ID IL36G_HUMAN Reviewed; 169 AA. AC Q9NZH8; Q56B91; Q6UVX7; Q7RTZ9; DT 08-NOV-2002, integrated into UniProtKB/Swiss-Prot. DT 01-OCT-2000, sequence version 1. DT 24-JAN-2024, entry version 174. DE RecName: Full=Interleukin-36 gamma; DE AltName: Full=IL-1-related protein 2; DE Short=IL-1RP2; DE AltName: Full=Interleukin-1 epsilon; DE Short=IL-1 epsilon; DE AltName: Full=Interleukin-1 family member 9; DE Short=IL-1F9; DE AltName: Full=Interleukin-1 homolog 1; DE Short=IL-1H1; DE Flags: Precursor; GN Name=IL36G {ECO:0000312|HGNC:HGNC:15741}; GN Synonyms=IL1E, IL1F9, IL1H1, IL1RP2; ORFNames=UNQ2456/PRO5737; 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), AND INDUCTION. RC TISSUE=Keratinocyte; 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 [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND CHARACTERIZATION. RC TISSUE=Epithelium; 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 [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=10860666; DOI=10.1006/geno.2000.6184; RA Busfield S.J., Comrack C.A., Yu G., Chickering T.W., Smutko J.S., Zhou H., RA Leiby K.R., Holmgren L.M., Gearing D.P., Pan Y.; RT "Identification and gene organization of three novel members of the IL-1 RT family on human chromosome 2."; RL Genomics 66:213-216(2000). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RX PubMed=11991722; DOI=10.1006/geno.2002.6751; RA Nicklin M.J.H., Barton J.L., Nguyen M., Fitzgerald M.G., Duff W.G., RA Kornman K.; RT "A sequence-based map of the nine genes of the human interleukin-1 RT cluster."; RL Genomics 79:718-725(2002). RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). 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 [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG SeattleSNPs variation discovery resource; RL Submitted (MAR-2005) to the EMBL/GenBank/DDBJ databases. RN [7] 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 [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). 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 FUNCTION, TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION. RX PubMed=20870894; DOI=10.1165/rcmb.2010-0075oc; RA Chustz R.T., Nagarkar D.R., Poposki J.A., Favoreto S. Jr., Avila P.C., RA Schleimer R.P., Kato A.; RT "Regulation and function of the IL-1 family cytokine IL-1F9 in human RT bronchial epithelial cells."; RL Am. J. Respir. Cell Mol. Biol. 45:145-153(2011). RN [10] RP FUNCTION, AND PROCESSING. 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 [11] RP FUNCTION, AND TISSUE SPECIFICITY. RX PubMed=23095752; DOI=10.1074/jbc.m112.385443; RA Bachmann M., Scheiermann P., Hardle L., Pfeilschifter J., Muhl H.; RT "IL-36gamma/IL-1F9, an innate T-bet target in myeloid cells."; RL J. Biol. Chem. 287:41684-41696(2012). RN [12] RP FUNCTION, AND INDUCTION. RX PubMed=23147407; DOI=10.1002/eji.201242711; RA Gresnigt M.S., Roesler B., Jacobs C.W., Becker K.L., Joosten L.A., RA van der Meer J.W., Netea M.G., Dinarello C.A., van de Veerdonk F.L.; RT "The IL-36 receptor pathway regulates Aspergillus fumigatus-induced Th1 and RT Th17 responses."; RL Eur. J. Immunol. 43:416-426(2013). RN [13] RP FUNCTION. RX PubMed=24829417; DOI=10.4049/jimmunol.1301481; RA Foster A.M., Baliwag J., Chen C.S., Guzman A.M., Stoll S.W., RA Gudjonsson J.E., Ward N.L., Johnston A.; RT "IL-36 promotes myeloid cell infiltration, activation, and inflammatory RT activity in skin."; RL J. Immunol. 192:6053-6061(2014). RN [14] RP PROTEOLYTIC CLEAVAGE. RX PubMed=30804664; DOI=10.2147/dddt.s194765; RA Guo J., Tu J., Hu Y., Song G., Yin Z.; RT "Cathepsin G cleaves and activates IL-36gamma and promotes the inflammation RT of psoriasis."; RL Drug Des. Dev. Ther. 13:581-588(2019). RN [15] RP SUBCELLULAR LOCATION, AND INTERACTION WITH TMED10. RX PubMed=32272059; DOI=10.1016/j.cell.2020.03.031; RA Zhang M., Liu L., Lin X., Wang Y., Li Y., Guo Q., Li S., Sun Y., Tao X., RA Zhang D., Lv X., Zheng L., Ge L.; RT "A Translocation Pathway for Vesicle-Mediated Unconventional Protein RT Secretion."; RL Cell 181:637-652(2020). CC -!- FUNCTION: Cytokine that binds to and signals through the IL1RL2/IL-36R CC receptor which in turn activates NF-kappa-B and MAPK signaling pathways CC in target cells. Part of the IL-36 signaling system that is thought to CC be present in epithelial barriers and to take part in local CC inflammatory response; similar to the IL-1 system with which it shares CC the coreceptor IL1RAP. Seems to be involved in skin inflammatory CC response by acting on keratinocytes, dendritic cells and indirectly on CC T-cells to drive tissue infiltration, cell maturation and cell CC proliferation. In cultured keratinocytes induces the expression of CC macrophage, T-cell, and neutrophil chemokines, such as CCL3, CCL4, CC CCL5, CCL2, CCL17, CCL22, CL20, CCL5, CCL2, CCL17, CCL22, CXCL8, CCL20 CC and CXCL1; also stimulates its own expression and that of the CC prototypic cutaneous pro-inflammatory parameters TNF-alpha, CC S100A7/psoriasin and inducible NOS. May play a role in pro-inflammatory CC responses during particular neutrophilic airway inflammation: activates CC mitogen-activated protein kinases and NF-kappa B in primary lung CC fibroblasts, and stimulates the expression of IL-8 and CXCL3 and Th17 CC chemokine CCL20 in lung fibroblasts. May be involved in the innate CC immune response to fungal pathogens, such as Aspergillus fumigatus. CC {ECO:0000269|PubMed:11466363, ECO:0000269|PubMed:20870894, CC ECO:0000269|PubMed:21965679, ECO:0000269|PubMed:23095752, CC ECO:0000269|PubMed:23147407, ECO:0000269|PubMed:24829417}. 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:0000269|PubMed:32272059}. CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:32272059}. Secreted CC {ECO:0000269|PubMed:20870894}. Note=The secretion is dependent on CC protein unfolding and facilitated by the cargo receptor TMED10; it CC results in protein translocation from the cytoplasm into the ERGIC CC (endoplasmic reticulum-Golgi intermediate compartment) followed by CC vesicle entry and secretion. {ECO:0000269|PubMed:32272059}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9NZH8-1; Sequence=Displayed; CC Name=2; CC IsoId=Q9NZH8-2; Sequence=VSP_013002; CC -!- TISSUE SPECIFICITY: Highly expressed in tissues containing epithelial CC cells: skin, lung, stomach and esophagus. Expressed in bronchial CC epithelial. In skin is expressed only in keratinocytes but not in CC fibroblasts, endothelial cells or melanocytes. Up-regulated in lesional CC psoriasis skin. Expressed in monocyte-derived dendritic cells and M1 CC macrophages. {ECO:0000269|PubMed:20870894, CC ECO:0000269|PubMed:23095752}. CC -!- INDUCTION: By TNF and by IFNG/IFN-gamma in keratinocytes. By CC Aspergillus fumigatus conidia in peripheral blood mnonocytes; involves CC CLEC7A and SYK. {ECO:0000269|PubMed:10744718, CC ECO:0000269|PubMed:23147407}. CC -!- PTM: N-terminal truncation leads to a dramatic enhancement of its CC activity (>1000-fold) (PubMed:21965679). Proteolytically cleaved by CC cathepsin CTSG (PubMed:30804664). {ECO:0000269|PubMed:21965679, CC ECO:0000269|PubMed:30804664}. CC -!- SIMILARITY: Belongs to the IL-1 family. {ECO:0000305}. CC -!- WEB RESOURCE: Name=Wikipedia; Note=Interleukin-1 entry; CC URL="https://en.wikipedia.org/wiki/Interleukin_1"; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/il1f9/"; 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; AF200492; AAF69248.1; -; mRNA. DR EMBL; AF206696; AAG35670.1; -; mRNA. DR EMBL; BN000002; CAD29874.1; -; Genomic_DNA. DR EMBL; AY359111; AAQ89469.1; -; mRNA. DR EMBL; AY968311; AAX59035.1; -; Genomic_DNA. DR EMBL; AC016724; AAY14987.1; -; Genomic_DNA. DR EMBL; BC096721; AAH96721.1; -; mRNA. DR EMBL; BC098130; AAH98130.1; -; mRNA. DR EMBL; BC098155; AAH98155.1; -; mRNA. DR EMBL; BC098337; AAH98337.1; -; mRNA. DR CCDS; CCDS2108.1; -. [Q9NZH8-1] DR CCDS; CCDS62992.1; -. [Q9NZH8-2] DR RefSeq; NP_001265497.1; NM_001278568.1. [Q9NZH8-2] DR RefSeq; NP_062564.1; NM_019618.3. [Q9NZH8-1] DR PDB; 4IZE; X-ray; 2.00 A; A=18-169. DR PDB; 4P0J; X-ray; 2.30 A; A/B=154-160. DR PDB; 4P0K; X-ray; 1.70 A; A=64-72, A=154-160. DR PDB; 4P0L; X-ray; 1.55 A; A=64-72, A=154-160. DR PDB; 6P9E; X-ray; 2.00 A; A=18-169. DR PDBsum; 4IZE; -. DR PDBsum; 4P0J; -. DR PDBsum; 4P0K; -. DR PDBsum; 4P0L; -. DR PDBsum; 6P9E; -. DR AlphaFoldDB; Q9NZH8; -. DR SMR; Q9NZH8; -. DR BioGRID; 121135; 81. DR IntAct; Q9NZH8; 4. DR STRING; 9606.ENSP00000259205; -. DR iPTMnet; Q9NZH8; -. DR PhosphoSitePlus; Q9NZH8; -. DR BioMuta; IL36G; -. DR EPD; Q9NZH8; -. DR MassIVE; Q9NZH8; -. DR PaxDb; 9606-ENSP00000259205; -. DR PeptideAtlas; Q9NZH8; -. DR PRIDE; Q9NZH8; -. DR ProteomicsDB; 83397; -. [Q9NZH8-1] DR ProteomicsDB; 83398; -. [Q9NZH8-2] DR Pumba; Q9NZH8; -. DR Antibodypedia; 33310; 366 antibodies from 33 providers. DR DNASU; 56300; -. DR Ensembl; ENST00000259205.5; ENSP00000259205.3; ENSG00000136688.11. [Q9NZH8-1] DR Ensembl; ENST00000376489.6; ENSP00000365672.2; ENSG00000136688.11. [Q9NZH8-2] DR GeneID; 56300; -. DR KEGG; hsa:56300; -. DR MANE-Select; ENST00000259205.5; ENSP00000259205.3; NM_019618.4; NP_062564.1. DR UCSC; uc002tio.3; human. [Q9NZH8-1] DR AGR; HGNC:15741; -. DR CTD; 56300; -. DR DisGeNET; 56300; -. DR GeneCards; IL36G; -. DR HGNC; HGNC:15741; IL36G. DR HPA; ENSG00000136688; Group enriched (esophagus, lymphoid tissue, skin). DR MIM; 605542; gene. DR neXtProt; NX_Q9NZH8; -. DR OpenTargets; ENSG00000136688; -. DR PharmGKB; PA38395; -. DR VEuPathDB; HostDB:ENSG00000136688; -. DR eggNOG; ENOG502STX9; Eukaryota. DR GeneTree; ENSGT00950000182943; -. DR HOGENOM; CLU_095373_1_1_1; -. DR InParanoid; Q9NZH8; -. DR OMA; MCLFCED; -. DR OrthoDB; 4634372at2759; -. DR PhylomeDB; Q9NZH8; -. DR TreeFam; TF300203; -. DR PathwayCommons; Q9NZH8; -. DR Reactome; R-HSA-9014826; Interleukin-36 pathway. DR SignaLink; Q9NZH8; -. DR BioGRID-ORCS; 56300; 12 hits in 1136 CRISPR screens. DR GeneWiki; IL1F9; -. DR GenomeRNAi; 56300; -. DR Pharos; Q9NZH8; Tbio. DR PRO; PR:Q9NZH8; -. DR Proteomes; UP000005640; Chromosome 2. DR RNAct; Q9NZH8; Protein. DR Bgee; ENSG00000136688; Expressed in periodontal ligament and 99 other cell types or tissues. DR ExpressionAtlas; Q9NZH8; baseline and differential. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; IBA:GO_Central. DR GO; GO:0005654; C:nucleoplasm; IDA:HPA. DR GO; GO:0005886; C:plasma membrane; IDA:HPA. DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central. DR GO; GO:0005149; F:interleukin-1 receptor binding; IEA:InterPro. DR GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc. DR GO; GO:0071222; P:cellular response to lipopolysaccharide; IBA:GO_Central. DR GO; GO:0019221; P:cytokine-mediated signaling pathway; 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:0010628; P:positive regulation of gene expression; IBA:GO_Central. DR Gene3D; 2.80.10.50; -; 1. DR InterPro; IPR000975; IL-1_fam. DR InterPro; IPR003297; IL-1RA/IL-36. DR InterPro; IPR008996; IL1/FGF. DR PANTHER; PTHR10078; INTERLEUKIN-1 FAMILY MEMBER; 1. DR PANTHER; PTHR10078:SF27; INTERLEUKIN-36 GAMMA; 1. DR Pfam; PF00340; IL1; 1. DR PRINTS; PR00264; INTERLEUKIN1. DR PRINTS; PR01360; INTRLEUKIN1X. DR SMART; SM00125; IL1; 1. DR SUPFAM; SSF50353; Cytokine; 1. DR Genevisible; Q9NZH8; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytokine; Cytoplasm; Immunity; KW Inflammatory response; Innate immunity; Reference proteome; Secreted. FT PROPEP 1..17 FT /evidence="ECO:0000269|PubMed:21965679" FT /id="PRO_0000430549" FT CHAIN 18..169 FT /note="Interleukin-36 gamma" FT /id="PRO_0000153648" FT VAR_SEQ 19..54 FT /note="MCKPITGTINDLNQQVWTLQGQNLVAVPRSDSVTPV -> I (in FT isoform 2)" FT /evidence="ECO:0000303|PubMed:12975309" FT /id="VSP_013002" FT VARIANT 69 FT /note="Q -> K (in dbSNP:rs6707930)" FT /id="VAR_024505" FT STRAND 23..29 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 33..38 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 41..46 FT /evidence="ECO:0007829|PDB:4IZE" FT HELIX 47..49 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 55..60 FT /evidence="ECO:0007829|PDB:4IZE" FT HELIX 64..66 FT /evidence="ECO:0007829|PDB:4P0L" FT HELIX 69..71 FT /evidence="ECO:0007829|PDB:4P0L" FT STRAND 73..80 FT /evidence="ECO:0007829|PDB:4IZE" FT TURN 81..83 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 84..89 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 91..94 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 96..101 FT /evidence="ECO:0007829|PDB:4IZE" FT HELIX 104..109 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 110..112 FT /evidence="ECO:0007829|PDB:4IZE" FT HELIX 115..117 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 118..124 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 127..135 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 139..142 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 150..153 FT /evidence="ECO:0007829|PDB:4IZE" FT STRAND 156..160 FT /evidence="ECO:0007829|PDB:4P0L" FT STRAND 163..167 FT /evidence="ECO:0007829|PDB:4IZE" SQ SEQUENCE 169 AA; 18721 MW; F00A9243706F4154 CRC64; MRGTPGDADG GGRAVYQSMC KPITGTINDL NQQVWTLQGQ NLVAVPRSDS VTPVTVAVIT CKYPEALEQG RGDPIYLGIQ NPEMCLYCEK VGEQPTLQLK EQKIMDLYGQ PEPVKPFLFY RAKTGRTSTL ESVAFPDWFI ASSKRDQPII LTSELGKSYN TAFELNIND //