STING_PIG
ID STING_PIG Reviewed; 378 AA.
AC B8XX90;
DT 08-FEB-2011, integrated into UniProtKB/Swiss-Prot.
DT 03-MAR-2009, sequence version 1.
DT 03-AUG-2022, entry version 62.
DE RecName: Full=Stimulator of interferon genes protein {ECO:0000303|PubMed:20346968};
DE Short=poSTING {ECO:0000303|PubMed:20346968};
DE AltName: Full=Transmembrane protein 173 {ECO:0000305};
GN Name=STING1 {ECO:0000250|UniProtKB:Q86WV6};
GN Synonyms=STING {ECO:0000303|PubMed:20346968},
GN TMEM173 {ECO:0000250|UniProtKB:Q86WV6};
OS Sus scrofa (Pig).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Laurasiatheria; Artiodactyla; Suina; Suidae; Sus.
OX NCBI_TaxID=9823;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=20346968; DOI=10.1016/j.dci.2010.03.005;
RA Xie L., Liu M., Fang L., Su X., Cai K., Wang D., Chen H., Xiao S.;
RT "Molecular cloning and functional characterization of porcine stimulator of
RT interferon genes (STING).";
RL Dev. Comp. Immunol. 34:847-854(2010).
RN [2]
RP INTERACTION WITH AFRICAN SWINE FEVER VIRUS PROTEIN A528R (MICROBIAL
RP INFECTION).
RX PubMed=33712518; DOI=10.4049/jimmunol.2001110;
RA Li D., Yang W., Li L., Li P., Ma Z., Zhang J., Qi X., Ren J., Ru Y.,
RA Niu Q., Liu Z., Liu X., Zheng H.;
RT "African Swine Fever Virus MGF-505-7R Negatively Regulates cGAS-STING-
RT Mediated Signaling Pathway.";
RL J. Immunol. 206:1844-1857(2021).
CC -!- FUNCTION: Facilitator of innate immune signaling that acts as a sensor
CC of cytosolic DNA from bacteria and viruses and promotes the production
CC of type I interferon (IFN-alpha and IFN-beta). Innate immune response
CC is triggered in response to non-CpG double-stranded DNA from viruses
CC and bacteria delivered to the cytoplasm. Acts by binding cyclic
CC dinucleotides: recognizes and binds cyclic di-GMP (c-di-GMP), a second
CC messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a messenger
CC produced by CGAS in response to DNA virus in the cytosol. Upon binding
CC of c-di-GMP or cGAMP, STING1 oligomerizes, translocates from the
CC endoplasmic reticulum and is phosphorylated by TBK1 on the pLxIS motif,
CC leading to recruitment and subsequent activation of the transcription
CC factor IRF3 to induce expression of type I interferon and exert a
CC potent anti-viral state. In addition to promote the production of type
CC I interferons, plays a direct role in autophagy. Following cGAMP-
CC binding, STING1 buds from the endoplasmic reticulum into COPII
CC vesicles, which then form the endoplasmic reticulum-Golgi intermediate
CC compartment (ERGIC). The ERGIC serves as the membrane source for WIPI2
CC recruitment and LC3 lipidation, leading to formation of autophagosomes
CC that target cytosolic DNA or DNA viruses for degradation by the
CC lysosome. The autophagy- and interferon-inducing activities can be
CC uncoupled and autophagy induction is independent of TBK1
CC phosphorylation (By similarity). Autophagy is also triggered upon
CC infection by bacteria: following c-di-GMP-binding, which is produced by
CC live Gram-positive bacteria, promotes reticulophagy (By similarity).
CC Exhibits 2',3' phosphodiester linkage-specific ligand recognition: can
CC bind both 2'-3' linked cGAMP (2'-3'-cGAMP) and 3'-3' linked cGAMP but
CC is preferentially activated by 2'-3' linked cGAMP. The preference for
CC 2'-3'-cGAMP, compared to other linkage isomers is probably due to the
CC ligand itself, whichs adopts an organized free-ligand conformation that
CC resembles the STING1-bound conformation and pays low energy costs in
CC changing into the active conformation. May be involved in translocon
CC function, the translocon possibly being able to influence the induction
CC of type I interferons (By similarity). May be involved in transduction
CC of apoptotic signals via its association with the major
CC histocompatibility complex class II (MHC-II) (By similarity).
CC {ECO:0000250|UniProtKB:Q3TBT3, ECO:0000250|UniProtKB:Q86WV6}.
CC -!- SUBUNIT: Homodimer; forms a homodimer in absence of cyclic nucleotide
CC (c-di-GMP or cGAMP); 'Lys-63'-linked ubiquitination at Lys-150 is
CC required for homodimerization (By similarity). Homotetramer; in
CC presence of cyclic nucleotide (c-di-GMP or cGAMP), forms tetramers and
CC higher-order oligomers through side-by-side packing (By similarity).
CC Interacts (when phosphorylated) with IRF3; following activation and
CC phosphorylation on the pLxIS motif by TBK1, recruits IRF3 (By
CC similarity). Interacts with DDX58/RIG-I, MAVS and SSR2 (By similarity).
CC Interacts with RNF5 and TRIM56 (By similarity). Interacts with TBK1;
CC when homodimer, leading to subsequent production of IFN-beta (By
CC similarity). Interacts with IFIT1 and IFIT2 (By similarity). Interacts
CC with TRIM29; this interaction induces STING1 ubiquitination and
CC subsequent degradation (By similarity). Associates with the MHC-II
CC complex (By similarity). Interacts with STEEP; the interaction is
CC increased upon cGAMP binding and promotes STING1 translocation to COPII
CC vesicles (By similarity). Interacts with SEC24A, SEC24B and SEC24C;
CC promoting translocation to COPII vesicles (By similarity). Interacts
CC (when ubiquitinated) with SQSTM1; leading to relocalization to
CC autophagosomes (By similarity). Interacts with SURF4 (By similarity).
CC Interacts with HNRNPA2B1 (By similarity). Interacts with ZDHHC1; ZDHHC1
CC constitutively interacts with STING1 and in presence of DNA viruses
CC activates it by promoting its cGAMP-induced oligomerization and the
CC recruitment of downstream signaling components (By similarity).
CC Interacts with ZDHHC11; in presence of DNA viruses promotes the
CC recruitment of IRF3 to STING1 (By similarity). Interacts with TOMM70
CC (By similarity). {ECO:0000250|UniProtKB:Q3TBT3,
CC ECO:0000250|UniProtKB:Q86WV6}.
CC -!- SUBUNIT: (Microbial infection) Interacts with African swine fever
CC virus/ASFV prtotein A528R; this interaction mediates STING1
CC degradation. {ECO:0000269|PubMed:33712518}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:20346968}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:Q86WV6, ECO:0000255}. Cytoplasm, perinuclear
CC region {ECO:0000250|UniProtKB:Q86WV6}. Endoplasmic reticulum-Golgi
CC intermediate compartment membrane {ECO:0000250|UniProtKB:Q86WV6};
CC Multi-pass membrane protein {ECO:0000255}. Golgi apparatus membrane
CC {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein
CC {ECO:0000255}. Cytoplasmic vesicle, autophagosome membrane
CC {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein
CC {ECO:0000255}. Mitochondrion outer membrane
CC {ECO:0000269|PubMed:20346968}; Multi-pass membrane protein
CC {ECO:0000255}. Cell membrane {ECO:0000250|UniProtKB:Q3TBT3}; Multi-pass
CC membrane protein {ECO:0000255}. Note=In response to double-stranded DNA
CC stimulation, translocates from the endoplasmic reticulum through the
CC endoplasmic reticulum-Golgi intermediate compartment and Golgi to post-
CC Golgi vesicles, where the kinase TBK1 is recruited. Upon cGAMP-binding,
CC translocates to the endoplasmic reticulum-Golgi intermediate
CC compartment (ERGIC) in a process that is dependent on COPII vesicles;
CC STING1-containing ERGIC serves as a membrane source for LC3 lipidation,
CC which is a key step in autophagosome biogenesis.
CC {ECO:0000250|UniProtKB:Q86WV6}.
CC -!- TISSUE SPECIFICITY: Expressed at higher level in the spleen, lymph
CC node, lung and bone marrow, followed by the small intestine, heart,
CC liver and brain, and to a lesser extent in the stomach and kidney.
CC {ECO:0000269|PubMed:20346968}.
CC -!- DOMAIN: In absence of cGAMP, the transmembrane and cytoplasmic regions
CC interact to form an integrated, domain-swapped dimeric assembly (By
CC similarity). In absence of cyclic nucleotide (c-di-GMP or cGAMP), the
CC protein is autoinhibited by an intramolecular interaction between the
CC cyclic dinucleotide-binding domain (CBD) and the C-terminal tail (CTT)
CC (By similarity). Following cGAMP-binding, the cyclic dinucleotide-
CC binding domain (CBD) is closed, leading to a 180 degrees rotation of
CC the CBD domain relative to the transmembrane domain. This rotation is
CC coupled to a conformational change in a loop on the side of the CBD
CC dimer, which leads to the formation of the STING1 tetramer and higher-
CC order oligomers through side-by-side packing (By similarity). The N-
CC terminal part of the CBD region was initially though to contain a fifth
CC transmembrane region (TM5) but is part of the folded, soluble CBD (By
CC similarity). {ECO:0000250|UniProtKB:E1C7U0,
CC ECO:0000250|UniProtKB:Q86WV6}.
CC -!- DOMAIN: The pLxIS motif constitutes an IRF3-binding motif: following
CC phosphorylation by TBK1, the phosphorylated pLxIS motif of STING1
CC recruits IRF3. IRF3 is then phosphorylated and activated by TBK1 to
CC induce type-I interferons and other cytokines.
CC {ECO:0000250|UniProtKB:Q86WV6}.
CC -!- DOMAIN: The N-terminal domain interacts with glycerophospholipids and
CC phospholipids. {ECO:0000250|UniProtKB:Q86WV6}.
CC -!- PTM: Phosphorylation by TBK1 leads to activation and production of IFN-
CC beta. Following cyclic nucleotide (c-di-GMP or cGAMP)-binding,
CC activation and translocation from the endoplasmic reticulum, STING1 is
CC phosphorylated by TBK1 at Ser-365 in the pLxIS motif. The
CC phosphorylated pLxIS motif constitutes an IRF3-binding motif, leading
CC to recruitment of the transcription factor IRF3 to induce type-I
CC interferons and other cytokines (By similarity). Phosphorylated on
CC tyrosine residues upon MHC-II aggregation (By similarity).
CC Dephosphorylation by PPP6C leads to inactivation and decreased
CC production of IFN-beta (By similarity). Phosphorylation at Ser-357 is
CC also required to activate IRF3 (By similarity).
CC {ECO:0000250|UniProtKB:Q3TBT3, ECO:0000250|UniProtKB:Q86WV6}.
CC -!- PTM: Ubiquitinated (By similarity). Ubiquitinated via 'Lys-63'-linked
CC ubiquitin chains in response to double-stranded DNA treatment, leading
CC to relocalization to autophagosomes and subsequent degradation; this
CC process is dependent on SQSTM1 (By similarity). 'Lys-63'-linked
CC ubiquitination mediated by TRIM56 at Lys-150 promotes homodimerization
CC and recruitment of the antiviral kinase TBK1 and subsequent production
CC of IFN-beta. 'Lys-48'-linked polyubiquitination at Lys-150 occurring
CC after viral infection is mediated by RNF5 and leads to proteasomal
CC degradation. 'Lys-11'-linked polyubiquitination at Lys-150 by RNF26
CC leads to stabilize STING1: it protects STING1 from RNF5-mediated 'Lys-
CC 48'-linked polyubiquitination (By similarity).
CC {ECO:0000250|UniProtKB:Q3TBT3, ECO:0000250|UniProtKB:Q86WV6}.
CC -!- PTM: Palmitoylation takes place in the Golgi apparatus and creates a
CC platform for the recruitment of TBK1. {ECO:0000250|UniProtKB:Q3TBT3}.
CC -!- SIMILARITY: Belongs to the STING family. {ECO:0000305}.
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DR EMBL; FJ455509; ACJ70708.1; -; mRNA.
DR RefSeq; NP_001136310.1; NM_001142838.1.
DR PDB; 6A03; X-ray; 2.60 A; A/B=152-342.
DR PDB; 6A04; X-ray; 1.90 A; A/B=152-342.
DR PDB; 6A05; X-ray; 2.20 A; A/B=152-342.
DR PDB; 6A06; X-ray; 1.79 A; A/B=152-342.
DR PDB; 6IYF; X-ray; 1.76 A; A/B=152-342.
DR PDBsum; 6A03; -.
DR PDBsum; 6A04; -.
DR PDBsum; 6A05; -.
DR PDBsum; 6A06; -.
DR PDBsum; 6IYF; -.
DR AlphaFoldDB; B8XX90; -.
DR SMR; B8XX90; -.
DR STRING; 9823.ENSSSCP00000015264; -.
DR PaxDb; B8XX90; -.
DR GeneID; 100217389; -.
DR KEGG; ssc:100217389; -.
DR CTD; 340061; -.
DR eggNOG; ENOG502R15M; Eukaryota.
DR InParanoid; B8XX90; -.
DR OrthoDB; 865174at2759; -.
DR Proteomes; UP000008227; Unplaced.
DR Proteomes; UP000314985; Unplaced.
DR GO; GO:0000421; C:autophagosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-KW.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:UniProtKB.
DR GO; GO:0033116; C:endoplasmic reticulum-Golgi intermediate compartment membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0000139; C:Golgi membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005741; C:mitochondrial outer membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0061507; F:2',3'-cyclic GMP-AMP binding; ISS:UniProtKB.
DR GO; GO:0035438; F:cyclic-di-GMP binding; ISS:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; ISS:UniProtKB.
DR GO; GO:0002218; P:activation of innate immune response; ISS:UniProtKB.
DR GO; GO:0000045; P:autophagosome assembly; ISS:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; ISS:UniProtKB.
DR GO; GO:0045087; P:innate immune response; ISS:UniProtKB.
DR GO; GO:0032728; P:positive regulation of interferon-beta production; ISS:UniProtKB.
DR GO; GO:0016239; P:positive regulation of macroautophagy; ISS:UniProtKB.
DR GO; GO:0032481; P:positive regulation of type I interferon production; ISS:UniProtKB.
DR GO; GO:0061709; P:reticulophagy; ISS:UniProtKB.
DR CDD; cd12146; STING_C; 1.
DR Gene3D; 3.40.50.12100; -; 1.
DR InterPro; IPR029158; STING.
DR InterPro; IPR033952; STING_C.
DR InterPro; IPR038623; STING_C_sf.
DR PANTHER; PTHR34339; PTHR34339; 1.
DR Pfam; PF15009; TMEM173; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Autophagy; Cell membrane; Cytoplasm; Cytoplasmic vesicle;
KW Endoplasmic reticulum; Golgi apparatus; Immunity; Innate immunity;
KW Isopeptide bond; Lipoprotein; Membrane; Mitochondrion;
KW Mitochondrion outer membrane; Nucleotide-binding; Palmitate;
KW Phosphoprotein; Reference proteome; Transmembrane; Transmembrane helix;
KW Ubl conjugation.
FT CHAIN 1..378
FT /note="Stimulator of interferon genes protein"
FT /id="PRO_0000404587"
FT TOPO_DOM 1..17
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 18..34
FT /note="Helical; Name=1"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT TOPO_DOM 35..44
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 45..69
FT /note="Helical; Name=2"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT TOPO_DOM 70..91
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 92..106
FT /note="Helical; Name=3"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT TOPO_DOM 107..116
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 117..134
FT /note="Helical; Name=4"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT TOPO_DOM 135..378
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT REGION 1..190
FT /note="Mediates interaction with ZDHHC1 and ZDHHC11"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT REGION 153..339
FT /note="Cyclic dinucleotide-binding domain (CBD)"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT REGION 339..378
FT /note="C-terminal tail (CTT)"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT MOTIF 362..365
FT /note="pLxIS motif"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 162
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 162
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 167
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 167
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 238..241
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 238
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 263
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 263
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT MOD_RES 357
FT /note="Phosphoserine; by TBK1"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT MOD_RES 365
FT /note="Phosphoserine; by TBK1"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT LIPID 88
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:Q3TBT3"
FT LIPID 91
FT /note="S-palmitoyl cysteine"
FT /evidence="ECO:0000250|UniProtKB:Q3TBT3"
FT CROSSLNK 150
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT HELIX 156..166
FT /evidence="ECO:0007829|PDB:6IYF"
FT HELIX 168..190
FT /evidence="ECO:0007829|PDB:6IYF"
FT STRAND 197..203
FT /evidence="ECO:0007829|PDB:6IYF"
FT HELIX 212..215
FT /evidence="ECO:0007829|PDB:6IYF"
FT STRAND 219..224
FT /evidence="ECO:0007829|PDB:6IYF"
FT STRAND 228..232
FT /evidence="ECO:0007829|PDB:6IYF"
FT STRAND 235..240
FT /evidence="ECO:0007829|PDB:6IYF"
FT STRAND 243..249
FT /evidence="ECO:0007829|PDB:6IYF"
FT STRAND 252..261
FT /evidence="ECO:0007829|PDB:6IYF"
FT HELIX 264..272
FT /evidence="ECO:0007829|PDB:6IYF"
FT HELIX 281..300
FT /evidence="ECO:0007829|PDB:6IYF"
FT HELIX 303..308
FT /evidence="ECO:0007829|PDB:6IYF"
FT STRAND 309..314
FT /evidence="ECO:0007829|PDB:6IYF"
FT STRAND 318..320
FT /evidence="ECO:0007829|PDB:6A06"
FT HELIX 325..337
FT /evidence="ECO:0007829|PDB:6IYF"
SQ SEQUENCE 378 AA; 41881 MW; F4AA581E6B96BDED CRC64;
MPYSSLHPSI PQPRGLRAQV AALVLLGACL VALWGLGELP EYTLRWLVLH LASQQIGLLV
KGLCSLAEEL CHVHSRYQSS YWRAARACLG CPIRCGALLL LSCYFYFSIR DKAGLPLPWM
LALLGLSQAL NILLGLQHLA PAEVSAICEK RNFNVAHGLA WSYYIGYLRL ILPGLRARIQ
AYNQRHKNVL GGIGNHRLHI LFPLDCGVPD DLSVADPNIR FLHELPQQSA DRAGIKGRVY
TNSIYELLEN GQPAGVCVLG YATPLQTLFA MSQDGRAGFS REDRLEQAKL FCRTLEDILA
DAPEAQNNCR LIVYQEPTEG GSFSLSQEIL RHLRQEEREV TMGSAETSVV PTSSTLSQEP
ELLISGMEQP LPLRSDIF
