ID STING_HUMAN Reviewed; 379 AA.
AC Q86WV6; A8K3P6; B6EB35; D6RBX0; D6RE01; D6RID9;
DT 09-JAN-2007, integrated into UniProtKB/Swiss-Prot.
DT 01-JUN-2003, sequence version 1.
DT 10-MAY-2017, entry version 115.
DE RecName: Full=Stimulator of interferon genes protein {ECO:0000303|PubMed:18724357};
DE Short=hSTING {ECO:0000303|PubMed:18724357, ECO:0000303|PubMed:26669264};
DE AltName: Full=Endoplasmic reticulum interferon stimulator;
DE Short=ERIS;
DE AltName: Full=Mediator of IRF3 activation {ECO:0000303|PubMed:18818105, ECO:0000303|PubMed:19285439};
DE Short=hMITA {ECO:0000303|PubMed:18818105, ECO:0000303|PubMed:19285439};
DE AltName: Full=Transmembrane protein 173;
GN Name=TMEM173;
GN Synonyms=ERIS, MITA {ECO:0000303|PubMed:18818105,
GN ECO:0000303|PubMed:19285439}, STING {ECO:0000303|PubMed:18724357,
GN ECO:0000303|PubMed:26669264};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBCELLULAR LOCATION, TISSUE
RP SPECIFICITY, INTERACTION WITH MAVS, PHOSPHORYLATION AT SER-358, AND
RP MUTAGENESIS OF 324-SER--SER-326 AND SER-358.
RX PubMed=18818105; DOI=10.1016/j.immuni.2008.09.003;
RA Zhong B., Yang Y., Li S., Wang Y.-Y., Li Y., Diao F., Lei C., He X.,
RA Zhang L., Tien P., Shu H.-B.;
RT "The adaptor protein MITA links virus-sensing receptors to IRF3
RT transcription factor activation.";
RL Immunity 29:538-550(2008).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ARG-232.
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15372022; DOI=10.1038/nature02919;
RA Schmutz J., Martin J., Terry A., Couronne O., Grimwood J., Lowry S.,
RA Gordon L.A., Scott D., Xie G., Huang W., Hellsten U., Tran-Gyamfi M.,
RA She X., Prabhakar S., Aerts A., Altherr M., Bajorek E., Black S.,
RA Branscomb E., Caoile C., Challacombe J.F., Chan Y.M., Denys M.,
RA Detter J.C., Escobar J., Flowers D., Fotopulos D., Glavina T.,
RA Gomez M., Gonzales E., Goodstein D., Grigoriev I., Groza M.,
RA Hammon N., Hawkins T., Haydu L., Israni S., Jett J., Kadner K.,
RA Kimball H., Kobayashi A., Lopez F., Lou Y., Martinez D., Medina C.,
RA Morgan J., Nandkeshwar R., Noonan J.P., Pitluck S., Pollard M.,
RA Predki P., Priest J., Ramirez L., Retterer J., Rodriguez A.,
RA Rogers S., Salamov A., Salazar A., Thayer N., Tice H., Tsai M.,
RA Ustaszewska A., Vo N., Wheeler J., Wu K., Yang J., Dickson M.,
RA Cheng J.-F., Eichler E.E., Olsen A., Pennacchio L.A., Rokhsar D.S.,
RA Richardson P., Lucas S.M., Myers R.M., Rubin E.M.;
RT "The DNA sequence and comparative analysis of human chromosome 5.";
RL Nature 431:268-274(2004).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Lung;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [5]
RP FUNCTION, SUBCELLULAR LOCATION, TISSUE SPECIFICITY, AND INTERACTION
RP WITH DDX58 AND SSR2.
RX PubMed=18724357; DOI=10.1038/nature07317;
RA Ishikawa H., Barber G.N.;
RT "STING is an endoplasmic reticulum adaptor that facilitates innate
RT immune signalling.";
RL Nature 455:674-678(2008).
RN [6]
RP UBIQUITINATION AT LYS-150, INTERACTION WITH RNF5, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF LYS-150.
RX PubMed=19285439; DOI=10.1016/j.immuni.2009.01.008;
RA Zhong B., Zhang L., Lei C., Li Y., Mao A.P., Yang Y., Wang Y.Y.,
RA Zhang X.L., Shu H.B.;
RT "The ubiquitin ligase RNF5 regulates antiviral responses by mediating
RT degradation of the adaptor protein MITA.";
RL Immunity 30:397-407(2009).
RN [7]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=19776740; DOI=10.1038/nature08476;
RA Ishikawa H., Ma Z., Barber G.N.;
RT "STING regulates intracellular DNA-mediated, type I interferon-
RT dependent innate immunity.";
RL Nature 461:788-792(2009).
RN [8]
RP INTERACTION WITH IFIT1; IFIT2; MAVS AND TBK1.
RX PubMed=19416887; DOI=10.1073/pnas.0900818106;
RA Li Y., Li C., Xue P., Zhong B., Mao A.P., Ran Y., Chen H., Wang Y.Y.,
RA Yang F., Shu H.B.;
RT "ISG56 is a negative-feedback regulator of virus-triggered signaling
RT and cellular antiviral response.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:7945-7950(2009).
RN [9]
RP FUNCTION, SUBCELLULAR LOCATION, HOMODIMERIZATION, PHOSPHORYLATION,
RP UBIQUITINATION, AND MUTAGENESIS OF 76-ARG--ARG-78 AND
RP 178-ARG--ARG-180.
RX PubMed=19433799; DOI=10.1073/pnas.0900850106;
RA Sun W., Li Y., Chen L., Chen H., You F., Zhou X., Zhou Y., Zhai Z.,
RA Chen D., Jiang Z.;
RT "ERIS, an endoplasmic reticulum IFN stimulator, activates innate
RT immune signaling through dimerization.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:8653-8658(2009).
RN [10]
RP FUNCTION, HOMODIMERIZATION, UBIQUITINATION AT LYS-150, AND MUTAGENESIS
RP OF LYS-20; LYS-137 AND LYS-150.
RX PubMed=21074459; DOI=10.1016/j.immuni.2010.10.013;
RA Tsuchida T., Zou J., Saitoh T., Kumar H., Abe T., Matsuura Y.,
RA Kawai T., Akira S.;
RT "The ubiquitin ligase TRIM56 regulates innate immune responses to
RT intracellular double-stranded DNA.";
RL Immunity 33:765-776(2010).
RN [11]
RP FUNCTION, AND C-DI-GMP-BINDING.
RX PubMed=21947006; DOI=10.1038/nature10429;
RA Burdette D.L., Monroe K.M., Sotelo-Troha K., Iwig J.S., Eckert B.,
RA Hyodo M., Hayakawa Y., Vance R.E.;
RT "STING is a direct innate immune sensor of cyclic di-GMP.";
RL Nature 478:515-518(2011).
RN [12]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=23027953; DOI=10.1073/pnas.1211302109;
RA Orzalli M.H., DeLuca N.A., Knipe D.M.;
RT "Nuclear IFI16 induction of IRF-3 signaling during herpesviral
RT infection and degradation of IFI16 by the viral ICP0 protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:E3008-E3017(2012).
RN [13]
RP FUNCTION.
RX PubMed=23707065; DOI=10.1016/j.celrep.2013.05.009;
RA Diner E.J., Burdette D.L., Wilson S.C., Monroe K.M.,
RA Kellenberger C.A., Hyodo M., Hayakawa Y., Hammond M.C., Vance R.E.;
RT "The innate immune DNA sensor cGAS produces a noncanonical cyclic
RT dinucleotide that activates human STING.";
RL Cell Rep. 3:1355-1361(2013).
RN [14]
RP FUNCTION.
RX PubMed=23722158; DOI=10.1038/nature12306;
RA Ablasser A., Goldeck M., Cavlar T., Deimling T., Witte G., Rohl I.,
RA Hopfner K.P., Ludwig J., Hornung V.;
RT "cGAS produces a 2'-5'-linked cyclic dinucleotide second messenger
RT that activates STING.";
RL Nature 498:380-384(2013).
RN [15]
RP FUNCTION.
RX PubMed=23258412; DOI=10.1126/science.1229963;
RA Wu J., Sun L., Chen X., Du F., Shi H., Chen C., Chen Z.J.;
RT "Cyclic GMP-AMP is an endogenous second messenger in innate immune
RT signaling by cytosolic DNA.";
RL Science 339:826-830(2013).
RN [16]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Liver;
RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014;
RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D.,
RA Wang L., Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human
RT liver phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [17]
RP TISSUE SPECIFICITY, AND VARIANTS SAVI LEU-147; SER-154 AND MET-155.
RX PubMed=25029335; DOI=10.1056/NEJMoa1312625;
RA Liu Y., Jesus A.A., Marrero B., Yang D., Ramsey S.E.,
RA Montealegre Sanchez G.A., Tenbrock K., Wittkowski H., Jones O.Y.,
RA Kuehn H.S., Lee C.C., DiMattia M.A., Cowen E.W., Gonzalez B.,
RA Palmer I., DiGiovanna J.J., Biancotto A., Kim H., Tsai W.L.,
RA Trier A.M., Huang Y., Stone D.L., Hill S., Kim H.J., St Hilaire C.,
RA Gurprasad S., Plass N., Chapelle D., Horkayne-Szakaly I., Foell D.,
RA Barysenka A., Candotti F., Holland S.M., Hughes J.D., Mehmet H.,
RA Issekutz A.C., Raffeld M., McElwee J., Fontana J.R., Minniti C.P.,
RA Moir S., Kastner D.L., Gadina M., Steven A.C., Wingfield P.T.,
RA Brooks S.R., Rosenzweig S.D., Fleisher T.A., Deng Z., Boehm M.,
RA Paller A.S., Goldbach-Mansky R.;
RT "Activated STING in a vascular and pulmonary syndrome.";
RL N. Engl. J. Med. 371:507-518(2014).
RN [18]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M.,
RA Ayoub D., Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [19]
RP FUNCTION, MUTAGENESIS OF SER-162, 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).
RN [20]
RP CHARACTERIZATION OF VARIANT ARG-232, AND FUNCTION.
RX PubMed=26300263; DOI=10.1016/j.molcel.2015.07.022;
RA Kranzusch P.J., Wilson S.C., Lee A.S., Berger J.M., Doudna J.A.,
RA Vance R.E.;
RT "Ancient origin of cGAS-STING reveals mechanism of universal 2',3'
RT cGAMP signaling.";
RL Mol. Cell 59:891-903(2015).
RN [21]
RP FUNCTION.
RX PubMed=26229117; DOI=10.1126/science.aab3632;
RA Bridgeman A., Maelfait J., Davenne T., Partridge T., Peng Y.,
RA Mayer A., Dong T., Kaever V., Borrow P., Rehwinkel J.;
RT "Viruses transfer the antiviral second messenger cGAMP between
RT cells.";
RL Science 349:1228-1232(2015).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (2.15 ANGSTROMS) OF 139-379, SUBUNIT, AND
RP C-DI-GMP-BINDING.
RX PubMed=22579474; DOI=10.1016/j.immuni.2012.03.019;
RA Ouyang S., Song X., Wang Y., Ru H., Shaw N., Jiang Y., Niu F., Zhu Y.,
RA Qiu W., Parvatiyar K., Li Y., Zhang R., Cheng G., Liu Z.J.;
RT "Structural analysis of the STING adaptor protein reveals a
RT hydrophobic dimer interface and mode of cyclic di-GMP binding.";
RL Immunity 36:1073-1086(2012).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (2.75 ANGSTROMS) OF 139-379, SUBUNIT, AND
RP C-DI-GMP-BINDING.
RX PubMed=22705373; DOI=10.1016/j.molcel.2012.05.029;
RA Yin Q., Tian Y., Kabaleeswaran V., Jiang X., Tu D., Eck M.J.,
RA Chen Z.J., Wu H.;
RT "Cyclic di-GMP sensing via the innate immune signaling protein
RT STING.";
RL Mol. Cell 46:735-745(2012).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (1.5 ANGSTROMS) OF 155-341, SUBUNIT,
RP C-DI-GMP-BINDING, AND MUTAGENESIS OF SER-162; GLY-166; TYR-240;
RP ASN-242; GLU-260; THR-263; PRO-264 AND THR-267.
RX PubMed=22728658; DOI=10.1038/nsmb.2331;
RA Shu C., Yi G., Watts T., Kao C.C., Li P.;
RT "Structure of STING bound to cyclic di-GMP reveals the mechanism of
RT cyclic dinucleotide recognition by the immune system.";
RL Nat. Struct. Mol. Biol. 19:722-724(2012).
RN [25]
RP X-RAY CRYSTALLOGRAPHY (2.2 ANGSTROMS) OF 149-379, SUBUNIT, AND
RP C-DI-GMP-BINDING.
RX PubMed=22728660; DOI=10.1038/nsmb.2332;
RA Shang G., Zhu D., Li N., Zhang J., Zhu C., Lu D., Liu C., Yu Q.,
RA Zhao Y., Xu S., Gu L.;
RT "Crystal structures of STING protein reveal basis for recognition of
RT cyclic di-GMP.";
RL Nat. Struct. Mol. Biol. 19:725-727(2012).
RN [26]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 141-379, SUBUNIT, AND
RP C-DI-GMP-BINDING.
RX PubMed=22728659; DOI=10.1038/nsmb.2333;
RA Huang Y.H., Liu X.Y., Du X.X., Jiang Z.F., Su X.D.;
RT "The structural basis for the sensing and binding of cyclic di-GMP by
RT STING.";
RL Nat. Struct. Mol. Biol. 19:728-730(2012).
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. May be involved in translocon
CC function, the translocon possibly being able to influence the
CC induction of type I interferons. May be involved in transduction
CC of apoptotic signals via its association with the major
CC histocompatibility complex class II (MHC-II). Mediates death
CC signaling via activation of the extracellular signal-regulated
CC kinase (ERK) pathway. Essential for the induction of IFN-beta in
CC response to human herpes simplex virus 1 (HHV-1) infection.
CC Exhibits 2',3' phosphodiester linkage-specific ligand recognition.
CC Can bind both 2'-3' linked cGAMP and 3'-3' linked cGAMP but is
CC preferentially activated by 2'-3' linked cGAMP (PubMed:26300263).
CC {ECO:0000269|PubMed:18724357, ECO:0000269|PubMed:18818105,
CC ECO:0000269|PubMed:19433799, ECO:0000269|PubMed:19776740,
CC ECO:0000269|PubMed:21074459, ECO:0000269|PubMed:21947006,
CC ECO:0000269|PubMed:23027953, ECO:0000269|PubMed:23258412,
CC ECO:0000269|PubMed:23707065, ECO:0000269|PubMed:23722158,
CC ECO:0000269|PubMed:26229117, ECO:0000269|PubMed:26300263,
CC ECO:0000269|PubMed:26669264}.
CC -!- SUBUNIT: Associates with the MHC-II complex (By similarity).
CC Homodimer; 'Lys-63'-linked ubiquitination at Lys-150 is required
CC for homodimerization. Interacts with DDX58/RIG-I, MAVS and SSR2.
CC Interacts with RNF5 and TRIM56. Interacts with TBK1; when
CC homodimer, leading to subsequent production of IFN-beta. Interacts
CC with IFIT1 and IFIT2. {ECO:0000250, ECO:0000269|PubMed:18724357,
CC ECO:0000269|PubMed:18818105, ECO:0000269|PubMed:19285439,
CC ECO:0000269|PubMed:19416887, ECO:0000269|PubMed:22579474,
CC ECO:0000269|PubMed:22705373, ECO:0000269|PubMed:22728658,
CC ECO:0000269|PubMed:22728659, ECO:0000269|PubMed:22728660}.
CC -!- INTERACTION:
CC Self; NbExp=2; IntAct=EBI-2800345, EBI-2800345;
CC P27958:- (xeno); NbExp=5; IntAct=EBI-2800345, EBI-8763498;
CC Q99IB8:- (xeno); NbExp=5; IntAct=EBI-2800345, EBI-6928570;
CC Q96A33:CCDC47; NbExp=2; IntAct=EBI-2800345, EBI-720151;
CC P39656:DDOST; NbExp=2; IntAct=EBI-2800345, EBI-358866;
CC Q16666:IFI16; NbExp=2; IntAct=EBI-2800345, EBI-2867186;
CC P51617:IRAK1; NbExp=2; IntAct=EBI-2800345, EBI-358664;
CC O94822:LTN1; NbExp=2; IntAct=EBI-2800345, EBI-1044684;
CC Q7Z434:MAVS; NbExp=7; IntAct=EBI-2800345, EBI-995373;
CC Q96N66:MBOAT7; NbExp=2; IntAct=EBI-2800345, EBI-6116499;
CC O95470:SGPL1; NbExp=2; IntAct=EBI-2800345, EBI-1046170;
CC P42226:STAT6; NbExp=12; IntAct=EBI-2800345, EBI-1186478;
CC P46977:STT3A; NbExp=2; IntAct=EBI-2800345, EBI-719212;
CC O15260:SURF4; NbExp=2; IntAct=EBI-2800345, EBI-1044848;
CC Q9UHD2:TBK1; NbExp=3; IntAct=EBI-2800345, EBI-356402;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:18724357, ECO:0000269|PubMed:19285439,
CC ECO:0000269|PubMed:19433799, ECO:0000269|PubMed:19776740}; Multi-
CC pass membrane protein {ECO:0000255}. Mitochondrion outer membrane
CC {ECO:0000269|PubMed:18724357, ECO:0000269|PubMed:19285439,
CC ECO:0000269|PubMed:19433799, ECO:0000269|PubMed:19776740}; Multi-
CC pass membrane protein {ECO:0000255}. Cell membrane
CC {ECO:0000250|UniProtKB:Q3TBT3}; Multi-pass membrane protein
CC {ECO:0000255}. Cytoplasm, perinuclear region
CC {ECO:0000269|PubMed:19433799}. Cytoplasm
CC {ECO:0000269|PubMed:23027953}. Note=In response to double-stranded
CC DNA stimulation, relocalizes to perinuclear region, where the
CC kinase TBK1 is recruited.
CC -!- TISSUE SPECIFICITY: Ubiquitously expressed. Expressed in skin
CC endothelial cells, alveolar type 2 pneumocytes, bronchial
CC epithelium and alveolar macrophages. {ECO:0000269|PubMed:18724357,
CC ECO:0000269|PubMed:18818105, ECO:0000269|PubMed:25029335}.
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
CC (PubMed:22579474, PubMed:22705373, PubMed:22728658,
CC PubMed:22728660 and PubMed:22728659).
CC -!- PTM: Phosphorylated on tyrosine residues upon MHC-II aggregation
CC (By similarity). Phosphorylated on Ser-358 by TBK1, leading to
CC activation and production of IFN-beta. {ECO:0000250,
CC ECO:0000269|PubMed:18818105, ECO:0000269|PubMed:19433799}.
CC -!- PTM: Ubiquitinated. 'Lys-63'-linked ubiquitination mediated by
CC TRIM56 at Lys-150 promotes homodimerization and recruitment of the
CC antiviral kinase TBK1 and subsequent production of IFN-beta. 'Lys-
CC 48'-linked polyubiquitination at Lys-150 occurring after viral
CC infection is mediated by RNF5 and leads to proteasomal
CC degradation. {ECO:0000269|PubMed:19285439,
CC ECO:0000269|PubMed:19433799, ECO:0000269|PubMed:21074459}.
CC -!- DISEASE: STING-associated vasculopathy, infantile-onset (SAVI)
CC [MIM:615934]: An autoinflammatory disease characterized by early-
CC onset systemic inflammation and cutaneous vasculopathy, resulting
CC in severe skin lesions. Violaceous, scaling lesions of fingers,
CC toes, nose, cheeks and ears progress to acral necrosis in most of
CC the patients. Some patients have severe interstitial lung disease.
CC {ECO:0000269|PubMed:25029335}. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
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}.
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; FJ222241; ACI46648.1; -; mRNA.
DR EMBL; AK290661; BAF83350.1; -; mRNA.
DR EMBL; AC138517; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC047779; AAH47779.1; -; mRNA.
DR CCDS; CCDS4215.1; -.
DR RefSeq; NP_938023.1; NM_198282.3.
DR UniGene; Hs.379754; -.
DR PDB; 4EF4; X-ray; 2.15 A; A/B=139-379.
DR PDB; 4EF5; X-ray; 2.45 A; A=139-379.
DR PDB; 4EMT; X-ray; 1.50 A; A/B=155-341.
DR PDB; 4EMU; X-ray; 1.90 A; A/B=155-341.
DR PDB; 4F5D; X-ray; 3.00 A; A/B=141-379.
DR PDB; 4F5E; X-ray; 2.60 A; A=141-379.
DR PDB; 4F5W; X-ray; 2.20 A; A=149-379.
DR PDB; 4F5Y; X-ray; 2.40 A; A/B=149-379.
DR PDB; 4F9E; X-ray; 2.75 A; A=139-379.
DR PDB; 4F9G; X-ray; 2.95 A; A/C=139-379.
DR PDB; 4KSY; X-ray; 1.88 A; A=138-379.
DR PDB; 4LOH; X-ray; 2.25 A; A/B=155-341.
DR PDB; 4LOI; X-ray; 1.89 A; A/B=155-341.
DR PDB; 4QXO; X-ray; 1.88 A; A=155-341.
DR PDB; 4QXP; X-ray; 2.51 A; A/B=155-341.
DR PDB; 4QXQ; X-ray; 2.42 A; A/B=155-341.
DR PDB; 4QXR; X-ray; 2.37 A; A/B=155-341.
DR PDB; 5BQX; X-ray; 2.00 A; A=138-379.
DR PDB; 5JEJ; X-ray; 2.00 A; C/D/E=342-377.
DR PDBsum; 4EF4; -.
DR PDBsum; 4EF5; -.
DR PDBsum; 4EMT; -.
DR PDBsum; 4EMU; -.
DR PDBsum; 4F5D; -.
DR PDBsum; 4F5E; -.
DR PDBsum; 4F5W; -.
DR PDBsum; 4F5Y; -.
DR PDBsum; 4F9E; -.
DR PDBsum; 4F9G; -.
DR PDBsum; 4KSY; -.
DR PDBsum; 4LOH; -.
DR PDBsum; 4LOI; -.
DR PDBsum; 4QXO; -.
DR PDBsum; 4QXP; -.
DR PDBsum; 4QXQ; -.
DR PDBsum; 4QXR; -.
DR PDBsum; 5BQX; -.
DR PDBsum; 5JEJ; -.
DR ProteinModelPortal; Q86WV6; -.
DR SMR; Q86WV6; -.
DR BioGrid; 130988; 33.
DR DIP; DIP-48847N; -.
DR IntAct; Q86WV6; 29.
DR STRING; 9606.ENSP00000331288; -.
DR GuidetoPHARMACOLOGY; 2902; -.
DR iPTMnet; Q86WV6; -.
DR PhosphoSitePlus; Q86WV6; -.
DR SwissPalm; Q86WV6; -.
DR BioMuta; TMEM173; -.
DR DMDM; 74727720; -.
DR EPD; Q86WV6; -.
DR MaxQB; Q86WV6; -.
DR PaxDb; Q86WV6; -.
DR PeptideAtlas; Q86WV6; -.
DR PRIDE; Q86WV6; -.
DR DNASU; 340061; -.
DR Ensembl; ENST00000330794; ENSP00000331288; ENSG00000184584.
DR GeneID; 340061; -.
DR KEGG; hsa:340061; -.
DR UCSC; uc003lep.4; human.
DR CTD; 340061; -.
DR DisGeNET; 340061; -.
DR GeneCards; TMEM173; -.
DR HGNC; HGNC:27962; TMEM173.
DR HPA; HPA038116; -.
DR HPA; HPA038534; -.
DR MalaCards; TMEM173; -.
DR MIM; 612374; gene.
DR MIM; 615934; phenotype.
DR neXtProt; NX_Q86WV6; -.
DR OpenTargets; ENSG00000184584; -.
DR PharmGKB; PA162405934; -.
DR eggNOG; ENOG410IH2R; Eukaryota.
DR eggNOG; ENOG4111M85; LUCA.
DR GeneTree; ENSGT00390000008582; -.
DR HOGENOM; HOG000076316; -.
DR HOVERGEN; HBG094065; -.
DR InParanoid; Q86WV6; -.
DR KO; K12654; -.
DR OMA; TWMLALL; -.
DR OrthoDB; EOG091G08B2; -.
DR PhylomeDB; Q86WV6; -.
DR TreeFam; TF324444; -.
DR Reactome; R-HSA-1834941; STING mediated induction of host immune responses.
DR Reactome; R-HSA-3134975; Regulation of innate immune responses to cytosolic DNA.
DR Reactome; R-HSA-3249367; STAT6-mediated induction of chemokines.
DR Reactome; R-HSA-3270619; IRF3-mediated induction of type I IFN.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR ChiTaRS; TMEM173; human.
DR GenomeRNAi; 340061; -.
DR PRO; PR:Q86WV6; -.
DR Proteomes; UP000005640; Chromosome 5.
DR Bgee; ENSG00000184584; -.
DR CleanEx; HS_TMEM173; -.
DR ExpressionAtlas; Q86WV6; baseline and differential.
DR Genevisible; Q86WV6; HS.
DR GO; GO:0030659; C:cytoplasmic vesicle membrane; TAS:Reactome.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:UniProtKB.
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; IDA:BHF-UCL.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:UniProtKB.
DR GO; GO:0005777; C:peroxisome; IEA:Ensembl.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0030667; C:secretory granule membrane; TAS:Reactome.
DR GO; GO:0035438; F:cyclic-di-GMP binding; IDA:UniProtKB.
DR GO; GO:0061507; F:cyclic-GMP-AMP binding; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR GO; GO:0019901; F:protein kinase binding; IDA:BHF-UCL.
DR GO; GO:0008134; F:transcription factor binding; IDA:BHF-UCL.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IEA:Ensembl.
DR GO; GO:0002218; P:activation of innate immune response; IMP:BHF-UCL.
DR GO; GO:0006915; P:apoptotic process; IEA:UniProtKB-KW.
DR GO; GO:0071360; P:cellular response to exogenous dsRNA; IMP:BHF-UCL.
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; IDA:UniProtKB.
DR GO; GO:0045087; P:innate immune response; IDA:UniProtKB.
DR GO; GO:0032608; P:interferon-beta production; IDA:UniProtKB.
DR GO; GO:0043312; P:neutrophil degranulation; TAS:Reactome.
DR GO; GO:0002230; P:positive regulation of defense response to virus by host; IMP:BHF-UCL.
DR GO; GO:0032092; P:positive regulation of protein binding; IDA:BHF-UCL.
DR GO; GO:0033160; P:positive regulation of protein import into nucleus, translocation; IDA:BHF-UCL.
DR GO; GO:0042993; P:positive regulation of transcription factor import into nucleus; IDA:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IDA:BHF-UCL.
DR GO; GO:0032481; P:positive regulation of type I interferon production; IDA:UniProtKB.
DR GO; GO:0032479; P:regulation of type I interferon production; TAS:Reactome.
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 3D-structure; Apoptosis; Cell membrane; Complete proteome; Cytoplasm;
KW Disease mutation; Endoplasmic reticulum; Immunity; Innate immunity;
KW Isopeptide bond; Membrane; Mitochondrion;
KW Mitochondrion outer membrane; Nucleotide-binding; Phosphoprotein;
KW Polymorphism; Reference proteome; Transmembrane; Transmembrane helix;
KW Ubl conjugation.
FT CHAIN 1 379 Stimulator of interferon genes protein.
FT /FTId=PRO_0000271116.
FT TOPO_DOM 1 20 Cytoplasmic. {ECO:0000255}.
FT TRANSMEM 21 41 Helical; Name=1. {ECO:0000255}.
FT TOPO_DOM 42 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 REGION 162 167 c-di-GMP binding.
FT REGION 238 241 c-di-GMP binding.
FT REGION 340 379 C-terminal tail (CTT).
FT BINDING 263 263 c-di-GMP.
FT MOD_RES 358 358 Phosphoserine; by TBK1.
FT {ECO:0000269|PubMed:18818105}.
FT CROSSLNK 150 150 Glycyl lysine isopeptide (Lys-Gly)
FT (interchain with G-Cter in ubiquitin).
FT {ECO:0000269|PubMed:19285439,
FT ECO:0000269|PubMed:21074459}.
FT VARIANT 71 71 R -> H (in dbSNP:rs11554776).
FT /FTId=VAR_029863.
FT VARIANT 147 147 V -> L (in SAVI; dbSNP:rs587777611).
FT {ECO:0000269|PubMed:25029335}.
FT /FTId=VAR_071878.
FT VARIANT 154 154 N -> S (in SAVI; dbSNP:rs587777609).
FT {ECO:0000269|PubMed:25029335}.
FT /FTId=VAR_071879.
FT VARIANT 155 155 V -> M (in SAVI; dbSNP:rs587777610).
FT {ECO:0000269|PubMed:25029335}.
FT /FTId=VAR_071880.
FT VARIANT 232 232 H -> R (activated by both 2'-3' linked
FT cGAMP and 3'-3' linked cGAMP;
FT dbSNP:rs1131769).
FT {ECO:0000269|PubMed:14702039,
FT ECO:0000269|PubMed:26300263}.
FT /FTId=VAR_029864.
FT VARIANT 293 293 R -> Q (in dbSNP:rs7380824).
FT /FTId=VAR_029865.
FT MUTAGEN 20 20 K->R: Does not affect amount of
FT ubiquitination.
FT {ECO:0000269|PubMed:21074459}.
FT MUTAGEN 76 78 RYR->AYA: Abolishes the endoplasmic
FT reticulum location.
FT {ECO:0000269|PubMed:19433799}.
FT MUTAGEN 137 137 K->R: Does not affect amount of
FT ubiquitination.
FT {ECO:0000269|PubMed:21074459}.
FT MUTAGEN 150 150 K->R: Abolishes ubiquitination,
FT homodimerization and subsequent
FT production of IFN-beta.
FT {ECO:0000269|PubMed:19285439,
FT ECO:0000269|PubMed:21074459}.
FT MUTAGEN 162 162 S->A: Slight decrease in c-di-GMP-
FT binding. Strongly increases response to
FT the synthetic compound 5,6-
FT dimethylxanthenone 4-acetic acid (DMXAA).
FT {ECO:0000269|PubMed:22728658,
FT ECO:0000269|PubMed:26669264}.
FT MUTAGEN 166 166 G->S: Slight decrease in c-di-GMP-
FT binding. {ECO:0000269|PubMed:22728658}.
FT MUTAGEN 178 180 RIR->AIA: Abolishes the endoplasmic
FT reticulum location.
FT {ECO:0000269|PubMed:19433799}.
FT MUTAGEN 240 240 Y->S: Strong decrease in c-di-GMP-
FT binding. {ECO:0000269|PubMed:22728658}.
FT MUTAGEN 242 242 N->A: Strong decrease in c-di-GMP-
FT binding. {ECO:0000269|PubMed:22728658}.
FT MUTAGEN 260 260 E->A: Strong decrease in c-di-GMP-
FT binding. {ECO:0000269|PubMed:22728658}.
FT MUTAGEN 263 263 T->A: Strong decrease in c-di-GMP-
FT binding. {ECO:0000269|PubMed:22728658}.
FT MUTAGEN 264 264 P->A: Strong decrease in c-di-GMP-
FT binding. {ECO:0000269|PubMed:22728658}.
FT MUTAGEN 267 267 T->A: Strong decrease in c-di-GMP-
FT binding. {ECO:0000269|PubMed:22728658}.
FT MUTAGEN 324 326 SLS->ALA: Induces a decrease in
FT phosphorylation by TBK1.
FT {ECO:0000269|PubMed:18818105}.
FT MUTAGEN 358 358 S->A: Induces a decrease in
FT phosphorylation by TBK1 and ability to
FT activate IRF-E.
FT {ECO:0000269|PubMed:18818105}.
FT CONFLICT 262 262 A -> T (in Ref. 2; BAF83350).
FT {ECO:0000305}.
FT CONFLICT 363 363 L -> F (in Ref. 2; BAF83350).
FT {ECO:0000305}.
FT HELIX 156 166 {ECO:0000244|PDB:4EMT}.
FT HELIX 168 185 {ECO:0000244|PDB:4EMT}.
FT TURN 186 189 {ECO:0000244|PDB:4EMT}.
FT STRAND 196 203 {ECO:0000244|PDB:4EMT}.
FT HELIX 212 215 {ECO:0000244|PDB:4EMT}.
FT STRAND 219 225 {ECO:0000244|PDB:4EMT}.
FT STRAND 228 230 {ECO:0000244|PDB:4QXO}.
FT STRAND 233 235 {ECO:0000244|PDB:4F5E}.
FT STRAND 237 240 {ECO:0000244|PDB:4QXO}.
FT STRAND 242 249 {ECO:0000244|PDB:4EMT}.
FT STRAND 252 261 {ECO:0000244|PDB:4EMT}.
FT HELIX 264 272 {ECO:0000244|PDB:4EMT}.
FT HELIX 275 277 {ECO:0000244|PDB:4EMT}.
FT HELIX 281 301 {ECO:0000244|PDB:4EMT}.
FT HELIX 303 306 {ECO:0000244|PDB:4EMT}.
FT STRAND 309 314 {ECO:0000244|PDB:4EMT}.
FT STRAND 318 320 {ECO:0000244|PDB:4QXP}.
FT HELIX 325 333 {ECO:0000244|PDB:4EMT}.
FT TURN 334 336 {ECO:0000244|PDB:4EMT}.
FT HELIX 372 374 {ECO:0000244|PDB:5JEJ}.
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; 42193 MW; CB54D6A4D4D8E7C0 CRC64;
MPHSSLHPSI PCPRGHGAQK AALVLLSACL VTLWGLGEPP EHTLRYLVLH LASLQLGLLL
NGVCSLAEEL RHIHSRYRGS YWRTVRACLG CPLRRGALLL LSIYFYYSLP NAVGPPFTWM
LALLGLSQAL NILLGLKGLA PAEISAVCEK GNFNVAHGLA WSYYIGYLRL ILPELQARIR
TYNQHYNNLL RGAVSQRLYI LLPLDCGVPD NLSMADPNIR FLDKLPQQTG DHAGIKDRVY
SNSIYELLEN GQRAGTCVLE YATPLQTLFA MSQYSQAGFS REDRLEQAKL FCRTLEDILA
DAPESQNNCR LIAYQEPADD SSFSLSQEVL RHLRQEEKEE VTVGSLKTSA VPSTSTMSQE
PELLISGMEK PLPLRTDFS
//
|
