STING_DANRE
ID STING_DANRE Reviewed; 398 AA.
AC E7F4N7; K4Q6R6;
DT 08-MAY-2019, integrated into UniProtKB/Swiss-Prot.
DT 08-MAR-2011, sequence version 1.
DT 03-AUG-2022, entry version 73.
DE RecName: Full=Stimulator of interferon genes protein {ECO:0000303|PubMed:23091644};
DE Short=STING {ECO:0000303|PubMed:23091644};
DE AltName: Full=Transmembrane protein 173 {ECO:0000305};
GN Name=sting1 {ECO:0000250|UniProtKB:Q86WV6};
GN Synonyms=sting {ECO:0000303|PubMed:23091644},
GN tmem173 {ECO:0000250|UniProtKB:Q86WV6};
OS Danio rerio (Zebrafish) (Brachydanio rerio).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Actinopterygii; Neopterygii; Teleostei; Ostariophysi; Cypriniformes;
OC Danionidae; Danioninae; Danio.
OX NCBI_TaxID=7955;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=23091644; DOI=10.1371/journal.pone.0047737;
RA Biacchesi S., Merour E., Lamoureux A., Bernard J., Bremont M.;
RT "Both STING and MAVS fish orthologs contribute to the induction of
RT interferon mediated by RIG-I.";
RL PLoS ONE 7:E47737-E47737(2012).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Tuebingen;
RX PubMed=23594743; DOI=10.1038/nature12111;
RA Howe K., Clark M.D., Torroja C.F., Torrance J., Berthelot C., Muffato M.,
RA Collins J.E., Humphray S., McLaren K., Matthews L., McLaren S., Sealy I.,
RA Caccamo M., Churcher C., Scott C., Barrett J.C., Koch R., Rauch G.J.,
RA White S., Chow W., Kilian B., Quintais L.T., Guerra-Assuncao J.A., Zhou Y.,
RA Gu Y., Yen J., Vogel J.H., Eyre T., Redmond S., Banerjee R., Chi J., Fu B.,
RA Langley E., Maguire S.F., Laird G.K., Lloyd D., Kenyon E., Donaldson S.,
RA Sehra H., Almeida-King J., Loveland J., Trevanion S., Jones M., Quail M.,
RA Willey D., Hunt A., Burton J., Sims S., McLay K., Plumb B., Davis J.,
RA Clee C., Oliver K., Clark R., Riddle C., Elliot D., Threadgold G.,
RA Harden G., Ware D., Begum S., Mortimore B., Kerry G., Heath P.,
RA Phillimore B., Tracey A., Corby N., Dunn M., Johnson C., Wood J., Clark S.,
RA Pelan S., Griffiths G., Smith M., Glithero R., Howden P., Barker N.,
RA Lloyd C., Stevens C., Harley J., Holt K., Panagiotidis G., Lovell J.,
RA Beasley H., Henderson C., Gordon D., Auger K., Wright D., Collins J.,
RA Raisen C., Dyer L., Leung K., Robertson L., Ambridge K., Leongamornlert D.,
RA McGuire S., Gilderthorp R., Griffiths C., Manthravadi D., Nichol S.,
RA Barker G., Whitehead S., Kay M., Brown J., Murnane C., Gray E.,
RA Humphries M., Sycamore N., Barker D., Saunders D., Wallis J., Babbage A.,
RA Hammond S., Mashreghi-Mohammadi M., Barr L., Martin S., Wray P.,
RA Ellington A., Matthews N., Ellwood M., Woodmansey R., Clark G., Cooper J.,
RA Tromans A., Grafham D., Skuce C., Pandian R., Andrews R., Harrison E.,
RA Kimberley A., Garnett J., Fosker N., Hall R., Garner P., Kelly D., Bird C.,
RA Palmer S., Gehring I., Berger A., Dooley C.M., Ersan-Urun Z., Eser C.,
RA Geiger H., Geisler M., Karotki L., Kirn A., Konantz J., Konantz M.,
RA Oberlander M., Rudolph-Geiger S., Teucke M., Lanz C., Raddatz G.,
RA Osoegawa K., Zhu B., Rapp A., Widaa S., Langford C., Yang F.,
RA Schuster S.C., Carter N.P., Harrow J., Ning Z., Herrero J., Searle S.M.,
RA Enright A., Geisler R., Plasterk R.H., Lee C., Westerfield M.,
RA de Jong P.J., Zon L.I., Postlethwait J.H., Nusslein-Volhard C.,
RA Hubbard T.J., Roest Crollius H., Rogers J., Stemple D.L.;
RT "The zebrafish reference genome sequence and its relationship to the human
RT genome.";
RL Nature 496:498-503(2013).
RN [3]
RP FUNCTION.
RX PubMed=30842662; DOI=10.1038/s41586-019-1006-9;
RA Gui X., Yang H., Li T., Tan X., Shi P., Li M., Du F., Chen Z.J.;
RT "Autophagy induction via STING trafficking is a primordial function of the
RT cGAS pathway.";
RL Nature 567:262-266(2019).
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) (PubMed:23091644). Innate
CC immune response is triggered in response to non-CpG double-stranded DNA
CC from viruses and bacteria delivered to the cytoplasm (PubMed:23091644).
CC Acts by binding cyclic dinucleotides: recognizes and binds cyclic di-
CC GMP (c-di-GMP), a second messenger produced by bacteria, and cyclic
CC GMP-AMP (cGAMP), a messenger produced by CGAS in response to DNA virus
CC in the cytosol (By similarity). Upon binding of c-di-GMP or cGAMP,
CC STING1 oligomerizes and is able to activate both NF-kappa-B and irf3
CC transcription pathways to induce expression of type I interferon and
CC exert a potent anti-viral state (PubMed:30842662). In addition to
CC promote the production of type I interferons, plays a direct role in
CC autophagy (PubMed:30842662). Following cGAMP-binding, STING1 buds from
CC the endoplasmic reticulum into COPII vesicles, which then form the
CC endoplasmic reticulum-Golgi intermediate compartment (ERGIC). The ERGIC
CC serves as the membrane source for LC3 lipidation, leading to formation
CC of autophagosomes that target cytosolic DNA or DNA viruses for
CC degradation by the lysosome. The autophagy- and interferon-inducing
CC activities can be uncoupled and autophagy induction is independent of
CC TBK1 phosphorylation. Exhibits 2',3' phosphodiester linkage-specific
CC ligand recognition: can bind both 2'-3' linked cGAMP and 3'-3' linked
CC cGAMP but is preferentially activated by 2'-3' linked cGAMP (By
CC similarity). {ECO:0000250|UniProtKB:Q86WV6,
CC ECO:0000269|PubMed:23091644, ECO:0000269|PubMed:30842662}.
CC -!- SUBUNIT: Homodimer; forms a homodimer in absence of cyclic nucleotide
CC (c-di-GMP or cGAMP) (By similarity). Homotetramer; in presence of
CC cyclic nucleotide (c-di-GMP or cGAMP), forms tetramers and higher-order
CC oligomers through side-by-side packing (By similarity). Interacts (when
CC phosphorylated) with irf3; following activation and phosphorylation by
CC tbk1, recruits irf3 (By similarity). {ECO:0000250|UniProtKB:E1C7U0}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:23091644}; Multi-pass membrane protein
CC {ECO:0000255}. Cytoplasm, perinuclear region
CC {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}. Note=In response to double-stranded DNA stimulation,
CC translocates from the endoplasmic reticulum through the endoplasmic
CC reticulum-Golgi intermediate compartment and Golgi to post-Golgi
CC 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 -!- 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 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, leading to recruitment of the transcription
CC factor irf3 to induce type-I interferons and other cytokines.
CC {ECO:0000250|UniProtKB:E1C7U0}.
CC -!- SIMILARITY: Belongs to the STING family. {ECO:0000305}.
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DR EMBL; HE856619; CCI55627.1; -; mRNA.
DR EMBL; FP017217; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_001265766.1; NM_001278837.1.
DR RefSeq; XP_005157178.1; XM_005157121.3.
DR PDB; 6MYD; X-ray; 1.40 A; B/D=381-388.
DR PDBsum; 6MYD; -.
DR AlphaFoldDB; E7F4N7; -.
DR SMR; E7F4N7; -.
DR STRING; 7955.ENSDARP00000105858; -.
DR PaxDb; E7F4N7; -.
DR Ensembl; ENSDART00000128218; ENSDARP00000105858; ENSDARG00000091058.
DR Ensembl; ENSDART00000186440; ENSDARP00000148153; ENSDARG00000091058.
DR GeneID; 101243556; -.
DR KEGG; dre:101243556; -.
DR CTD; 340061; -.
DR ZFIN; ZDB-GENE-120921-1; sting1.
DR eggNOG; ENOG502R15M; Eukaryota.
DR GeneTree; ENSGT00390000008582; -.
DR HOGENOM; CLU_062449_0_0_1; -.
DR InParanoid; E7F4N7; -.
DR OMA; FAMSQYG; -.
DR OrthoDB; 865174at2759; -.
DR TreeFam; TF324444; -.
DR Reactome; R-DRE-1834941; STING mediated induction of host immune responses.
DR Reactome; R-DRE-3134975; Regulation of innate immune responses to cytosolic DNA.
DR Reactome; R-DRE-3249367; STAT6-mediated induction of chemokines.
DR Reactome; R-DRE-3270619; IRF3-mediated induction of type I IFN.
DR Reactome; R-DRE-6798695; Neutrophil degranulation.
DR PRO; PR:E7F4N7; -.
DR Proteomes; UP000000437; Genome assembly.
DR Proteomes; UP000814640; Chromosome 14.
DR Bgee; ENSDARG00000091058; Expressed in spleen and 10 other tissues.
DR GO; GO:0005776; C:autophagosome; IBA:GO_Central.
DR GO; GO:0000421; C:autophagosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:UniProtKB-KW.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:ZFIN.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IBA:GO_Central.
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:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0061507; F:2',3'-cyclic GMP-AMP binding; IBA:GO_Central.
DR GO; GO:0035438; F:cyclic-di-GMP binding; IBA:GO_Central.
DR GO; GO:0002218; P:activation of innate immune response; IBA:GO_Central.
DR GO; GO:0000045; P:autophagosome assembly; IBA:GO_Central.
DR GO; GO:0039528; P:cytoplasmic pattern recognition receptor signaling pathway in response to virus; IDA:ZFIN.
DR GO; GO:0051607; P:defense response to virus; IBA:GO_Central.
DR GO; GO:0045087; P:innate immune response; IMP:ZFIN.
DR GO; GO:0038061; P:NIK/NF-kappaB signaling; IGI:ZFIN.
DR GO; GO:0002230; P:positive regulation of defense response to virus by host; IDA:ZFIN.
DR GO; GO:0016239; P:positive regulation of macroautophagy; IDA:UniProtKB.
DR GO; GO:0032481; P:positive regulation of type I interferon production; IBA:GO_Central.
DR GO; GO:0010506; P:regulation of autophagy; IGI:ZFIN.
DR GO; GO:0009615; P:response to virus; IMP:ZFIN.
DR GO; GO:0061709; P:reticulophagy; IBA:GO_Central.
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; Cytoplasm; Cytoplasmic vesicle; Endoplasmic reticulum;
KW Golgi apparatus; Immunity; Innate immunity; Isopeptide bond; Membrane;
KW Nucleotide-binding; Phosphoprotein; Reference proteome; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..398
FT /note="Stimulator of interferon genes protein"
FT /id="PRO_0000447212"
FT TOPO_DOM 1..16
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 17..37
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 38..44
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 45..65
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 66..91
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT TRANSMEM 92..112
FT /note="Helical; Name=3"
FT /evidence="ECO:0000255"
FT TOPO_DOM 113..120
FT /note="Lumenal"
FT /evidence="ECO:0000305"
FT TRANSMEM 121..141
FT /note="Helical; Name=4"
FT /evidence="ECO:0000255"
FT TOPO_DOM 142..398
FT /note="Cytoplasmic"
FT /evidence="ECO:0000305"
FT REGION 150..331
FT /note="Cyclic dinucleotide-binding domain (CBD)"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT REGION 375..398
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 159
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 159
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 164
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 164
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 230..233
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 230
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 254
FT /ligand="2',3'-cGAMP"
FT /ligand_id="ChEBI:CHEBI:143093"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT BINDING 254
FT /ligand="cyclic di-3',5'-guanylate"
FT /ligand_id="ChEBI:CHEBI:58805"
FT /evidence="ECO:0000250|UniProtKB:Q86WV6"
FT CONFLICT 113
FT /note="K -> E (in Ref. 1; CCI55627)"
FT /evidence="ECO:0000305"
FT CONFLICT 205
FT /note="E -> G (in Ref. 1; CCI55627)"
FT /evidence="ECO:0000305"
FT CONFLICT 356
FT /note="Q -> R (in Ref. 1; CCI55627)"
FT /evidence="ECO:0000305"
FT STRAND 383..386
FT /evidence="ECO:0007829|PDB:6MYD"
SQ SEQUENCE 398 AA; 45299 MW; C69754947495A62F CRC64;
MSVMGEDALV PRARSRLPVM CAAGLGFLTL AVAWLLDSDK FSERAGIIAF GLMLERFIYC
ICLLAEELLF HSRQRYHGRM SEIFRACFRG SGILGMCAIF LMLMLGGVSF SVKQWSHFNL
MCAGYMLLNS LGVLGPAPVE ISEICEAKKM NVAHGLAWSF YIGYLKFLLP ALEVNVREYS
RRERLSSPRL HILLPLNARV PSKPEEEDTN VVFHENLPDL KLDRAGVRKR SYTNSVYKIT
HNNETFSCIL EYATPLLTLY QMSQESSAGF GERERKQQVL LFYRTLSQIL DNSLECRNRY
RLILLNDEHT GDPHYLSREL FQNLKQQDGE IFMDPTNEVH PVPEEGPVGN CNGALQATFH
EEPMSDEPTL MFSRPQSLRS EPVETTDYFN PSSAMKQN
