ID STING_RAT Reviewed; 379 AA.
AC F1M391;
DT 05-OCT-2016, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 2.
DT 10-MAY-2017, entry version 48.
DE RecName: Full=Stimulator of interferon genes protein {ECO:0000303|PubMed:26669264};
DE Short=rSTING {ECO:0000303|PubMed:26669264};
DE AltName: Full=Transmembrane protein 173;
GN Name=Tmem173 {ECO:0000312|RGD:1562552};
GN Synonyms=Sting {ECO:0000303|PubMed:26669264};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha;
OC Muroidea; Muridae; Murinae; Rattus.
OX NCBI_TaxID=10116 {ECO:0000312|Proteomes:UP000002494};
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RX PubMed=15057822; DOI=10.1038/nature02426;
RA Gibbs R.A., Weinstock G.M., Metzker M.L., Muzny D.M., Sodergren E.J.,
RA Scherer S., Scott G., Steffen D., Worley K.C., Burch P.E., Okwuonu G.,
RA Hines S., Lewis L., Deramo C., Delgado O., Dugan-Rocha S., Miner G.,
RA Morgan M., Hawes A., Gill R., Holt R.A., Adams M.D., Amanatides P.G.,
RA Baden-Tillson H., Barnstead M., Chin S., Evans C.A., Ferriera S.,
RA Fosler C., Glodek A., Gu Z., Jennings D., Kraft C.L., Nguyen T.,
RA Pfannkoch C.M., Sitter C., Sutton G.G., Venter J.C., Woodage T.,
RA Smith D., Lee H.-M., Gustafson E., Cahill P., Kana A.,
RA Doucette-Stamm L., Weinstock K., Fechtel K., Weiss R.B., Dunn D.M.,
RA Green E.D., Blakesley R.W., Bouffard G.G., De Jong P.J., Osoegawa K.,
RA Zhu B., Marra M., Schein J., Bosdet I., Fjell C., Jones S.,
RA Krzywinski M., Mathewson C., Siddiqui A., Wye N., McPherson J.,
RA Zhao S., Fraser C.M., Shetty J., Shatsman S., Geer K., Chen Y.,
RA Abramzon S., Nierman W.C., Havlak P.H., Chen R., Durbin K.J., Egan A.,
RA Ren Y., Song X.-Z., Li B., Liu Y., Qin X., Cawley S., Cooney A.J.,
RA D'Souza L.M., Martin K., Wu J.Q., Gonzalez-Garay M.L., Jackson A.R.,
RA Kalafus K.J., McLeod M.P., Milosavljevic A., Virk D., Volkov A.,
RA Wheeler D.A., Zhang Z., Bailey J.A., Eichler E.E., Tuzun E.,
RA Birney E., Mongin E., Ureta-Vidal A., Woodwark C., Zdobnov E.,
RA Bork P., Suyama M., Torrents D., Alexandersson M., Trask B.J.,
RA Young J.M., Huang H., Wang H., Xing H., Daniels S., Gietzen D.,
RA Schmidt J., Stevens K., Vitt U., Wingrove J., Camara F., Mar Alba M.,
RA Abril J.F., Guigo R., Smit A., Dubchak I., Rubin E.M., Couronne O.,
RA Poliakov A., Huebner N., Ganten D., Goesele C., Hummel O.,
RA Kreitler T., Lee Y.-A., Monti J., Schulz H., Zimdahl H.,
RA Himmelbauer H., Lehrach H., Jacob H.J., Bromberg S.,
RA Gullings-Handley J., Jensen-Seaman M.I., Kwitek A.E., Lazar J.,
RA Pasko D., Tonellato P.J., Twigger S., Ponting C.P., Duarte J.M.,
RA Rice S., Goodstadt L., Beatson S.A., Emes R.D., Winter E.E.,
RA Webber C., Brandt P., Nyakatura G., Adetobi M., Chiaromonte F.,
RA Elnitski L., Eswara P., Hardison R.C., Hou M., Kolbe D., Makova K.,
RA Miller W., Nekrutenko A., Riemer C., Schwartz S., Taylor J., Yang S.,
RA Zhang Y., Lindpaintner K., Andrews T.D., Caccamo M., Clamp M.,
RA Clarke L., Curwen V., Durbin R.M., Eyras E., Searle S.M., Cooper G.M.,
RA Batzoglou S., Brudno M., Sidow A., Stone E.A., Payseur B.A.,
RA Bourque G., Lopez-Otin C., Puente X.S., Chakrabarti K., Chatterji S.,
RA Dewey C., Pachter L., Bray N., Yap V.B., Caspi A., Tesler G.,
RA Pevzner P.A., Haussler D., Roskin K.M., Baertsch R., Clawson H.,
RA Furey T.S., Hinrichs A.S., Karolchik D., Kent W.J., Rosenbloom K.R.,
RA Trumbower H., Weirauch M., Cooper D.N., Stenson P.D., Ma B., Brent M.,
RA Arumugam M., Shteynberg D., Copley R.R., Taylor M.S., Riethman H.,
RA Mudunuri U., Peterson J., Guyer M., Felsenfeld A., Old S., Mockrin S.,
RA Collins F.S.;
RT "Genome sequence of the Brown Norway rat yields insights into
RT mammalian evolution.";
RL Nature 428:493-521(2004).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Brown Norway;
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP FUNCTION, X-RAY CRYSTALLOGRAPHY (1.55 ANGSTROMS) OF 140-337 OF
RP APOPROTEIN AND IN COMPLEX WITH 2'-3' LINKED CGAMP, SUBUNIT,
RP MUTAGENESIS OF PRO-141; GLU-143; VAL-144; SER-145; GLU-149; GLU-150;
RP LYS-151 AND THR-230, AND MISCELLANEOUS.
RX PubMed=26669264; DOI=10.1038/srep18035;
RA Zhang H., Han M.J., Tao J., Ye Z.Y., Du X.X., Deng M.J., Zhang X.Y.,
RA Li L.F., Jiang Z.F., Su X.D.;
RT "Rat and human STINGs profile similarly towards anticancer/antiviral
RT compounds.";
RL Sci. Rep. 5:18035-18035(2015).
CC -!- FUNCTION: Facilitator of innate immune signaling that acts as a
CC sensor of cytosolic DNA from bacteria and viruses and promotes the
CC production of type I interferon (IFN-alpha and IFN-beta). Innate
CC immune response is triggered in response to non-CpG double-
CC stranded DNA from viruses and bacteria delivered to the cytoplasm.
CC Acts by recognizing and binding cyclic di-GMP (c-di-GMP), a second
CC messenger produced by bacteria, and cyclic GMP-AMP (cGAMP), a
CC messenger produced in response to DNA virus in the cytosol: upon
CC binding of c-di-GMP or cGAMP, autoinhibition is alleviated and
CC TMEM173/STING is able to activate both NF-kappa-B and IRF3
CC transcription pathways to induce expression of type I interferon
CC and exert a potent anti-viral state (PubMed:26669264). May be
CC involved in translocon function, the translocon possibly being
CC able to influence the induction of type I interferons. May be
CC involved in transduction of apoptotic signals via its association
CC with the major histocompatibility complex class II (MHC-II).
CC Mediates death signaling via activation of the extracellular
CC signal-regulated kinase (ERK) pathway (By similarity). Exhibits
CC 2',3' phosphodiester linkage-specific ligand recognition. Can bind
CC both 2'-3' linked cGAMP and 3'-3' linked cGAMP; the precise
CC binding affinity may be species-specific and rat TMEM173/STING is
CC preferentially activated by 3'-3' linked cGAMP (PubMed:26669264).
CC {ECO:0000250|UniProtKB:Q86WV6, ECO:0000269|PubMed:26669264}.
CC -!- SUBUNIT: Associates with the MHC-II complex (By similarity).
CC Homodimer (PubMed:26669264). 'Lys-63'-linked ubiquitination at
CC Lys-151 is required for homodimerization. Interacts with
CC DDX58/RIG-I, MAVS and SSR2. Interacts with RNF5 and TRIM56.
CC Interacts with TBK1; when homodimer, leading to subsequent
CC production of IFN-beta (By similarity). Interacts with IFIT1 and
CC IFIT2 (By similarity). {ECO:0000250|UniProtKB:Q86WV6,
CC ECO:0000269|PubMed:26669264}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein
CC {ECO:0000255}. Mitochondrion outer membrane
CC {ECO:0000250|UniProtKB:Q86WV6}; Multi-pass membrane protein
CC {ECO:0000255}. Cell membrane {ECO:0000250|UniProtKB:Q3TBT3};
CC Multi-pass membrane protein {ECO:0000255}. Cytoplasm, perinuclear
CC region {ECO:0000250|UniProtKB:Q86WV6}. Cytoplasm
CC {ECO:0000250|UniProtKB:Q86WV6}. Note=In response to double-
CC stranded DNA stimulation, relocalizes to perinuclear region, where
CC the kinase TBK1 is recruited. {ECO:0000250|UniProtKB:Q86WV6}.
CC -!- DOMAIN: The c-di-GMP-binding domain (CBD) forms a homodimer via
CC hydrophobic interactions and binds both the cyclic diguanylate
CC monophosphate (c-di-GMP) and the cyclic GMP-AMP (cGAMP)
CC messengers. In absence of c-di-GMP or cGAMP, the protein is
CC autoinhibited by an intramolecular interaction between the CBD and
CC the C-terminal tail (CTT). Binding of c-di-GMP or cGAMP to the CBD
CC releases the autoinhibition by displacing the CTT, leading to
CC activate both NF-kappa-B and IRF3 transcription pathways to induce
CC expression of type I interferon. The N-terminal part of the CBD
CC region was initially though to contain a fifth transmembrane
CC region (TM5) but is part of the folded, soluble CBD (By
CC similarity). {ECO:0000250|UniProtKB:Q86WV6}.
CC -!- PTM: Phosphorylated on tyrosine residues upon MHC-II aggregation.
CC Phosphorylated on Ser-358 by TBK1, leading to activation and
CC production of IFN-beta (By similarity).
CC {ECO:0000250|UniProtKB:Q86WV6}.
CC -!- PTM: Ubiquitinated. 'Lys-63'-linked ubiquitination mediated by
CC TRIM56 at Lys-151 promotes homodimerization and recruitment of the
CC antiviral kinase TBK1 and subsequent production of IFN-beta. 'Lys-
CC 48'-linked polyubiquitination at Lys-151 occurring after viral
CC infection is mediated by RNF5 and leads to proteasomal degradation
CC (By similarity). {ECO:0000250|UniProtKB:Q86WV6}.
CC -!- MISCELLANEOUS: Contrary to human and rat TMEM173/STING, mouse
CC TMEM173/STING mediates not only responses to cyclic nucleotide
CC signaling molecules, but is also strongly activated by antiviral
CC and anticancer molecules, such as 5,6-dimethylxanthenone 4-acetic
CC acid (DMXAA) and 10-carboxymethyl-9-acridanone (CMA).
CC {ECO:0000269|PubMed:26669264}.
CC -!- SIMILARITY: Belongs to the TMEM173 family. {ECO:0000305}.
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DR EMBL; AABR07072583; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC135285; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH473974; EDL76277.1; -; Genomic_DNA.
DR RefSeq; NP_001102592.1; NM_001109122.1.
DR UniGene; Rn.41472; -.
DR SMR; F1M391; -.
DR STRING; 10116.ENSRNOP00000063348; -.
DR PaxDb; F1M391; -.
DR PRIDE; F1M391; -.
DR Ensembl; ENSRNOT00000068386; ENSRNOP00000063348; ENSRNOG00000042137.
DR GeneID; 498840; -.
DR KEGG; rno:498840; -.
DR CTD; 340061; -.
DR RGD; 1562552; Tmem173.
DR eggNOG; ENOG410IH2R; Eukaryota.
DR eggNOG; ENOG4111M85; LUCA.
DR GeneTree; ENSGT00390000008582; -.
DR KO; K12654; -.
DR OMA; TWMLALL; -.
DR OrthoDB; EOG091G08B2; -.
DR TreeFam; TF324444; -.
DR Reactome; R-RNO-1834941; STING mediated induction of host immune responses.
DR Reactome; R-RNO-3134975; Regulation of innate immune responses to cytosolic DNA.
DR Reactome; R-RNO-3249367; STAT6-mediated induction of chemokines.
DR Reactome; R-RNO-3270619; IRF3-mediated induction of type I IFN.
DR Reactome; R-RNO-6798695; Neutrophil degranulation.
DR PRO; PR:F1M391; -.
DR Proteomes; UP000002494; Chromosome 18.
DR GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR GO; GO:0005829; C:cytosol; IEA:Ensembl.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005794; C:Golgi apparatus; IEA:Ensembl.
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:0005654; C:nucleoplasm; IEA:Ensembl.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005777; C:peroxisome; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0035438; F:cyclic-di-GMP binding; IEA:Ensembl.
DR GO; GO:0061507; F:cyclic-GMP-AMP binding; IDA:UniProtKB.
DR GO; GO:0042803; F:protein homodimerization activity; IEA:Ensembl.
DR GO; GO:0019901; F:protein kinase binding; IEA:Ensembl.
DR GO; GO:0008134; F:transcription factor binding; IEA:Ensembl.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IEA:Ensembl.
DR GO; GO:0002218; P:activation of innate immune response; IEA:Ensembl.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0071360; P:cellular response to exogenous dsRNA; IEA:Ensembl.
DR GO; GO:0035458; P:cellular response to interferon-beta; IEA:Ensembl.
DR GO; GO:0071407; P:cellular response to organic cyclic compound; IDA:UniProtKB.
DR GO; GO:0051607; P:defense response to virus; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0032608; P:interferon-beta production; IEA:Ensembl.
DR GO; GO:0002230; P:positive regulation of defense response to virus by host; IEA:Ensembl.
DR GO; GO:0032092; P:positive regulation of protein binding; IEA:Ensembl.
DR GO; GO:0033160; P:positive regulation of protein import into nucleus, translocation; IEA:Ensembl.
DR GO; GO:0042993; P:positive regulation of transcription factor import into nucleus; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0032481; P:positive regulation of type I interferon production; IDA:UniProtKB.
DR CDD; cd12146; STING_C; 1.
DR InterPro; IPR029158; STING.
DR InterPro; IPR033952; STING_C.
DR Pfam; PF15009; TMEM173; 1.
PE 1: Evidence at protein level;
KW Apoptosis; Cell membrane; Complete proteome; Cytoplasm;
KW Endoplasmic reticulum; Immunity; Innate immunity; Isopeptide bond;
KW Membrane; Mitochondrion; Mitochondrion outer membrane;
KW Nucleotide-binding; Phosphoprotein; Reference proteome; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT CHAIN 1 379 Stimulator of interferon genes protein.
FT /FTId=PRO_0000437256.
FT TOPO_DOM 1 19 Cytoplasmic. {ECO:0000255}.
FT TRANSMEM 20 40 Helical; Name=1. {ECO:0000255}.
FT TOPO_DOM 41 46 Extracellular. {ECO:0000255}.
FT TRANSMEM 47 67 Helical; Name=2. {ECO:0000255}.
FT TOPO_DOM 68 86 Cytoplasmic. {ECO:0000255}.
FT TRANSMEM 87 106 Helical; Name=3. {ECO:0000255}.
FT TOPO_DOM 107 115 Extracellular. {ECO:0000255}.
FT TRANSMEM 116 136 Helical; Name=4. {ECO:0000255}.
FT TOPO_DOM 137 379 Cytoplasmic. {ECO:0000255}.
FT REGION 153 340 c-di-GMP-binding domain (CBD).
FT {ECO:0000269|PubMed:26669264}.
FT REGION 162 167 c-di-GMP binding.
FT {ECO:0000305|PubMed:26669264}.
FT REGION 238 241 c-di-GMP binding.
FT {ECO:0000305|PubMed:26669264}.
FT REGION 340 379 C-terminal tail (CTT).
FT {ECO:0000250|UniProtKB:Q86WV6}.
FT BINDING 263 263 c-di-GMP. {ECO:0000305|PubMed:26669264}.
FT MOD_RES 358 358 Phosphoserine; by TBK1.
FT {ECO:0000250|UniProtKB:Q86WV6}.
FT CROSSLNK 151 151 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT {ECO:0000250|UniProtKB:Q3TBT3}.
FT MUTAGEN 141 141 P->A: Abolishes response to 2'-3' linked
FT cGAMP and 3'-3' linked cGAMP and
FT production of interferon IFNB1.
FT {ECO:0000269|PubMed:26669264}.
FT MUTAGEN 143 143 E->A: Abolishes response to 2'-3' linked
FT cGAMP and 3'-3' linked cGAMP and
FT production of interferon IFNB1.
FT {ECO:0000269|PubMed:26669264}.
FT MUTAGEN 144 144 V->A: Decreases response to 2'-3' linked
FT cGAMP and 3'-3' linked cGAMP and
FT production of interferon IFNB1.
FT {ECO:0000269|PubMed:26669264}.
FT MUTAGEN 145 145 S->A: Abolishes response to 2'-3' linked
FT cGAMP and 3'-3' linked cGAMP and
FT production of interferon IFNB1.
FT {ECO:0000269|PubMed:26669264}.
FT MUTAGEN 149 149 E->A,R: Abolishes response to 2'-3'
FT linked cGAMP and 3'-3' linked cGAMP and
FT production of interferon IFNB1.
FT {ECO:0000269|PubMed:26669264}.
FT MUTAGEN 150 150 E->A: Abolishes response to 2'-3' linked
FT cGAMP and 3'-3' linked cGAMP and
FT production of interferon IFNB1.
FT {ECO:0000269|PubMed:26669264}.
FT MUTAGEN 151 151 K->R: Abolishes response to 2'-3' linked
FT cGAMP and 3'-3' linked cGAMP and
FT production of interferon IFNB1.
FT {ECO:0000269|PubMed:26669264}.
FT MUTAGEN 230 230 T->I,L,M,V: No effect on response to 2'-
FT 3' linked cGAMP and production of
FT interferon IFNB1. Strongly increases
FT affinity for the synthetic compound 5,6-
FT dimethylxanthenone 4-acetic acid (DMXAA).
FT {ECO:0000269|PubMed:26669264}.
CC --------------------------------------------------------------------------
CC The following FT lines are automated annotations from the MyHits database.
CC --------------------------------------------------------------------------
FT MYHIT 45 337 ipfam:TMEM173 [T]
SQ SEQUENCE 379 AA; 42655 MW; 69AB884C9DA209EC CRC64;
MPYSNLHPSI PRPRSYRFKL AAFVLLVGSL MSLWMTGEPP SHTLHYLALH VASQQLGLLL
KKLCCLAEEL CHVQSRYQGS YWKAVRACVG SPICFMALIL LSFYFYCSLE NTSDLRLAWH
LGILVLSKSL SMTLDLQSLA PAEVSAVCEE KNFNVAHGLA WSYYIGYLKL ILPGLQARIR
MFNQLHNNML SGAGSRRLYI LFPLDCGVPD DLSVADPNIR FRDMLPQQNT DRAGVKNRAY
SNSVYELLEN GQPAGACILE YATPLQTLFA MSQDGKAGFS REDRLEQAKL FCRTLEEILA
DVPESRNHCR LIVYQESEEG NSFSLSQEVL RHIRQEEKEE VTMSGPPTSV APRPSLLSQE
PRLLISGMEQ PLPLRTDLI
//
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