I36RA_MOUSE
ID I36RA_MOUSE Reviewed; 156 AA.
AC Q9QYY1; Q9JIG2;
DT 08-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 08-NOV-2002, sequence version 2.
DT 03-AUG-2022, entry version 153.
DE RecName: Full=Interleukin-36 receptor antagonist protein;
DE Short=IL-36Ra {ECO:0000303|PubMed:21965679};
DE AltName: Full=Interleukin-1 HY1;
DE Short=IL-1HY1;
DE AltName: Full=Interleukin-1 delta;
DE Short=IL-1 delta;
DE AltName: Full=Interleukin-1 family member 5;
DE Short=IL-1F5;
DE AltName: Full=Interleukin-1 homolog 3;
DE Short=IL-1H3;
DE AltName: Full=Interleukin-1-like protein 1;
DE Short=IL-1L1;
GN Name=IL36RN {ECO:0000312|MGI:MGI:1859325};
GN Synonyms=Fil1d, Il1f5, Il1h3, Il1hy1;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11093146;
RX DOI=10.1002/1521-4141(200011)30:11<3299::aid-immu3299>3.0.co;2-s;
RA Barton J.L., Herbst R., Bosisio D., Higgins L., Nicklin M.J.H.;
RT "A tissue specific IL-1 receptor antagonist homolog from the IL-1 cluster
RT lacks IL-1, IL-1ra, IL-18 and IL-18 antagonist activities.";
RL Eur. J. Immunol. 30:3299-3308(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=10744718; DOI=10.1074/jbc.275.14.10308;
RA Kumar S., McDonnell P.C., Lehr R., Tierney L., Tzimas M.N., Griswold D.E.,
RA Capper E.A., Tal-Singer R., Wells G.I., Doyle M.L., Young P.R.;
RT "Identification and initial characterization of four novel members of the
RT interleukin-1 family.";
RL J. Biol. Chem. 275:10308-10314(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=11466363; DOI=10.4049/jimmunol.167.3.1440;
RA Debets R., Timans J.C., Homey B., Zurawski S., Sana T.R., Lo S., Wagner J.,
RA Edwards G., Clifford T., Menon S., Bazan J.F., Kastelein R.A.;
RT "Two novel IL-1 family members, IL-1 delta and IL-1 epsilon, function as an
RT antagonist and agonist of NF-kappa B activation through the orphan IL-1
RT receptor-related protein 2.";
RL J. Immunol. 167:1440-1446(2001).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Stomach, and Tongue;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=17908936; DOI=10.1084/jem.20070157;
RA Blumberg H., Dinh H., Trueblood E.S., Pretorius J., Kugler D., Weng N.,
RA Kanaly S.T., Towne J.E., Willis C.R., Kuechle M.K., Sims J.E.,
RA Peschon J.J.;
RT "Opposing activities of two novel members of the IL-1 ligand family
RT regulate skin inflammation.";
RL J. Exp. Med. 204:2603-2614(2007).
RN [6]
RP FUNCTION.
RX PubMed=18284608; DOI=10.1111/j.1471-4159.2008.05304.x;
RA Costelloe C., Watson M., Murphy A., McQuillan K., Loscher C.,
RA Armstrong M.E., Garlanda C., Mantovani A., O'Neill L.A., Mills K.H.,
RA Lynch M.A.;
RT "IL-1F5 mediates anti-inflammatory activity in the brain through induction
RT of IL-4 following interaction with SIGIRR/TIR8.";
RL J. Neurochem. 105:1960-1969(2008).
RN [7]
RP FUNCTION.
RX PubMed=21860022; DOI=10.1182/blood-2011-05-356873;
RA Vigne S., Palmer G., Lamacchia C., Martin P., Talabot-Ayer D.,
RA Rodriguez E., Ronchi F., Sallusto F., Dinh H., Sims J.E., Gabay C.;
RT "IL-36R ligands are potent regulators of dendritic and T cells.";
RL Blood 118:5813-5823(2011).
RN [8]
RP FUNCTION, AND CLEAVAGE OF INITIATOR METHIONINE.
RX PubMed=21965679; DOI=10.1074/jbc.m111.267922;
RA Towne J.E., Renshaw B.R., Douangpanya J., Lipsky B.P., Shen M., Gabel C.A.,
RA Sims J.E.;
RT "Interleukin-36 (IL-36) ligands require processing for full agonist (IL-
RT 36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity.";
RL J. Biol. Chem. 286:42594-42602(2011).
RN [9]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 3-156, AND DISULFIDE BOND.
RX PubMed=12974628; DOI=10.1021/bi0341197;
RA Dunn E.F., Gay N.J., Bristow A.F., Gearing D.P., O'Neill L.A.J., Pei X.Y.;
RT "High-resolution structure of murine interleukin 1 homologue IL-1F5 reveals
RT unique loop conformations for receptor binding specificity.";
RL Biochemistry 42:10938-10944(2003).
CC -!- FUNCTION: Inhibits the activity of interleukin-36 (IL36A,IL36B and
CC IL36G) by binding to receptor IL1RL2/IL-36R and preventing its
CC association with the coreceptor IL1RAP for signaling. Part of the IL-36
CC signaling system that is thought to be present in epithelial barriers
CC and to take part in local inflammatory response; similar to the IL-1
CC system with which it shares the coreceptor. Proposed to play a role in
CC skin inflammation. May be involved in the innate immune response to
CC fungal pathogens. May activate an anti-inflammatory signaling pathway
CC by recruiting SIGIRR. {ECO:0000269|PubMed:17908936,
CC ECO:0000269|PubMed:18284608, ECO:0000269|PubMed:21860022,
CC ECO:0000269|PubMed:21965679}.
CC -!- SUBUNIT: Interacts with cargo receptor TMED10; the interaction mediates
CC the translocation from the cytoplasm into the ERGIC (endoplasmic
CC reticulum-Golgi intermediate compartment) and thereby secretion.
CC {ECO:0000250|UniProtKB:Q9UBH0}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q9UBH0}.
CC Secreted {ECO:0000250|UniProtKB:Q9UBH0}. Note=The secretion is
CC dependent on protein unfolding and facilitated by the cargo receptor
CC TMED10; it results in protein translocation from the cytoplasm into the
CC ERGIC (endoplasmic reticulum-Golgi intermediate compartment) followed
CC by vesicle entry and secretion. {ECO:0000250|UniProtKB:Q9UBH0}.
CC -!- TISSUE SPECIFICITY: Highly abundant in embryonic tissue and tissues
CC containing epithelial cells.
CC -!- PTM: Removal of N-terminal methionine is necessary for full
CC antagonistic activity. {ECO:0000269|PubMed:21965679}.
CC -!- DISRUPTION PHENOTYPE: In combination with transgenic IL36A exacerbates
CC skin abnormalities (acanthosis, hyperkeratosis, presence of a mixed
CC inflammatory cell infiltrate and increased cytokine and chemokine
CC expression). {ECO:0000269|PubMed:17908936}.
CC -!- MISCELLANEOUS: Bioactive (processed) recombinant IL36RN inhibits
CC effects of IL-36 when used in 100- 1000-fold molar excess.
CC {ECO:0000269|PubMed:21860022}.
CC -!- SIMILARITY: Belongs to the IL-1 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAB59831.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AJ250429; CAB59831.1; ALT_INIT; mRNA.
DR EMBL; AF200495; AAF69251.1; -; mRNA.
DR EMBL; AF230378; AAF91275.1; -; mRNA.
DR EMBL; AK008977; BAB26002.1; -; mRNA.
DR EMBL; AK009741; BAB26471.1; -; mRNA.
DR CCDS; CCDS50519.1; -.
DR RefSeq; NP_001139559.1; NM_001146087.1.
DR RefSeq; NP_001139560.1; NM_001146088.1.
DR RefSeq; NP_062324.2; NM_019451.2.
DR PDB; 1MD6; X-ray; 1.60 A; A=3-156.
DR PDBsum; 1MD6; -.
DR AlphaFoldDB; Q9QYY1; -.
DR SMR; Q9QYY1; -.
DR STRING; 10090.ENSMUSP00000028360; -.
DR PhosphoSitePlus; Q9QYY1; -.
DR MaxQB; Q9QYY1; -.
DR PaxDb; Q9QYY1; -.
DR PRIDE; Q9QYY1; -.
DR ProteomicsDB; 273302; -.
DR Antibodypedia; 35211; 289 antibodies from 32 providers.
DR DNASU; 54450; -.
DR Ensembl; ENSMUST00000028360; ENSMUSP00000028360; ENSMUSG00000026983.
DR Ensembl; ENSMUST00000114490; ENSMUSP00000110134; ENSMUSG00000026983.
DR Ensembl; ENSMUST00000168941; ENSMUSP00000126028; ENSMUSG00000026983.
DR GeneID; 54450; -.
DR KEGG; mmu:54450; -.
DR UCSC; uc008ios.2; mouse.
DR CTD; 26525; -.
DR MGI; MGI:1859325; Il1f5.
DR VEuPathDB; HostDB:ENSMUSG00000026983; -.
DR eggNOG; ENOG502SRSC; Eukaryota.
DR GeneTree; ENSGT00950000182943; -.
DR HOGENOM; CLU_095373_2_1_1; -.
DR InParanoid; Q9QYY1; -.
DR OMA; NRWLDAR; -.
DR OrthoDB; 1410755at2759; -.
DR PhylomeDB; Q9QYY1; -.
DR TreeFam; TF300203; -.
DR Reactome; R-MMU-9014826; Interleukin-36 pathway.
DR BioGRID-ORCS; 54450; 2 hits in 73 CRISPR screens.
DR EvolutionaryTrace; Q9QYY1; -.
DR PRO; PR:Q9QYY1; -.
DR Proteomes; UP000000589; Chromosome 2.
DR RNAct; Q9QYY1; protein.
DR Bgee; ENSMUSG00000026983; Expressed in lip and 37 other tissues.
DR ExpressionAtlas; Q9QYY1; baseline and differential.
DR Genevisible; Q9QYY1; MM.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0005152; F:interleukin-1 receptor antagonist activity; IEA:InterPro.
DR GO; GO:0005149; F:interleukin-1 receptor binding; IEA:InterPro.
DR GO; GO:0019732; P:antifungal humoral response; ISO:MGI.
DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IBA:GO_Central.
DR GO; GO:0006954; P:inflammatory response; IBA:GO_Central.
DR GO; GO:0002437; P:inflammatory response to antigenic stimulus; IBA:GO_Central.
DR GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
DR GO; GO:0001960; P:negative regulation of cytokine-mediated signaling pathway; ISO:MGI.
DR GO; GO:0032689; P:negative regulation of interferon-gamma production; ISO:MGI.
DR GO; GO:0032700; P:negative regulation of interleukin-17 production; ISO:MGI.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IGI:MGI.
DR InterPro; IPR020877; IL-1_CS.
DR InterPro; IPR000975; IL-1_fam.
DR InterPro; IPR003297; IL-1RA/IL-36.
DR InterPro; IPR027171; IL-36RA.
DR InterPro; IPR008996; IL1/FGF.
DR PANTHER; PTHR10078; PTHR10078; 1.
DR PANTHER; PTHR10078:SF32; PTHR10078:SF32; 1.
DR Pfam; PF00340; IL1; 1.
DR PRINTS; PR00264; INTERLEUKIN1.
DR PRINTS; PR01360; INTRLEUKIN1X.
DR SUPFAM; SSF50353; SSF50353; 1.
DR PROSITE; PS00253; INTERLEUKIN_1; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytokine; Cytoplasm; Disulfide bond; Immunity;
KW Innate immunity; Reference proteome; Secreted.
FT INIT_MET 1
FT /note="Removed"
FT /evidence="ECO:0000269|PubMed:21965679"
FT CHAIN 2..156
FT /note="Interleukin-36 receptor antagonist protein"
FT /id="PRO_0000153643"
FT DISULFID 9..155
FT /evidence="ECO:0000269|PubMed:12974628"
FT CONFLICT 2
FT /note="Missing (in Ref. 3; AAF69251)"
FT /evidence="ECO:0000305"
FT STRAND 8..14
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 19..23
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 26..29
FT /evidence="ECO:0007829|PDB:1MD6"
FT HELIX 32..35
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 43..47
FT /evidence="ECO:0007829|PDB:1MD6"
FT HELIX 53..55
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 57..62
FT /evidence="ECO:0007829|PDB:1MD6"
FT TURN 63..66
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 67..70
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 73..76
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 80..83
FT /evidence="ECO:0007829|PDB:1MD6"
FT HELIX 86..91
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 92..94
FT /evidence="ECO:0007829|PDB:1MD6"
FT HELIX 97..99
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 100..105
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 110..117
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 121..124
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 126..131
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 133..135
FT /evidence="ECO:0007829|PDB:1MD6"
FT STRAND 150..154
FT /evidence="ECO:0007829|PDB:1MD6"
SQ SEQUENCE 156 AA; 17136 MW; A4D1EE2F93CF77A7 CRC64;
MMVLSGALCF RMKDSALKVL YLHNNQLLAG GLHAEKVIKG EEISVVPNRA LDASLSPVIL
GVQGGSQCLS CGTEKGPILK LEPVNIMELY LGAKESKSFT FYRRDMGLTS SFESAAYPGW
FLCTSPEADQ PVRLTQIPED PAWDAPITDF YFQQCD
