ID TLR3_HUMAN Reviewed; 904 AA. AC O15455; B2RAI7; B7Z7K0; E6Y0F0; E6Y0F1; E9PGH4; Q4VAL2; Q504W0; DT 31-JAN-2002, integrated into UniProtKB/Swiss-Prot. DT 01-JAN-1998, sequence version 1. DT 27-MAR-2024, entry version 220. DE RecName: Full=Toll-like receptor 3 {ECO:0000305}; DE AltName: CD_antigen=CD283; DE Flags: Precursor; GN Name=TLR3 {ECO:0000312|HGNC:HGNC:11849}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; OC Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=9435236; DOI=10.1073/pnas.95.2.588; RA Rock F.L., Hardiman G., Timans J.C., Kastelein R.A., Bazan J.F.; RT "A family of human receptors structurally related to Drosophila Toll."; RL Proc. Natl. Acad. Sci. U.S.A. 95:588-593(1998). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY. RC TISSUE=Neuron; RX PubMed=17085778; DOI=10.1385/jmn:29:3:185; RA Lafon M., Megret F., Lafage M., Prehaud C.; RT "The innate immune facet of brain: human neurons express TLR-3 and sense RT viral dsRNA."; RL J. Mol. Neurosci. 29:185-194(2006). RN [3] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1). RX PubMed=18810425; DOI=10.1007/s00251-008-0332-0; RA Nakajima T., Ohtani H., Satta Y., Uno Y., Akari H., Ishida T., Kimura A.; RT "Natural selection in the TLR-related genes in the course of primate RT evolution."; RL Immunogenetics 60:727-735(2008). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT PHE-412. RA Macquin C., Bahram S.; RT "TLR polymorphism."; RL Submitted (JAN-2006) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT RP PHE-412. RC TISSUE=Testis, and Thymus; 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., Sudo H., RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., RA Aotsuka S., 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., Fujimori Y., RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., RA 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 [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., RA Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 and RT 4."; RL Nature 434:724-731(2005). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., RA Hunkapiller M.W., Myers E.W., Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). RC TISSUE=Placenta; 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 project: RT the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [9] RP PROTEIN SEQUENCE OF 24-38. RX PubMed=15340161; DOI=10.1110/ps.04682504; RA Zhang Z., Henzel W.J.; RT "Signal peptide prediction based on analysis of experimentally verified RT cleavage sites."; RL Protein Sci. 13:2819-2824(2004). RN [10] RP FUNCTION, AND INTERACTION WITH TICAM1. RX PubMed=12471095; DOI=10.4049/jimmunol.169.12.6668; RA Yamamoto M., Sato S., Mori K., Hoshino K., Takeuchi O., Takeda K., RA Akira S.; RT "A novel Toll/IL-1 receptor domain-containing adapter that preferentially RT activates the IFN-beta promoter in the Toll-like receptor signaling."; RL J. Immunol. 169:6668-6672(2002). RN [11] RP FUNCTION, AND INTERACTION WITH TICAM1. RC TISSUE=Lung; RX PubMed=12539043; DOI=10.1038/ni886; RA Oshiumi H., Matsumoto M., Funami K., Akazawa T., Seya T.; RT "TICAM-1, an adapter molecule that participates in Toll-like receptor 3 RT mediated interferon-beta induction."; RL Nat. Immunol. 4:161-167(2003). RN [12] RP FUNCTION, SUBUNIT, AND MUTAGENESIS OF CYS-95; CYS-122; ASN-196 AND ASN-247. RX PubMed=16144834; DOI=10.1074/jbc.m507163200; RA de Bouteiller O., Merck E., Hasan U.A., Hubac S., Benguigui B., RA Trinchieri G., Bates E.E., Caux C.; RT "Recognition of double-stranded RNA by human toll-like receptor 3 and RT downstream receptor signaling requires multimerization and an acidic pH."; RL J. Biol. Chem. 280:38133-38145(2005). RN [13] RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH SRC. RX PubMed=16858407; DOI=10.1038/sj.emboj.7601222; RA Johnsen I.B., Nguyen T.T., Ringdal M., Tryggestad A.M., Bakke O., Lien E., RA Espevik T., Anthonsen M.W.; RT "Toll-like receptor 3 associates with c-Src tyrosine kinase on endosomes to RT initiate antiviral signaling."; RL EMBO J. 25:3335-3346(2006). RN [14] RP FUNCTION, AND MUTAGENESIS OF HIS-539 AND ASN-541. RX PubMed=16720699; DOI=10.1073/pnas.0603245103; RA Bell J.K., Askins J., Hall P.R., Davies D.R., Segal D.M.; RT "The dsRNA binding site of human Toll-like receptor 3."; RL Proc. Natl. Acad. Sci. U.S.A. 103:8792-8797(2006). RN [15] RP PHOSPHORYLATION AT TYR-759 AND TYR-858, FUNCTION, AND MUTAGENESIS OF RP TYR-759. RX PubMed=17178723; DOI=10.1074/jbc.c600226200; RA Sarkar S.N., Elco C.P., Peters K.L., Chattopadhyay S., Sen G.C.; RT "Two tyrosine residues of Toll-like receptor 3 trigger different steps of RT NF-kappa B activation."; RL J. Biol. Chem. 282:3423-3427(2007). RN [16] RP FUNCTION, DOUBLE-STRANDED RNA-BINDING, AND HOMODIMERIZATION. RX PubMed=18172197; DOI=10.1073/pnas.0710779105; RA Leonard J.N., Ghirlando R., Askins J., Bell J.K., Margulies D.H., RA Davies D.R., Segal D.M.; RT "The TLR3 signaling complex forms by cooperative receptor dimerization."; RL Proc. Natl. Acad. Sci. U.S.A. 105:258-263(2008). RN [17] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-52 AND ASN-57. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [18] RP FUNCTION, PROTEOLYTIC PROCESSING, SUBCELLULAR LOCATION, AND INTERACTION RP WITH UNC93B1. RX PubMed=22611194; DOI=10.1073/pnas.1115091109; RA Garcia-Cattaneo A., Gobert F.X., Muller M., Toscano F., Flores M., RA Lescure A., Del Nery E., Benaroch P.; RT "Cleavage of Toll-like receptor 3 by cathepsins B and H is essential for RT signaling."; RL Proc. Natl. Acad. Sci. U.S.A. 109:9053-9058(2012). RN [19] RP INTERACTION WITH WDFY1 AND TICAM1, SUBCELLULAR LOCATION, AND MUTAGENESIS OF RP TYR-759 AND TYR-858. RX PubMed=25736436; DOI=10.15252/embr.201439637; RA Hu Y.H., Zhang Y., Jiang L.Q., Wang S., Lei C.Q., Sun M.S., Shu H.B., RA Liu Y.; RT "WDFY1 mediates TLR3/4 signaling by recruiting TRIF."; RL EMBO Rep. 16:447-455(2015). RN [20] RP UBIQUITINATION AT LYS-831 BY TRIM3, AND MUTAGENESIS OF LYS-831. RX PubMed=32878999; DOI=10.1073/pnas.2002472117; RA Li W.W., Nie Y., Yang Y., Ran Y., Luo W.W., Xiong M.G., Wang S.Y., Xu Z.S., RA Wang Y.Y.; RT "Ubiquitination of TLR3 by TRIM3 signals its ESCRT-mediated trafficking to RT the endolysosomes for innate antiviral response."; RL Proc. Natl. Acad. Sci. U.S.A. 117:23707-23716(2020). RN [21] RP FUNCTION, AND UBIQUITINATION BY RNF170. RX PubMed=31076723; DOI=10.1038/s41423-019-0236-y; RA Song X., Liu S., Wang W., Ma Z., Cao X., Jiang M.; RT "E3 ubiquitin ligase RNF170 inhibits innate immune responses by targeting RT and degrading TLR3 in murine cells."; RL Cell. Mol. Immunol. 17:865-874(2020). RN [22] RP UBIQUITINATION AT LYS-812, AND MUTAGENESIS OF LYS-812. RX PubMed=37158982; DOI=10.1084/jem.20220727; RA Lin Y.S., Chang Y.C., Chao T.L., Tsai Y.M., Jhuang S.J., Ho Y.H., Lai T.Y., RA Liu Y.L., Chen C.Y., Tsai C.Y., Hsueh Y.P., Chang S.Y., Chuang T.H., RA Lee C.Y., Hsu L.C.; RT "The Src-ZNRF1 axis controls TLR3 trafficking and interferon responses to RT limit lung barrier damage."; RL J. Exp. Med. 220:0-0(2023). RN [23] RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) OF 22-703, FUNCTION, DISULFIDE BONDS, RP SUBUNIT, GLYCOSYLATION AT ASN-52; ASN-70; ASN-196; ASN-252; ASN-265; RP ASN-275; ASN-291; ASN-398; ASN-413; ASN-507 AND ASN-636, AND IDENTIFICATION RP BY MASS SPECTROMETRY. RX PubMed=16043704; DOI=10.1073/pnas.0505077102; RA Bell J.K., Botos I., Hall P.R., Askins J., Shiloach J., Segal D.M., RA Davies D.R.; RT "The molecular structure of the Toll-like receptor 3 ligand-binding RT domain."; RL Proc. Natl. Acad. Sci. U.S.A. 102:10976-10980(2005). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 27-700, DISULFIDE BONDS, AND RP GLYCOSYLATION AT ASN-124; ASN-252; ASN-275; ASN-291; ASN-398; ASN-413 AND RP ASN-507. RX PubMed=15961631; DOI=10.1126/science.1115253; RA Choe J., Kelker M.S., Wilson I.A.; RT "Crystal structure of human toll-like receptor 3 (TLR3) ectodomain."; RL Science 309:581-585(2005). RN [25] RP X-RAY CRYSTALLOGRAPHY (3.52 ANGSTROMS) OF 22-702 IN COMPLEX WITH ANTIBODY, RP DISULFIDE BONDS, SUBUNIT, DS-RNA BINDING REGIONS, AND GLYCOSYLATION AT RP ASN-52; ASN-70; ASN-124; ASN-247; ASN-252; ASN-265; ASN-275; ASN-291; RP ASN-398; ASN-413 AND ASN-507. RX PubMed=22579623; DOI=10.1016/j.jmb.2012.05.006; RA Luo J., Obmolova G., Malia T.J., Wu S.J., Duffy K.E., Marion J.D., RA Bell J.K., Ge P., Zhou Z.H., Teplyakov A., Zhao Y., Lamb R.J., Jordan J.L., RA San Mateo L.R., Sweet R.W., Gilliland G.L.; RT "Lateral clustering of TLR3:dsRNA signaling units revealed by TLR3ecd:3Fabs RT quaternary structure."; RL J. Mol. Biol. 421:112-124(2012). RN [26] {ECO:0007744|PDB:7C76} RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS) IN COMPLEX WITH UNC93B1, RP AND INTERACTION WITH UNC93B1. RX PubMed=33432245; DOI=10.1038/s41594-020-00542-w; RA Ishida H., Asami J., Zhang Z., Nishizawa T., Shigematsu H., Ohto U., RA Shimizu T.; RT "Cryo-EM structures of Toll-like receptors in complex with UNC93B1."; RL Nat. Struct. Mol. Biol. 28:173-180(2021). RN [27] RP VARIANT IMD83 SER-554. RX PubMed=17872438; DOI=10.1126/science.1139522; RA Zhang S.-Y., Jouanguy E., Ugolini S., Smahi A., Elain G., Romero P., RA Segal D., Sancho-Shimizu V., Lorenzo L., Puel A., Picard C., Chapgier A., RA Plancoulaine S., Titeux M., Cognet C., von Bernuth H., Ku C.-L., RA Casrouge A., Zhang X.-X., Barreiro L., Leonard J., Hamilton C., Lebon P., RA Heron B., Vallee L., Quintana-Murci L., Hovnanian A., Rozenberg F., RA Vivier E., Geissmann F., Tardieu M., Abel L., Casanova J.-L.; RT "TLR3 deficiency in patients with herpes simplex encephalitis."; RL Science 317:1522-1527(2007). RN [28] RP VARIANT PHE-412. RX PubMed=18753640; DOI=10.1056/nejmoa0802437; RA Yang Z., Stratton C., Francis P.J., Kleinman M.E., Tan P.L., Gibbs D., RA Tong Z., Chen H., Constantine R., Yang X., Chen Y., Zeng J., Davey L., RA Ma X., Hau V.S., Wang C., Harmon J., Buehler J., Pearson E., Patel S., RA Kaminoh Y., Watkins S., Luo L., Zabriskie N.A., Bernstein P.S., Cho W., RA Schwager A., Hinton D.R., Klein M.L., Hamon S.C., Simmons E., Yu B., RA Campochiaro B., Sunness J.S., Campochiaro P., Jorde L., Parmigiani G., RA Zack D.J., Katsanis N., Ambati J., Zhang K.; RT "Toll-like receptor 3 and geographic atrophy in age-related macular RT degeneration."; RL N. Engl. J. Med. 359:1456-1463(2008). RN [29] RP ERRATUM OF PUBMED:18753640. RA Yang Z., Stratton C., Francis P.J., Kleinman M.E., Tan P.L., Gibbs D., RA Tong Z., Chen H., Constantine R., Yang X., Chen Y., Zeng J., Davey L., RA Ma X., Hau V.S., Wang C., Harmon J., Buehler J., Pearson E., Patel S., RA Kaminoh Y., Watkins S., Luo L., Zabriskie N.A., Bernstein P.S., Cho W., RA Schwager A., Hinton D.R., Klein M.L., Hamon S.C., Simmons E., Yu B., RA Campochiaro B., Sunness J.S., Campochiaro P., Jorde L., Parmigiani G., RA Zack D.J., Katsanis N., Ambati J., Zhang K.; RL N. Engl. J. Med. 359:1859-1859(2008). RN [30] RP VARIANT PHE-412. RX PubMed=22174453; DOI=10.4049/jimmunol.1102179; RA Sironi M., Biasin M., Cagliani R., Forni D., De Luca M., Saulle I., RA Lo Caputo S., Mazzotta F., Macias J., Pineda J.A., Caruz A., Clerici M.; RT "A common polymorphism in TLR3 confers natural resistance to HIV-1 RT infection."; RL J. Immunol. 188:818-823(2012). RN [31] RP VARIANTS PRO-134; GLY-251; SER-554; LEU-732; 746-GLU--HIS-904 DEL; RP 769-TRP--HIS-904 DEL; GLN-867 AND VAL-870, AND CHARACTERIZATION OF VARIANTS RP PRO-134; GLY-251; SER-554; LEU-732; 746-GLU--HIS-904 DEL; 769-TRP--HIS-904 RP DEL; GLN-867 AND VAL-870. RX PubMed=32972995; DOI=10.1126/science.abd4570; RG COVID-STORM Clinicians; RG COVID Clinicians; RG Imagine COVID Group; RG French COVID Cohort Study Group; RG CoV-Contact Cohort; RG Amsterdam UMC Covid-19 Biobank; RG COVID Human Genetic Effort; RG NIAID-USUHS/TAGC COVID Immunity Group; RA Zhang Q., Bastard P., Liu Z., Le Pen J., Moncada-Velez M., Chen J., RA Ogishi M., Sabli I.K.D., Hodeib S., Korol C., Rosain J., Bilguvar K., RA Ye J., Bolze A., Bigio B., Yang R., Arias A.A., Zhou Q., Zhang Y., RA Onodi F., Korniotis S., Karpf L., Philippot Q., Chbihi M., Bonnet-Madin L., RA Dorgham K., Smith N., Schneider W.M., Razooky B.S., Hoffmann H.H., RA Michailidis E., Moens L., Han J.E., Lorenzo L., Bizien L., Meade P., RA Neehus A.L., Ugurbil A.C., Corneau A., Kerner G., Zhang P., Rapaport F., RA Seeleuthner Y., Manry J., Masson C., Schmitt Y., Schlueter A., Le Voyer T., RA Khan T., Li J., Fellay J., Roussel L., Shahrooei M., Alosaimi M.F., RA Mansouri D., Al-Saud H., Al-Mulla F., Almourfi F., Al-Muhsen S.Z., RA Alsohime F., Al Turki S., Hasanato R., van de Beek D., Biondi A., RA Bettini L.R., D'Angio' M., Bonfanti P., Imberti L., Sottini A., Paghera S., RA Quiros-Roldan E., Rossi C., Oler A.J., Tompkins M.F., Alba C., RA Vandernoot I., Goffard J.C., Smits G., Migeotte I., Haerynck F., RA Soler-Palacin P., Martin-Nalda A., Colobran R., Morange P.E., Keles S., RA Coelkesen F., Ozcelik T., Yasar K.K., Senoglu S., Karabela S.N., RA Rodriguez-Gallego C., Novelli G., Hraiech S., Tandjaoui-Lambiotte Y., RA Duval X., Laouenan C., Snow A.L., Dalgard C.L., Milner J.D., Vinh D.C., RA Mogensen T.H., Marr N., Spaan A.N., Boisson B., Boisson-Dupuis S., RA Bustamante J., Puel A., Ciancanelli M.J., Meyts I., Maniatis T., RA Soumelis V., Amara A., Nussenzweig M., Garcia-Sastre A., Krammer F., RA Pujol A., Duffy D., Lifton R.P., Zhang S.Y., Gorochov G., Beziat V., RA Jouanguy E., Sancho-Shimizu V., Rice C.M., Abel L., Notarangelo L.D., RA Cobat A., Su H.C., Casanova J.L.; RT "Inborn errors of type I IFN immunity in patients with life-threatening RT COVID-19."; RL Science 370:0-0(2020). CC -!- FUNCTION: Key component of innate and adaptive immunity. TLRs (Toll- CC like receptors) control host immune response against pathogens through CC recognition of molecular patterns specific to microorganisms. TLR3 is a CC nucleotide-sensing TLR which is activated by double-stranded RNA, a CC sign of viral infection. Acts via the adapter TRIF/TICAM1, leading to CC NF-kappa-B activation, IRF3 nuclear translocation, cytokine secretion CC and the inflammatory response. {ECO:0000269|PubMed:12471095, CC ECO:0000269|PubMed:12539043, ECO:0000269|PubMed:16043704, CC ECO:0000269|PubMed:16144834, ECO:0000269|PubMed:16720699, CC ECO:0000269|PubMed:16858407, ECO:0000269|PubMed:17178723, CC ECO:0000269|PubMed:18172197, ECO:0000269|PubMed:22611194}. CC -!- SUBUNIT: Monomer and homodimer; dimerization is triggered by ligand- CC binding, the signaling unit is composed of one ds-RNA of around 40 bp CC and two TLR3 molecules, and lateral clustering of signaling units along CC the length of the ds-RNA ligand is required for TLR3 signal CC transduction. Interacts (via transmembrane domain) with UNC93B1; the CC interaction is required for transport from the ER to the endosomes CC (PubMed:33432245). Interacts with SRC; upon binding of double-stranded CC RNA. Interacts with TICAM1 (via the TIR domain) in response to CC poly(I:C) and this interaction is enhanced in the presence of WDFY1 CC (PubMed:25736436). The tyrosine-phosphorylated form (via TIR domain) CC interacts with WDFY1 (via WD repeat 2) in response to poly(I:C) CC (PubMed:25736436). {ECO:0000269|PubMed:12471095, CC ECO:0000269|PubMed:12539043, ECO:0000269|PubMed:16043704, CC ECO:0000269|PubMed:16144834, ECO:0000269|PubMed:16858407, CC ECO:0000269|PubMed:22579623, ECO:0000269|PubMed:22611194, CC ECO:0000269|PubMed:25736436, ECO:0000269|PubMed:31076723, CC ECO:0000269|PubMed:33432245}. CC -!- INTERACTION: CC O15455; P27986: PIK3R1; NbExp=2; IntAct=EBI-6116630, EBI-79464; CC O15455; O15455: TLR3; NbExp=5; IntAct=EBI-6116630, EBI-6116630; CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane; Single-pass type CC I membrane protein. Endosome membrane. Early endosome CC {ECO:0000269|PubMed:25736436}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=O15455-1; Sequence=Displayed; CC Name=2; CC IsoId=O15455-2; Sequence=VSP_054188; CC -!- TISSUE SPECIFICITY: Expressed at high level in placenta and pancreas. CC Also detected in CD11c+ immature dendritic cells. Only expressed in CC dendritic cells and not in other leukocytes, including monocyte CC precursors. TLR3 is the TLR that is expressed most strongly in the CC brain, especially in astrocytes, glia, and neurons. CC {ECO:0000269|PubMed:17085778}. CC -!- DOMAIN: ds-RNA binding is mediated by LRR 1 to 3, and LRR 17 to 18. CC -!- PTM: Heavily N-glycosylated, except on that part of the surface of the CC ectodomain that is involved in ligand binding. CC {ECO:0000269|PubMed:15961631, ECO:0000269|PubMed:16043704, CC ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:22579623}. CC -!- PTM: TLR3 signaling requires a proteolytic cleavage mediated by CC cathepsins CTSB and CTSH, the cleavage occurs between amino acids 252 CC and 346. The cleaved form of TLR3 is the predominant form found in CC endosomes. {ECO:0000269|PubMed:22611194}. CC -!- PTM: Ubiquitinated by TRIM3; leading to recognition and sorting of CC polyubiquitinated TLR3 by the ESCRT complexes (PubMed:32878999). CC Ubiquitinated by ZNRF1 via 'Lys-63'-linked ubiquitin chains; leading to CC TLR3 lysosomal trafficking and degradation (PubMed:37158982). CC Ubiquitinated by RNF170 at Lys-765 via 'Lys-48'-linked ubiquitin CC chains; leading to TLR3 proteasomal degradation (PubMed:31076723). CC {ECO:0000269|PubMed:31076723, ECO:0000269|PubMed:32878999, CC ECO:0000269|PubMed:37158982}. CC -!- POLYMORPHISM: The Phe-412 allele (dbSNP:rs3775291) occurs with a CC frequency of 30% in populations with European and Asian ancestry, and CC confers some natural resistance to HIV-1 infection. CC -!- DISEASE: Immunodeficiency 83, susceptibility to viral infections CC (IMD83) [MIM:613002]: An immunologic disorder characterized by CC increased susceptibility to severe viral infections, including herpes CC simplex virus (HSV), varicella zoster virus (VZV), influenza A virus CC (IAV), hantavirus, and possibly respiratory syncytial virus (RSV). CC IMD83 clinical manifestations include acute infection-induced CC encephalitis and pneumonitis. The susceptibility to encephalitis or CC pneumonitis appears to result from impaired TLR3-dependent interferon CC production by nonhematopoietic cells that reside within the central CC nervous system or lung epithelial cells. IMD83 transmission pattern is CC consistent with autosomal dominant or autosomal recessive inheritance CC with incomplete penetrance. {ECO:0000269|PubMed:17872438}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the Toll-like receptor family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=TLR3base; Note=TLR3 mutation db; CC URL="http://structure.bmc.lu.se/idbase/TLR3base/"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; U88879; AAC34134.1; -; mRNA. DR EMBL; DQ445682; ABE01399.1; -; mRNA. DR EMBL; AB445631; BAG55028.1; -; mRNA. DR EMBL; DQ360814; ABC86908.1; -; Genomic_DNA. DR EMBL; DQ360815; ABC86909.1; -; Genomic_DNA. DR EMBL; DQ360816; ABC86910.1; -; Genomic_DNA. DR EMBL; AK302143; BAH13636.1; -; mRNA. DR EMBL; AK314208; BAG36884.1; -; mRNA. DR EMBL; AC104070; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; CH471056; EAX04628.1; -; Genomic_DNA. DR EMBL; BC094737; AAH94737.1; -; mRNA. DR EMBL; BC096333; AAH96333.1; -; mRNA. DR EMBL; BC096334; AAH96334.1; -; mRNA. DR EMBL; BC096335; AAH96335.1; -; mRNA. DR CCDS; CCDS3846.1; -. [O15455-1] DR RefSeq; NP_003256.1; NM_003265.2. [O15455-1] DR RefSeq; XP_016864066.1; XM_017008577.1. DR PDB; 1ZIW; X-ray; 2.10 A; A=27-700. DR PDB; 2A0Z; X-ray; 2.40 A; A=22-703. DR PDB; 2MK9; NMR; -; A/B=698-730. DR PDB; 2MKA; NMR; -; A/B/C=698-730. DR PDB; 3ULU; X-ray; 3.52 A; A=22-702. DR PDB; 3ULV; X-ray; 3.52 A; A=22-702. DR PDB; 5GS0; X-ray; 3.27 A; A/B=27-697. DR PDB; 7C76; EM; 3.40 A; A=1-904. DR PDB; 7WV3; EM; 2.26 A; A/B/C/D=24-904. DR PDB; 7WV4; EM; 3.35 A; A/B/C/D=27-697. DR PDB; 7WV5; EM; 3.10 A; A/B=27-697. DR PDB; 7WVE; EM; 3.11 A; A/B=27-697. DR PDB; 7WVF; EM; 3.91 A; A/B=27-697. DR PDB; 7WVJ; EM; 3.26 A; A/B=27-697. DR PDB; 8AR1; NMR; -; A=698-746. DR PDBsum; 1ZIW; -. DR PDBsum; 2A0Z; -. DR PDBsum; 2MK9; -. DR PDBsum; 2MKA; -. DR PDBsum; 3ULU; -. DR PDBsum; 3ULV; -. DR PDBsum; 5GS0; -. DR PDBsum; 7C76; -. DR PDBsum; 7WV3; -. DR PDBsum; 7WV4; -. DR PDBsum; 7WV5; -. DR PDBsum; 7WVE; -. DR PDBsum; 7WVF; -. DR PDBsum; 7WVJ; -. DR PDBsum; 8AR1; -. DR AlphaFoldDB; O15455; -. DR BMRB; O15455; -. DR EMDB; EMD-30293; -. DR EMDB; EMD-32844; -. DR EMDB; EMD-32845; -. DR EMDB; EMD-32846; -. DR EMDB; EMD-32851; -. DR EMDB; EMD-32852; -. DR EMDB; EMD-32853; -. DR SMR; O15455; -. DR BioGRID; 112953; 47. DR DIP; DIP-29660N; -. DR IntAct; O15455; 15. DR MINT; O15455; -. DR STRING; 9606.ENSP00000296795; -. DR BindingDB; O15455; -. DR ChEMBL; CHEMBL1075113; -. DR TCDB; 8.A.43.1.35; the neat-domain containing methaemoglobin heme sequestration (n-mhs) family. DR GlyCosmos; O15455; 15 sites, No reported glycans. DR GlyGen; O15455; 17 sites, 1 O-linked glycan (1 site). DR iPTMnet; O15455; -. DR PhosphoSitePlus; O15455; -. DR BioMuta; TLR3; -. DR EPD; O15455; -. DR jPOST; O15455; -. DR MassIVE; O15455; -. DR MaxQB; O15455; -. DR PaxDb; 9606-ENSP00000296795; -. DR PeptideAtlas; O15455; -. DR ProteomicsDB; 20320; -. DR ProteomicsDB; 48678; -. [O15455-1] DR Pumba; O15455; -. DR ABCD; O15455; 13 sequenced antibodies. DR Antibodypedia; 17502; 1231 antibodies from 48 providers. DR DNASU; 7098; -. DR Ensembl; ENST00000296795.8; ENSP00000296795.3; ENSG00000164342.14. [O15455-1] DR Ensembl; ENST00000504367.1; ENSP00000423684.1; ENSG00000164342.14. [O15455-2] DR Ensembl; ENST00000508051.2; ENSP00000513677.1; ENSG00000164342.14. [O15455-2] DR Ensembl; ENST00000512264.1; ENSP00000513668.1; ENSG00000164342.14. [O15455-2] DR Ensembl; ENST00000698354.1; ENSP00000513676.1; ENSG00000164342.14. [O15455-2] DR GeneID; 7098; -. DR KEGG; hsa:7098; -. DR MANE-Select; ENST00000296795.8; ENSP00000296795.3; NM_003265.3; NP_003256.1. DR UCSC; uc003iyq.4; human. [O15455-1] DR AGR; HGNC:11849; -. DR CTD; 7098; -. DR DisGeNET; 7098; -. DR GeneCards; TLR3; -. DR HGNC; HGNC:11849; TLR3. DR HPA; ENSG00000164342; Low tissue specificity. DR MalaCards; TLR3; -. DR MIM; 603029; gene. DR MIM; 613002; phenotype. DR neXtProt; NX_O15455; -. DR OpenTargets; ENSG00000164342; -. DR Orphanet; 1930; Herpes simplex virus encephalitis. DR PharmGKB; PA36551; -. DR VEuPathDB; HostDB:ENSG00000164342; -. DR eggNOG; KOG4641; Eukaryota. DR GeneTree; ENSGT00940000159678; -. DR HOGENOM; CLU_006000_4_1_1; -. DR InParanoid; O15455; -. DR OMA; PYIYFWG; -. DR OrthoDB; 3428126at2759; -. DR PhylomeDB; O15455; -. DR TreeFam; TF325595; -. DR PathwayCommons; O15455; -. DR Reactome; R-HSA-1679131; Trafficking and processing of endosomal TLR. DR Reactome; R-HSA-168164; Toll Like Receptor 3 (TLR3) Cascade. DR Reactome; R-HSA-168927; TICAM1, RIP1-mediated IKK complex recruitment. DR Reactome; R-HSA-1810476; RIP-mediated NFkB activation via ZBP1. DR Reactome; R-HSA-5602410; TLR3 deficiency - HSE. DR Reactome; R-HSA-5602415; UNC93B1 deficiency - HSE. DR Reactome; R-HSA-5602566; TICAM1 deficiency - HSE. DR Reactome; R-HSA-5602571; TRAF3 deficiency - HSE. DR Reactome; R-HSA-9013957; TLR3-mediated TICAM1-dependent programmed cell death. DR Reactome; R-HSA-9013973; TICAM1-dependent activation of IRF3/IRF7. DR Reactome; R-HSA-9014325; TICAM1,TRAF6-dependent induction of TAK1 complex. DR SignaLink; O15455; -. DR SIGNOR; O15455; -. DR BioGRID-ORCS; 7098; 12 hits in 1155 CRISPR screens. DR ChiTaRS; TLR3; human. DR EvolutionaryTrace; O15455; -. DR GeneWiki; TLR_3; -. DR GenomeRNAi; 7098; -. DR Pharos; O15455; Tbio. DR PRO; PR:O15455; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; O15455; Protein. DR Bgee; ENSG00000164342; Expressed in jejunal mucosa and 169 other cell types or tissues. DR ExpressionAtlas; O15455; baseline and differential. DR GO; GO:0005737; C:cytoplasm; IDA:BHF-UCL. DR GO; GO:0005769; C:early endosome; IDA:UniProt. DR GO; GO:0036020; C:endolysosome membrane; TAS:Reactome. DR GO; GO:0005789; C:endoplasmic reticulum membrane; TAS:Reactome. DR GO; GO:0010008; C:endosome membrane; ISS:UniProt. DR GO; GO:0031012; C:extracellular matrix; IBA:GO_Central. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0000139; C:Golgi membrane; TAS:Reactome. DR GO; GO:0005765; C:lysosomal membrane; HDA:UniProtKB. DR GO; GO:0016020; C:membrane; NAS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; TAS:ProtInc. DR GO; GO:0003725; F:double-stranded RNA binding; IDA:UniProtKB. DR GO; GO:0042802; F:identical protein binding; IPI:IntAct. DR GO; GO:0038187; F:pattern recognition receptor activity; IDA:BHF-UCL. DR GO; GO:0038023; F:signaling receptor activity; TAS:ProtInc. DR GO; GO:0004888; F:transmembrane signaling receptor activity; NAS:UniProtKB. DR GO; GO:0007250; P:activation of NF-kappaB-inducing kinase activity; NAS:UniProtKB. 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:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB. DR GO; GO:0071346; P:cellular response to type II interferon; IEA:Ensembl. DR GO; GO:0098586; P:cellular response to virus; IEA:Ensembl. DR GO; GO:0071466; P:cellular response to xenobiotic stimulus; IEA:Ensembl. DR GO; GO:0042742; P:defense response to bacterium; TAS:ProtInc. DR GO; GO:0051607; P:defense response to virus; IEP:ARUK-UCL. DR GO; GO:0009597; P:detection of virus; NAS:UniProtKB. DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:UniProtKB. DR GO; GO:0006972; P:hyperosmotic response; NAS:UniProtKB. DR GO; GO:0007252; P:I-kappaB phosphorylation; IDA:BHF-UCL. DR GO; GO:0090594; P:inflammatory response to wounding; IDA:UniProt. DR GO; GO:0045087; P:innate immune response; TAS:BHF-UCL. DR GO; GO:0007254; P:JNK cascade; IEA:Ensembl. DR GO; GO:0008584; P:male gonad development; IEA:Ensembl. DR GO; GO:0001774; P:microglial cell activation; IEA:Ensembl. DR GO; GO:0097527; P:necroptotic signaling pathway; IDA:UniProtKB. DR GO; GO:0045671; P:negative regulation of osteoclast differentiation; NAS:UniProtKB. DR GO; GO:0045766; P:positive regulation of angiogenesis; IEA:Ensembl. DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl. DR GO; GO:0043123; P:positive regulation of canonical NF-kappaB signal transduction; IEA:Ensembl. DR GO; GO:0032722; P:positive regulation of chemokine production; IDA:BHF-UCL. DR GO; GO:1900017; P:positive regulation of cytokine production involved in inflammatory response; IEA:Ensembl. DR GO; GO:0010628; P:positive regulation of gene expression; IMP:UniProtKB. DR GO; GO:0050729; P:positive regulation of inflammatory response; IC:BHF-UCL. DR GO; GO:0032727; P:positive regulation of interferon-alpha production; IDA:UniProtKB. DR GO; GO:0032728; P:positive regulation of interferon-beta production; IDA:UniProtKB. DR GO; GO:0032735; P:positive regulation of interleukin-12 production; ISS:BHF-UCL. DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IDA:BHF-UCL. DR GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:BHF-UCL. DR GO; GO:0046330; P:positive regulation of JNK cascade; IDA:UniProt. DR GO; GO:0060907; P:positive regulation of macrophage cytokine production; IEA:Ensembl. DR GO; GO:1901224; P:positive regulation of non-canonical NF-kappaB signal transduction; IDA:BHF-UCL. DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; ISS:BHF-UCL. DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; ISS:BHF-UCL. DR GO; GO:0032729; P:positive regulation of type II interferon production; IDA:UniProtKB. DR GO; GO:0034346; P:positive regulation of type III interferon production; IEA:Ensembl. DR GO; GO:0002730; P:regulation of dendritic cell cytokine production; IEA:Ensembl. DR GO; GO:0043331; P:response to dsRNA; IBA:GO_Central. DR GO; GO:0043330; P:response to exogenous dsRNA; IDA:MGI. DR GO; GO:0007165; P:signal transduction; TAS:ProtInc. DR GO; GO:0034138; P:toll-like receptor 3 signaling pathway; IDA:BHF-UCL. DR GO; GO:0002224; P:toll-like receptor signaling pathway; IDA:UniProt. DR GO; GO:0034343; P:type III interferon production; IEA:Ensembl. DR Gene3D; 3.80.10.10; Ribonuclease Inhibitor; 1. DR Gene3D; 3.40.50.10140; Toll/interleukin-1 receptor homology (TIR) domain; 1. DR InterPro; IPR000483; Cys-rich_flank_reg_C. DR InterPro; IPR001611; Leu-rich_rpt. DR InterPro; IPR003591; Leu-rich_rpt_typical-subtyp. DR InterPro; IPR032675; LRR_dom_sf. DR InterPro; IPR000157; TIR_dom. DR InterPro; IPR041015; TLR3_TMD. DR InterPro; IPR017241; Toll-like_receptor. DR InterPro; IPR035897; Toll_tir_struct_dom_sf. DR PANTHER; PTHR24365; TOLL-LIKE RECEPTOR; 1. DR PANTHER; PTHR24365:SF524; TOLL-LIKE RECEPTOR 3; 1. DR Pfam; PF13516; LRR_6; 1. DR Pfam; PF13855; LRR_8; 6. DR Pfam; PF01582; TIR; 1. DR Pfam; PF17968; Tlr3_TMD; 1. DR PRINTS; PR00019; LEURICHRPT. DR SMART; SM00365; LRR_SD22; 8. DR SMART; SM00369; LRR_TYP; 16. DR SMART; SM00082; LRRCT; 1. DR SMART; SM00255; TIR; 1. DR SUPFAM; SSF52058; L domain-like; 2. DR SUPFAM; SSF52200; Toll/Interleukin receptor TIR domain; 1. DR PROSITE; PS51450; LRR; 19. DR PROSITE; PS50104; TIR; 1. DR Genevisible; O15455; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Direct protein sequencing; KW Disease variant; Disulfide bond; Endoplasmic reticulum; Endosome; KW Glycoprotein; Immunity; Inflammatory response; Innate immunity; KW Isopeptide bond; Leucine-rich repeat; Membrane; Phosphoprotein; Receptor; KW Reference proteome; Repeat; RNA-binding; Signal; Transmembrane; KW Transmembrane helix; Ubl conjugation. FT SIGNAL 1..23 FT /evidence="ECO:0000269|PubMed:15340161" FT CHAIN 24..904 FT /note="Toll-like receptor 3" FT /id="PRO_0000034715" FT TOPO_DOM 24..704 FT /note="Lumenal" FT /evidence="ECO:0000255" FT TRANSMEM 705..725 FT /note="Helical" FT /evidence="ECO:0000255" FT TOPO_DOM 726..904 FT /note="Cytoplasmic" FT /evidence="ECO:0000255" FT DOMAIN 24..51 FT /note="LRRNT" FT REPEAT 52..73 FT /note="LRR 1" FT REPEAT 76..97 FT /note="LRR 2" FT REPEAT 100..121 FT /note="LRR 3" FT REPEAT 124..145 FT /note="LRR 4" FT REPEAT 148..168 FT /note="LRR 5" FT REPEAT 172..193 FT /note="LRR 6" FT REPEAT 198..219 FT /note="LRR 7" FT REPEAT 222..244 FT /note="LRR 8" FT REPEAT 249..270 FT /note="LRR 9" FT REPEAT 275..296 FT /note="LRR 10" FT REPEAT 299..320 FT /note="LRR 11" FT REPEAT 323..344 FT /note="LRR 12" FT REPEAT 356..377 FT /note="LRR 13" FT REPEAT 380..400 FT /note="LRR 14" FT REPEAT 408..429 FT /note="LRR 15" FT REPEAT 432..454 FT /note="LRR 16" FT REPEAT 465..486 FT /note="LRR 17" FT REPEAT 507..528 FT /note="LRR 18" FT REPEAT 531..552 FT /note="LRR 19" FT REPEAT 563..584 FT /note="LRR 20" FT REPEAT 587..608 FT /note="LRR 21" FT REPEAT 611..632 FT /note="LRR 22" FT DOMAIN 645..698 FT /note="LRRCT" FT DOMAIN 754..897 FT /note="TIR" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204" FT MOD_RES 759 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:17178723" FT MOD_RES 858 FT /note="Phosphotyrosine" FT /evidence="ECO:0000269|PubMed:17178723" FT CARBOHYD 52 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16043704, FT ECO:0000269|PubMed:19159218, ECO:0000269|PubMed:22579623" FT CARBOHYD 57 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:19159218" FT CARBOHYD 70 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16043704, FT ECO:0000269|PubMed:22579623" FT CARBOHYD 124 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15961631, FT ECO:0000269|PubMed:22579623" FT CARBOHYD 196 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16043704" FT CARBOHYD 247 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:22579623" FT CARBOHYD 252 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15961631, FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623" FT CARBOHYD 265 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16043704, FT ECO:0000269|PubMed:22579623" FT CARBOHYD 275 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15961631, FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623" FT CARBOHYD 291 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15961631, FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623" FT CARBOHYD 398 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15961631, FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623" FT CARBOHYD 413 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15961631, FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623" FT CARBOHYD 507 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:15961631, FT ECO:0000269|PubMed:16043704, ECO:0000269|PubMed:22579623" FT CARBOHYD 636 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:16043704" FT CARBOHYD 662 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 28..37 FT DISULFID 95..122 FT DISULFID 649..677 FT DISULFID 651..696 FT CROSSLNK 765 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:37158982" FT CROSSLNK 812 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:37158982" FT CROSSLNK 831 FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with FT G-Cter in ubiquitin)" FT /evidence="ECO:0000269|PubMed:32878999" FT VAR_SEQ 1..277 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_054188" FT VARIANT 134 FT /note="S -> P (no effect on IFNL1 induction)" FT /evidence="ECO:0000269|PubMed:32972995" FT /id="VAR_084046" FT VARIANT 251 FT /note="R -> G (no effect on IFNL1 induction; FT dbSNP:rs780051344)" FT /evidence="ECO:0000269|PubMed:32972995" FT /id="VAR_084047" FT VARIANT 284 FT /note="N -> I (in dbSNP:rs5743316)" FT /id="VAR_052361" FT VARIANT 307 FT /note="Y -> D (in dbSNP:rs5743317)" FT /id="VAR_052362" FT VARIANT 412 FT /note="L -> F (in dbSNP:rs3775291)" FT /evidence="ECO:0000269|PubMed:14702039, FT ECO:0000269|PubMed:18753640, ECO:0000269|PubMed:22174453, FT ECO:0000269|Ref.4" FT /id="VAR_021976" FT VARIANT 554 FT /note="P -> S (in IMD83; causes TLR3 deficiency and FT predisposition to herpes simplex encephalitis; inhibition FT of IFNL1 induction; dbSNP:rs121434431)" FT /evidence="ECO:0000269|PubMed:17872438, FT ECO:0000269|PubMed:32972995" FT /id="VAR_054887" FT VARIANT 732 FT /note="F -> L (no effect on IFNL1 induction; FT dbSNP:rs988586598 and dbSNP:rs774476397)" FT /evidence="ECO:0000269|PubMed:32972995" FT /id="VAR_084048" FT VARIANT 737 FT /note="S -> T (in dbSNP:rs5743318)" FT /id="VAR_024664" FT VARIANT 746..904 FT /note="Missing (inhibition of IFNL1 induction)" FT /evidence="ECO:0000269|PubMed:32972995" FT /id="VAR_084049" FT VARIANT 769..904 FT /note="Missing (inhibition of IFNL1 induction)" FT /evidence="ECO:0000269|PubMed:32972995" FT /id="VAR_084050" FT VARIANT 867 FT /note="R -> Q (inhibition of IFNL1 induction; FT dbSNP:rs199768900)" FT /evidence="ECO:0000269|PubMed:32972995" FT /id="VAR_084051" FT VARIANT 870 FT /note="M -> V (inhibition of IFNL1 induction)" FT /evidence="ECO:0000269|PubMed:32972995" FT /id="VAR_084052" FT MUTAGEN 95 FT /note="C->A: Reduced response to ds-RNA." FT /evidence="ECO:0000269|PubMed:16144834" FT MUTAGEN 122 FT /note="C->A: Reduced response to ds-RNA." FT /evidence="ECO:0000269|PubMed:16144834" FT MUTAGEN 196 FT /note="N->G: Reduced expression levels; when associated FT with R-247." FT /evidence="ECO:0000269|PubMed:16144834" FT MUTAGEN 247 FT /note="N->R: Reduced response to ds-RNA. Reduced expression FT levels; when associated with G-196." FT /evidence="ECO:0000269|PubMed:16144834" FT MUTAGEN 539 FT /note="H->A: No effect." FT /evidence="ECO:0000269|PubMed:16720699" FT MUTAGEN 539 FT /note="H->E: Loss of RNA binding. Constitutive activation FT of NF-kappa-B." FT /evidence="ECO:0000269|PubMed:16720699" FT MUTAGEN 541 FT /note="N->A: Loss of RNA binding. Abolishes activation of FT NF-kappa-B." FT /evidence="ECO:0000269|PubMed:16720699" FT MUTAGEN 759 FT /note="Y->F: Reduced activation of NF-kappa-B in response FT to ds-RNA. Reduced induction of IL-8 in response to ds-RNA. FT Loss of interaction with WDFY1." FT /evidence="ECO:0000269|PubMed:17178723, FT ECO:0000269|PubMed:25736436" FT MUTAGEN 812 FT /note="K->R: Loss of ubiquitination by ZNRF1." FT /evidence="ECO:0000269|PubMed:37158982" FT MUTAGEN 831 FT /note="K->R: Loss of ubiquitination by TRIM3." FT /evidence="ECO:0000269|PubMed:32878999" FT MUTAGEN 858 FT /note="Y->F: Loss of interaction with WDFY1." FT /evidence="ECO:0000269|PubMed:25736436" FT CONFLICT 290 FT /note="G -> R (in Ref. 5; BAG36884)" FT /evidence="ECO:0000305" FT CONFLICT 575 FT /note="D -> N (in Ref. 8; AAH94737)" FT /evidence="ECO:0000305" FT CONFLICT 605 FT /note="V -> A (in Ref. 5; BAG36884)" FT /evidence="ECO:0000305" FT CONFLICT 663 FT /note="E -> G (in Ref. 5; BAG36884)" FT /evidence="ECO:0000305" FT STRAND 31..36 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 47..49 FT /evidence="ECO:0007829|PDB:2A0Z" FT STRAND 54..57 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 68..74 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 78..81 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 94..97 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 103..105 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 108..110 FT /evidence="ECO:0007829|PDB:5GS0" FT TURN 118..121 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 126..129 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 142..145 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 151..153 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 166..168 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 175..177 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 188..191 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 192..194 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 198..203 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 216..219 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 220..223 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 225..227 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 234..245 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 252..254 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 265..268 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 269..273 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 278..280 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 291..296 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 302..304 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 310..313 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 315..320 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 326..328 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 338..340 FT /evidence="ECO:0007829|PDB:7WV3" FT TURN 348..353 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 359..361 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 372..377 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 383..385 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 390..392 FT /evidence="ECO:0007829|PDB:7WV3" FT TURN 398..401 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 402..404 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 405..407 FT /evidence="ECO:0007829|PDB:7WV5" FT STRAND 411..413 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 424..429 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 435..437 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 444..446 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 450..452 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 460..462 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 467..470 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 473..478 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 484..486 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 492..494 FT /evidence="ECO:0007829|PDB:7WV5" FT TURN 501..504 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 510..512 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 523..528 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 534..536 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 543..546 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 548..550 FT /evidence="ECO:0007829|PDB:7C76" FT TURN 557..560 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 566..568 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 579..584 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 590..592 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 603..608 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 614..616 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 627..634 FT /evidence="ECO:0007829|PDB:1ZIW" FT STRAND 638..641 FT /evidence="ECO:0007829|PDB:1ZIW" FT TURN 651..653 FT /evidence="ECO:0007829|PDB:7WV3" FT STRAND 655..658 FT /evidence="ECO:0007829|PDB:1ZIW" FT HELIX 671..674 FT /evidence="ECO:0007829|PDB:7WV3" FT STRAND 676..680 FT /evidence="ECO:0007829|PDB:7WV3" FT TURN 681..685 FT /evidence="ECO:0007829|PDB:7WV3" FT HELIX 688..690 FT /evidence="ECO:0007829|PDB:2A0Z" FT STRAND 694..696 FT /evidence="ECO:0007829|PDB:7C76" FT TURN 697..699 FT /evidence="ECO:0007829|PDB:7C76" FT HELIX 702..725 FT /evidence="ECO:0007829|PDB:7C76" FT HELIX 738..745 FT /evidence="ECO:0007829|PDB:8AR1" SQ SEQUENCE 904 AA; 103829 MW; 034E05ECA7A4D2F7 CRC64; MRQTLPCIYF WGGLLPFGML CASSTTKCTV SHEVADCSHL KLTQVPDDLP TNITVLNLTH NQLRRLPAAN FTRYSQLTSL DVGFNTISKL EPELCQKLPM LKVLNLQHNE LSQLSDKTFA FCTNLTELHL MSNSIQKIKN NPFVKQKNLI TLDLSHNGLS STKLGTQVQL ENLQELLLSN NKIQALKSEE LDIFANSSLK KLELSSNQIK EFSPGCFHAI GRLFGLFLNN VQLGPSLTEK LCLELANTSI RNLSLSNSQL STTSNTTFLG LKWTNLTMLD LSYNNLNVVG NDSFAWLPQL EYFFLEYNNI QHLFSHSLHG LFNVRYLNLK RSFTKQSISL ASLPKIDDFS FQWLKCLEHL NMEDNDIPGI KSNMFTGLIN LKYLSLSNSF TSLRTLTNET FVSLAHSPLH ILNLTKNKIS KIESDAFSWL GHLEVLDLGL NEIGQELTGQ EWRGLENIFE IYLSYNKYLQ LTRNSFALVP SLQRLMLRRV ALKNVDSSPS PFQPLRNLTI LDLSNNNIAN INDDMLEGLE KLEILDLQHN NLARLWKHAN PGGPIYFLKG LSHLHILNLE SNGFDEIPVE VFKDLFELKI IDLGLNNLNT LPASVFNNQV SLKSLNLQKN LITSVEKKVF GPAFRNLTEL DMRFNPFDCT CESIAWFVNW INETHTNIPE LSSHYLCNTP PHYHGFPVRL FDTSSCKDSA PFELFFMINT SILLIFIFIV LLIHFEGWRI SFYWNVSVHR VLGFKEIDRQ TEQFEYAAYI IHAYKDKDWV WEHFSSMEKE DQSLKFCLEE RDFEAGVFEL EAIVNSIKRS RKIIFVITHH LLKDPLCKRF KVHHAVQQAI EQNLDSIILV FLEEIPDYKL NHALCLRRGM FKSHCILNWP VQKERIGAFR HKLQVALGSK NSVH //