SIGIR_HUMAN
ID SIGIR_HUMAN Reviewed; 410 AA.
AC Q6IA17; Q3KQY2; Q6UXI3; Q9H733;
DT 27-SEP-2005, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2010, sequence version 3.
DT 03-AUG-2022, entry version 158.
DE RecName: Full=Single Ig IL-1-related receptor;
DE AltName: Full=Single Ig IL-1R-related molecule;
DE AltName: Full=Single immunoglobulin domain-containing IL1R-related protein;
DE AltName: Full=Toll/interleukin-1 receptor 8;
DE Short=TIR8;
GN Name=SIGIRR; ORFNames=UNQ301/PRO342;
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 [LARGE SCALE MRNA] (ISOFORM 2), AND VARIANT ARG-312.
RX PubMed=12975309; DOI=10.1101/gr.1293003;
RA Clark H.F., Gurney A.L., Abaya E., Baker K., Baldwin D.T., Brush J.,
RA Chen J., Chow B., Chui C., Crowley C., Currell B., Deuel B., Dowd P.,
RA Eaton D., Foster J.S., Grimaldi C., Gu Q., Hass P.E., Heldens S., Huang A.,
RA Kim H.S., Klimowski L., Jin Y., Johnson S., Lee J., Lewis L., Liao D.,
RA Mark M.R., Robbie E., Sanchez C., Schoenfeld J., Seshagiri S., Simmons L.,
RA Singh J., Smith V., Stinson J., Vagts A., Vandlen R.L., Watanabe C.,
RA Wieand D., Woods K., Xie M.-H., Yansura D.G., Yi S., Yu G., Yuan J.,
RA Zhang M., Zhang Z., Goddard A.D., Wood W.I., Godowski P.J., Gray A.M.;
RT "The secreted protein discovery initiative (SPDI), a large-scale effort to
RT identify novel human secreted and transmembrane proteins: a bioinformatics
RT assessment.";
RL Genome Res. 13:2265-2270(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ARG-312.
RC TISSUE=Colon;
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ARG-312.
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT ARG-312.
RC TISSUE=Lung, and Pancreas;
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 [6]
RP CHARACTERIZATION.
RX PubMed=10346978; DOI=10.1006/cyto.1998.0452;
RA Thomassen E., Renshaw B.R., Sims J.E.;
RT "Identification and characterization of SIGIRR, a molecule representing a
RT novel subtype of the IL-1R superfamily.";
RL Cytokine 11:389-399(1999).
RN [7]
RP FUNCTION, AND TISSUE SPECIFICITY.
RX PubMed=14715412;
RA Polentarutti N., Rol G.P., Muzio M., Bosisio D., Camnasio M., Riva F.,
RA Zoja C., Benigni A., Tomasoni S., Vecchi A., Garlanda C., Mantovani A.;
RT "Unique pattern of expression and inhibition of IL-1 signaling by the IL-1
RT receptor family member TIR8/SIGIRR.";
RL Eur. Cytokine Netw. 14:211-218(2003).
RN [8]
RP FUNCTION, AND INTERACTION WITH IL1R1; TLR4; TLR5; TLR9; TRAF6 AND IRAK1.
RX PubMed=12925853; DOI=10.1038/ni968;
RA Wald D., Qin J., Zhao Z., Qian Y., Naramura M., Tian L., Towne J.,
RA Sims J.E., Stark G.R., Li X.;
RT "SIGIRR, a negative regulator of Toll-like receptor-interleukin 1 receptor
RT signaling.";
RL Nat. Immunol. 4:920-927(2003).
RN [9]
RP FUNCTION, AND IDENTIFICATION IN IL1 AND LPS RECEPTOR COMPLEXES.
RX PubMed=15866876; DOI=10.1074/jbc.m501363200;
RA Qin J., Qian Y., Yao J., Grace C., Li X.;
RT "SIGIRR inhibits interleukin-1 receptor- and toll-like receptor 4-mediated
RT signaling through different mechanisms.";
RL J. Biol. Chem. 280:25233-25241(2005).
RN [10]
RP INDUCTION, AND TISSUE SPECIFICITY.
RX PubMed=21077278; DOI=10.1111/j.1365-2249.2010.04254.x;
RA Kadota C., Ishihara S., Aziz M.M., Rumi M.A., Oshima N., Mishima Y.,
RA Moriyama I., Yuki T., Amano Y., Kinoshita Y.;
RT "Down-regulation of single immunoglobulin interleukin-1R-related molecule
RT (SIGIRR)/TIR8 expression in intestinal epithelial cells during
RT inflammation.";
RL Clin. Exp. Immunol. 162:348-361(2010).
RN [11]
RP INTERACTION WITH PALM3.
RX PubMed=21187075; DOI=10.1016/j.bbrc.2010.12.104;
RA Chen X., Wu X., Zhao Y., Wang G., Feng J., Li Q., Qian G.;
RT "A novel binding protein of single immunoglobulin IL-1 receptor-related
RT molecule: Paralemmin-3.";
RL Biochem. Biophys. Res. Commun. 404:1029-1033(2011).
RN [12]
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., Wang L.,
RA Ye M., Zou H.;
RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver
RT phosphoproteome.";
RL J. Proteomics 96:253-262(2014).
RN [13]
RP VARIANTS TYR-80; ARG-115 AND ARG-312, AND FUNCTION.
RX PubMed=25963006; DOI=10.1542/peds.2014-3386;
RA Sampath V., Menden H., Helbling D., Li K., Gastonguay A., Ramchandran R.,
RA Dimmock D.P.;
RT "SIGIRR genetic variants in premature infants with necrotizing
RT enterocolitis.";
RL Pediatrics 135:E1530-E1534(2015).
CC -!- FUNCTION: Acts as a negative regulator of the Toll-like and IL-1R
CC receptor signaling pathways. Attenuates the recruitment of receptor-
CC proximal signaling components to the TLR4 receptor, probably through an
CC TIR-TIR domain interaction with TLR4. Through its extracellular domain
CC interferes with the heterodimerization of Il1R1 and IL1RAP.
CC {ECO:0000269|PubMed:12925853, ECO:0000269|PubMed:14715412,
CC ECO:0000269|PubMed:15866876, ECO:0000269|PubMed:25963006}.
CC -!- SUBUNIT: Interacts with IL1R1, IRAK1, TLR4, TLR5, TLR9 and TRAF6. Upon
CC IL-1 stimulation found in a complex at least composed of IL1R1, SIGIRR,
CC MYD88, IRAK1 and TRAF6. Upon stimulation with LPC found in a complex at
CC least composed of TLR4, SIG1IR, MYD88, IRAK1 and TRAF6. Interacts with
CC PALM3. {ECO:0000269|PubMed:12925853, ECO:0000269|PubMed:15866876,
CC ECO:0000269|PubMed:21187075}.
CC -!- INTERACTION:
CC Q6IA17; A6NDB9: PALM3; NbExp=4; IntAct=EBI-719672, EBI-6873185;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000305}; Single-pass type III
CC membrane protein {ECO:0000305}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=Q6IA17-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q6IA17-2; Sequence=VSP_015717;
CC -!- TISSUE SPECIFICITY: Mainly expressed in epithelial tissues such as
CC kidney, lung and gut. {ECO:0000269|PubMed:14715412,
CC ECO:0000269|PubMed:21077278}.
CC -!- INDUCTION: Down-regulated during inflammation by inhibition of an SP1-
CC mediated pathway. {ECO:0000269|PubMed:21077278}.
CC -!- SIMILARITY: Belongs to the interleukin-1 receptor family.
CC {ECO:0000305}.
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DR EMBL; AY358342; AAQ88708.1; -; mRNA.
DR EMBL; AK025099; BAB15066.1; -; mRNA.
DR EMBL; CR457338; CAG33619.1; -; mRNA.
DR EMBL; AC138230; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; BC003591; AAH03591.1; -; mRNA.
DR EMBL; BC025953; AAH25953.1; -; mRNA.
DR EMBL; BC106007; AAI06008.1; -; mRNA.
DR CCDS; CCDS31325.1; -. [Q6IA17-1]
DR RefSeq; NP_001128525.1; NM_001135053.1. [Q6IA17-1]
DR RefSeq; NP_001128526.1; NM_001135054.1. [Q6IA17-1]
DR RefSeq; NP_068577.2; NM_021805.2. [Q6IA17-1]
DR AlphaFoldDB; Q6IA17; -.
DR SMR; Q6IA17; -.
DR BioGRID; 121873; 16.
DR IntAct; Q6IA17; 4.
DR STRING; 9606.ENSP00000403104; -.
DR GlyGen; Q6IA17; 4 sites.
DR iPTMnet; Q6IA17; -.
DR PhosphoSitePlus; Q6IA17; -.
DR SwissPalm; Q6IA17; -.
DR BioMuta; SIGIRR; -.
DR DMDM; 311033538; -.
DR EPD; Q6IA17; -.
DR jPOST; Q6IA17; -.
DR MassIVE; Q6IA17; -.
DR MaxQB; Q6IA17; -.
DR PaxDb; Q6IA17; -.
DR PeptideAtlas; Q6IA17; -.
DR PRIDE; Q6IA17; -.
DR ProteomicsDB; 66356; -. [Q6IA17-1]
DR ProteomicsDB; 66357; -. [Q6IA17-2]
DR Antibodypedia; 9633; 313 antibodies from 29 providers.
DR DNASU; 59307; -.
DR Ensembl; ENST00000332725.7; ENSP00000333656.3; ENSG00000185187.13. [Q6IA17-1]
DR Ensembl; ENST00000397632.7; ENSP00000380756.3; ENSG00000185187.13. [Q6IA17-1]
DR Ensembl; ENST00000431843.7; ENSP00000403104.2; ENSG00000185187.13. [Q6IA17-1]
DR GeneID; 59307; -.
DR KEGG; hsa:59307; -.
DR MANE-Select; ENST00000431843.7; ENSP00000403104.2; NM_001135054.2; NP_001128526.1.
DR UCSC; uc001lpd.3; human. [Q6IA17-1]
DR CTD; 59307; -.
DR DisGeNET; 59307; -.
DR GeneCards; SIGIRR; -.
DR HGNC; HGNC:30575; SIGIRR.
DR HPA; ENSG00000185187; Low tissue specificity.
DR MIM; 605478; gene.
DR neXtProt; NX_Q6IA17; -.
DR OpenTargets; ENSG00000185187; -.
DR PharmGKB; PA142670915; -.
DR VEuPathDB; HostDB:ENSG00000185187; -.
DR eggNOG; ENOG502QVF7; Eukaryota.
DR GeneTree; ENSGT01050000244846; -.
DR HOGENOM; CLU_040046_0_0_1; -.
DR InParanoid; Q6IA17; -.
DR OMA; LEQDWCT; -.
DR PhylomeDB; Q6IA17; -.
DR TreeFam; TF325519; -.
DR PathwayCommons; Q6IA17; -.
DR Reactome; R-HSA-166058; MyD88:MAL(TIRAP) cascade initiated on plasma membrane.
DR Reactome; R-HSA-9008059; Interleukin-37 signaling.
DR SignaLink; Q6IA17; -.
DR BioGRID-ORCS; 59307; 13 hits in 1077 CRISPR screens.
DR ChiTaRS; SIGIRR; human.
DR GeneWiki; SIGIRR; -.
DR GenomeRNAi; 59307; -.
DR Pharos; Q6IA17; Tbio.
DR PRO; PR:Q6IA17; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; Q6IA17; protein.
DR Bgee; ENSG00000185187; Expressed in granulocyte and 174 other tissues.
DR ExpressionAtlas; Q6IA17; baseline and differential.
DR Genevisible; Q6IA17; HS.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IMP:HGNC-UCL.
DR GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR GO; GO:0006953; P:acute-phase response; ISS:HGNC-UCL.
DR GO; GO:0032682; P:negative regulation of chemokine production; ISS:HGNC-UCL.
DR GO; GO:0001960; P:negative regulation of cytokine-mediated signaling pathway; ISS:HGNC-UCL.
DR GO; GO:0043433; P:negative regulation of DNA-binding transcription factor activity; IMP:HGNC-UCL.
DR GO; GO:0031665; P:negative regulation of lipopolysaccharide-mediated signaling pathway; TAS:HGNC-UCL.
DR GO; GO:0007165; P:signal transduction; IEA:InterPro.
DR Gene3D; 2.60.40.10; -; 1.
DR Gene3D; 3.40.50.10140; -; 1.
DR InterPro; IPR007110; Ig-like_dom.
DR InterPro; IPR036179; Ig-like_dom_sf.
DR InterPro; IPR013783; Ig-like_fold.
DR InterPro; IPR015621; IL-1_rcpt_fam.
DR InterPro; IPR000157; TIR_dom.
DR InterPro; IPR035897; Toll_tir_struct_dom_sf.
DR PANTHER; PTHR11890; PTHR11890; 1.
DR Pfam; PF01582; TIR; 1.
DR SMART; SM00255; TIR; 1.
DR SUPFAM; SSF48726; SSF48726; 1.
DR SUPFAM; SSF52200; SSF52200; 1.
DR PROSITE; PS50835; IG_LIKE; 1.
DR PROSITE; PS50104; TIR; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Disulfide bond; Glycoprotein; Immunoglobulin domain;
KW Membrane; Phosphoprotein; Reference proteome; Signal-anchor; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..410
FT /note="Single Ig IL-1-related receptor"
FT /id="PRO_0000099065"
FT TOPO_DOM 1..118
FT /note="Extracellular"
FT /evidence="ECO:0000255"
FT TRANSMEM 119..139
FT /note="Helical; Signal-anchor for type III membrane
FT protein"
FT /evidence="ECO:0000255"
FT TOPO_DOM 140..410
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 9..109
FT /note="Ig-like C2-type"
FT DOMAIN 163..307
FT /note="TIR"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00204"
FT REGION 340..390
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 340..354
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 373..390
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 383
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q9JLZ8"
FT CARBOHYD 31
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 73
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 86
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 102
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 32..98
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00114"
FT VAR_SEQ 358..410
FT /note="VRGPVFGEPSAPPHTSGVSLGESRSSEVDVSDLGSRNYSARTDFYCLVSKDD
FT M -> MPAQPHSPTGEAQHRAEWGQAQGTGPGGALGVEDSSRHREPLHGLCPGGARPSV
FT CLGTSWASQAITAGGEQGQPLAVGLGQGCGWPPQASRSPHPRCPGACFWRAISSTAHQW
FT GLAGREPEQRSGRLGSRLAKLQCPHRLLLPGVQG (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:12975309"
FT /id="VSP_015717"
FT VARIANT 80
FT /note="S -> Y (in dbSNP:rs117739035)"
FT /evidence="ECO:0000269|PubMed:25963006"
FT /id="VAR_074164"
FT VARIANT 115
FT /note="P -> R (in dbSNP:rs111819059)"
FT /evidence="ECO:0000269|PubMed:25963006"
FT /id="VAR_074165"
FT VARIANT 312
FT /note="Q -> R (in dbSNP:rs3210908)"
FT /evidence="ECO:0000269|PubMed:12975309,
FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15489334,
FT ECO:0000269|PubMed:25963006, ECO:0000269|Ref.3"
FT /id="VAR_058702"
FT CONFLICT 410
FT /note="M -> I (in Ref. 3; CAG33619)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 410 AA; 45679 MW; BA4564C2ABAB5104 CRC64;
MPGVCDRAPD FLSPSEDQVL RPALGSSVAL NCTAWVVSGP HCSLPSVQWL KDGLPLGIGG
HYSLHEYSWV KANLSEVLVS SVLGVNVTST EVYGAFTCSI QNISFSSFTL QRAGPTSHVA
AVLASLLVLL ALLLAALLYV KCRLNVLLWY QDAYGEVEIN DGKLYDAYVS YSDCPEDRKF
VNFILKPQLE RRRGYKLFLD DRDLLPRAEP SADLLVNLSR CRRLIVVLSD AFLSRAWCSH
SFREGLCRLL ELTRRPIFIT FEGQRRDPAH PALRLLRQHR HLVTLLLWRP GSVTPSSDFW
KEVQLALPRK VQYRPVEGDP QTQLQDDKDP MLILRGRVPE GRALDSEVDP DPEGDLGVRG
PVFGEPSAPP HTSGVSLGES RSSEVDVSDL GSRNYSARTD FYCLVSKDDM
