By similarity).
Interacts (when ubiquitinated) with SQSTM1; leading to relocalization to autophagosomes (By similarity).
Interacts with SURF4 (By similarity).
Interacts with HNRNPA2B1 (By similarity).
Interacts with ZDHHC1; ZDHHC1 constitutively interacts with STING1 and in presence of DNA viruses activates it by promoting its cGAMP-induced oligomerization and the recruitment of downstream signaling components (By similarity).
Interacts with ZDHHC11; in presence of DNA viruses promotes the recruitment of IRF3 to STING1 (By similarity).
Interacts with TOMM70 (By similarity).
Interacts with TAB1; promoting recruitment of TAB1 to the endoplasmic reticulum membrane and subsequent activation of MAP3K7/TAK1 (By similarity).
Interacts (via transmembrane domain) with TMEM203 (By similarity).
(Microbial infection) Interacts with African swine fever virus/ASFV protein A528R; this interaction mediates STING1 degradation.
(Microbial infection) Interacts with African swine fever virus/ASFV minor capsid protein p17.
(Microbial infection) Interacts with Pseudorabies virus protein UL13; this interaction mediates STING1 degradation in a RNF5-dependent manner.
Protein-protein interaction databases
Structure
Family & Domains
Features
Showing features for region, motif.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Region | 1-190 | Mediates interaction with ZDHHC1 and ZDHHC11 | ||||
Sequence: MPYSSLHPSIPQPRGLRAQVAALVLLGACLVALWGLGELPEYTLRWLVLHLASQQIGLLVKGLCSLAEELCHVHSRYQSSYWRAARACLGCPIRCGALLLLSCYFYFSIRDKAGLPLPWMLALLGLSQALNILLGLQHLAPAEVSAICEKRNFNVAHGLAWSYYIGYLRLILPGLRARIQAYNQRHKNVL | ||||||
Region | 153-339 | Cyclic dinucleotide-binding domain (CBD) | ||||
Sequence: FNVAHGLAWSYYIGYLRLILPGLRARIQAYNQRHKNVLGGIGNHRLHILFPLDCGVPDDLSVADPNIRFLHELPQQSADRAGIKGRVYTNSIYELLENGQPAGVCVLGYATPLQTLFAMSQDGRAGFSREDRLEQAKLFCRTLEDILADAPEAQNNCRLIVYQEPTEGGSFSLSQEILRHLRQEERE | ||||||
Region | 339-378 | C-terminal tail (CTT) | ||||
Sequence: EVTMGSAETSVVPTSSTLSQEPELLISGMEQPLPLRSDIF | ||||||
Motif | 362-365 | pLxIS motif | ||||
Sequence: LLIS |
Domain
In absence of cGAMP, the transmembrane and cytoplasmic regions interact to form an integrated, domain-swapped dimeric assembly (By similarity).
In absence of cyclic nucleotide (c-di-GMP or cGAMP), the protein is autoinhibited by an intramolecular interaction between the cyclic dinucleotide-binding domain (CBD) and the C-terminal tail (CTT) (By similarity).
Following cGAMP-binding, the cyclic dinucleotide-binding domain (CBD) is closed, leading to a 180 degrees rotation of the CBD domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the CBD dimer, which leads to the formation of the STING1 tetramer and higher-order oligomers through side-by-side packing (By similarity).
The N-terminal part of the CBD region was initially though to contain a fifth transmembrane region (TM5) but is part of the folded, soluble CBD (By similarity).
In absence of cyclic nucleotide (c-di-GMP or cGAMP), the protein is autoinhibited by an intramolecular interaction between the cyclic dinucleotide-binding domain (CBD) and the C-terminal tail (CTT) (By similarity).
Following cGAMP-binding, the cyclic dinucleotide-binding domain (CBD) is closed, leading to a 180 degrees rotation of the CBD domain relative to the transmembrane domain. This rotation is coupled to a conformational change in a loop on the side of the CBD dimer, which leads to the formation of the STING1 tetramer and higher-order oligomers through side-by-side packing (By similarity).
The N-terminal part of the CBD region was initially though to contain a fifth transmembrane region (TM5) but is part of the folded, soluble CBD (By similarity).
The pLxIS motif constitutes an IRF3-binding motif: following phosphorylation by TBK1, the phosphorylated pLxIS motif of STING1 recruits IRF3. IRF3 is then phosphorylated and activated by TBK1 to induce type-I interferons and other cytokines.
The N-terminal domain interacts with glycerophospholipids and phospholipids.
Sequence similarities
Belongs to the STING family.
Keywords
- Domain
Phylogenomic databases
Family and domain databases
Sequence
- Sequence statusComplete
- Length378
- Mass (Da)41,881
- Last updated2009-03-03 v1
- ChecksumF4AA581E6B96BDED
Keywords
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
FJ455509 EMBL· GenBank· DDBJ | ACJ70708.1 EMBL· GenBank· DDBJ | mRNA |