IL36A_HUMAN
ID IL36A_HUMAN Reviewed; 158 AA.
AC Q9UHA7; B2RAD9; Q53SR7; Q5BLR4; Q7RTZ8;
DT 08-NOV-2002, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-2000, sequence version 1.
DT 03-AUG-2022, entry version 161.
DE RecName: Full=Interleukin-36 alpha;
DE AltName: Full=FIL1 epsilon;
DE AltName: Full=Interleukin-1 epsilon;
DE Short=IL-1 epsilon;
DE AltName: Full=Interleukin-1 family member 6;
DE Short=IL-1F6;
DE Flags: Precursor;
GN Name=IL36A {ECO:0000312|HGNC:HGNC:15562}; Synonyms=FIL1E, IL1E, IL1F6;
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].
RX PubMed=10625660; DOI=10.1074/jbc.275.2.1169;
RA Smith D.E., Renshaw B.R., Ketchem R.R., Kubin M., Garka K.E., Sims J.E.;
RT "Four new members expand the IL-1 superfamily.";
RL J. Biol. Chem. 275:1169-1175(2000).
RN [2]
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 [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], AND VARIANT ARG-12.
RC TISSUE=Esophagus;
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 [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS ARG-12; THR-63 AND ARG-134.
RG SeattleSNPs variation discovery resource;
RL Submitted (FEB-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [7]
RP TISSUE SPECIFICITY, AND INDUCTION.
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 [8]
RP FUNCTION.
RX PubMed=14734551; DOI=10.1074/jbc.m400117200;
RA Towne J.E., Garka K.E., Renshaw B.R., Virca G.D., Sims J.E.;
RT "Interleukin (IL)-1F6, IL-1F8, and IL-1F9 signal through IL-1Rrp2 and IL-
RT 1RAcP to activate the pathway leading to NF-kappaB and MAPKs.";
RL J. Biol. Chem. 279:13677-13688(2004).
RN [9]
RP NITRATION [LARGE SCALE ANALYSIS] AT TYR-96, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Pituitary adenoma;
RX PubMed=16777052; DOI=10.1016/j.ab.2006.05.024;
RA Zhan X., Desiderio D.M.;
RT "Nitroproteins from a human pituitary adenoma tissue discovered with a
RT nitrotyrosine affinity column and tandem mass spectrometry.";
RL Anal. Biochem. 354:279-289(2006).
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.
RX PubMed=21881584; DOI=10.1038/jid.2011.234;
RA Carrier Y., Ma H.L., Ramon H.E., Napierata L., Small C., O'Toole M.,
RA Young D.A., Fouser L.A., Nickerson-Nutter C., Collins M.,
RA Dunussi-Joannopoulos K., Medley Q.G.;
RT "Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in
RT vivo: implications in psoriasis pathogenesis.";
RL J. Invest. Dermatol. 131:2428-2437(2011).
RN [12]
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 [13]
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 linked to a pro-inflammatory response. Part of the IL-
CC 36 signaling system that is thought to be present in epithelial
CC barriers and to take part in local inflammatory response; similar to
CC the IL-1 system with which it shares the coreceptor IL1RAP. Seems to be
CC involved in skin inflammatory response by acting on keratinocytes,
CC dendritic cells and indirectly on T-cells to drive tissue infiltration,
CC cell maturation and cell proliferation. In cultured keratinocytes
CC induces the expression of macrophage, T-cell, and neutrophil
CC chemokines, such as CCL3, CCL4, CCL5, CCL2, CCL17, CCL22, CL20, CCL5,
CC CCL2, CCL17, CCL22, CXCL8, CCL20 and CXCL1, and the production of pro-
CC inflammatory cytokines such as TNF-alpha, IL-8 and IL-6. In cultured
CC monocytes up-regulates expression of IL-1A, IL-1B and IL-6. In myeloid
CC dendritic cells involved in cell maturation by up-regulating surface
CC expression of CD83, CD86 and HLA-DR. In monocyte-derived dendritic
CC cells facilitates dendritic cell maturation and drives T-cell
CC proliferation. May play a role in pro-inflammatory effects in the lung.
CC {ECO:0000269|PubMed:14734551, ECO:0000269|PubMed:21881584,
CC ECO:0000269|PubMed:21965679, ECO:0000269|PubMed:24829417}.
CC -!- SUBUNIT: Interacts with TMED10; the interaction mediates the
CC translocation from the cytoplasm into the ERGIC (endoplasmic reticulum-
CC Golgi intermediate compartment) and thereby secretion.
CC {ECO:0000269|PubMed:32272059}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:32272059}. Secreted
CC {ECO:0000269|PubMed:32272059}. 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 -!- TISSUE SPECIFICITY: Expressed in immune system and fetal brain, but not
CC in other tissues tested or in multiple hematopoietic cell lines.
CC Predominantly expressed in skin keratinocytes but not in fibroblasts,
CC endothelial cells or melanocytes. Increased in lesional psoriasis skin.
CC {ECO:0000269|PubMed:11466363}.
CC -!- INDUCTION: By Il-1 and TNF-alpha. {ECO:0000269|PubMed:11466363}.
CC -!- PTM: N-terminal truncation leads to a dramatic enhancement of its
CC activity (>1000-fold). {ECO:0000269|PubMed:21965679}.
CC -!- MISCELLANEOUS: Initial experiments using non-processed full-length
CC protein found in vitro activity only in the ug range.
CC {ECO:0000269|PubMed:14734551}.
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/il1f6/";
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DR EMBL; AF201831; AAF25211.1; -; mRNA.
DR EMBL; BN000002; CAD29875.1; -; Genomic_DNA.
DR EMBL; AK314149; BAG36836.1; -; mRNA.
DR EMBL; AY944686; AAX20113.1; -; Genomic_DNA.
DR EMBL; AC016724; AAY14988.1; -; Genomic_DNA.
DR EMBL; BC107042; AAI07043.1; -; mRNA.
DR EMBL; BC107043; AAI07044.1; -; mRNA.
DR CCDS; CCDS42734.1; -.
DR RefSeq; NP_055255.1; NM_014440.2.
DR RefSeq; XP_005263696.1; XM_005263639.2.
DR RefSeq; XP_011509267.1; XM_011510965.1.
DR RefSeq; XP_016859295.1; XM_017003806.1.
DR PDB; 6HPI; NMR; -; A=1-158.
DR PDBsum; 6HPI; -.
DR AlphaFoldDB; Q9UHA7; -.
DR SMR; Q9UHA7; -.
DR BioGRID; 118055; 35.
DR IntAct; Q9UHA7; 12.
DR STRING; 9606.ENSP00000259211; -.
DR iPTMnet; Q9UHA7; -.
DR PhosphoSitePlus; Q9UHA7; -.
DR BioMuta; IL36A; -.
DR DMDM; 25008601; -.
DR MassIVE; Q9UHA7; -.
DR PaxDb; Q9UHA7; -.
DR PeptideAtlas; Q9UHA7; -.
DR PRIDE; Q9UHA7; -.
DR ProteomicsDB; 84293; -.
DR Antibodypedia; 33315; 352 antibodies from 31 providers.
DR DNASU; 27179; -.
DR Ensembl; ENST00000259211.7; ENSP00000259211.6; ENSG00000136694.9.
DR GeneID; 27179; -.
DR KEGG; hsa:27179; -.
DR MANE-Select; ENST00000259211.7; ENSP00000259211.6; NM_014440.3; NP_055255.1.
DR UCSC; uc010yxr.3; human.
DR CTD; 27179; -.
DR DisGeNET; 27179; -.
DR GeneCards; IL36A; -.
DR HGNC; HGNC:15562; IL36A.
DR HPA; ENSG00000136694; Group enriched (esophagus, lymphoid tissue).
DR MIM; 605509; gene.
DR neXtProt; NX_Q9UHA7; -.
DR OpenTargets; ENSG00000136694; -.
DR PharmGKB; PA38389; -.
DR VEuPathDB; HostDB:ENSG00000136694; -.
DR eggNOG; ENOG502TDU1; Eukaryota.
DR GeneTree; ENSGT00950000182943; -.
DR HOGENOM; CLU_095373_1_0_1; -.
DR InParanoid; Q9UHA7; -.
DR OMA; PFLFYHN; -.
DR OrthoDB; 1502484at2759; -.
DR PhylomeDB; Q9UHA7; -.
DR TreeFam; TF300203; -.
DR PathwayCommons; Q9UHA7; -.
DR Reactome; R-HSA-9014826; Interleukin-36 pathway.
DR SignaLink; Q9UHA7; -.
DR BioGRID-ORCS; 27179; 9 hits in 1056 CRISPR screens.
DR GeneWiki; IL1F6; -.
DR GenomeRNAi; 27179; -.
DR Pharos; Q9UHA7; Tbio.
DR PRO; PR:Q9UHA7; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q9UHA7; protein.
DR Bgee; ENSG00000136694; Expressed in lower esophagus mucosa and 71 other tissues.
DR Genevisible; Q9UHA7; HS.
DR GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IBA:GO_Central.
DR GO; GO:0005125; F:cytokine activity; IBA:GO_Central.
DR GO; GO:0005149; F:interleukin-1 receptor binding; NAS:UniProtKB.
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:0006955; P:immune response; NAS:UniProtKB.
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:0010628; P:positive regulation of gene expression; IBA:GO_Central.
DR GO; GO:0032755; P:positive regulation of interleukin-6 production; IEA:Ensembl.
DR InterPro; IPR000975; IL-1_fam.
DR InterPro; IPR027163; IL-36_alpha.
DR InterPro; IPR008996; IL1/FGF.
DR PANTHER; PTHR10078; PTHR10078; 1.
DR PANTHER; PTHR10078:SF25; PTHR10078:SF25; 1.
DR Pfam; PF00340; IL1; 1.
DR PRINTS; PR00264; INTERLEUKIN1.
DR SUPFAM; SSF50353; SSF50353; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytokine; Cytoplasm; Immunity; Inflammatory response;
KW Innate immunity; Nitration; Reference proteome; Secreted.
FT PROPEP 1..5
FT /evidence="ECO:0000269|PubMed:21965679"
FT /id="PRO_0000430545"
FT CHAIN 6..158
FT /note="Interleukin-36 alpha"
FT /id="PRO_0000153644"
FT MOD_RES 96
FT /note="3'-nitrotyrosine"
FT /evidence="ECO:0007744|PubMed:16777052"
FT VARIANT 12
FT /note="Q -> R (in dbSNP:rs895497)"
FT /evidence="ECO:0000269|PubMed:14702039, ECO:0000269|Ref.4"
FT /id="VAR_024504"
FT VARIANT 63
FT /note="I -> T (in dbSNP:rs28938798)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_025055"
FT VARIANT 134
FT /note="G -> R (in dbSNP:rs28947175)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_025056"
FT STRAND 11..15
FT /evidence="ECO:0007829|PDB:6HPI"
FT HELIX 16..18
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 23..26
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 29..32
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 43..48
FT /evidence="ECO:0007829|PDB:6HPI"
FT HELIX 52..54
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 62..68
FT /evidence="ECO:0007829|PDB:6HPI"
FT TURN 69..71
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 76..78
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 80..85
FT /evidence="ECO:0007829|PDB:6HPI"
FT HELIX 92..97
FT /evidence="ECO:0007829|PDB:6HPI"
FT TURN 103..105
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 107..114
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 116..123
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 127..129
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 139..142
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 145..148
FT /evidence="ECO:0007829|PDB:6HPI"
FT STRAND 155..157
FT /evidence="ECO:0007829|PDB:6HPI"
SQ SEQUENCE 158 AA; 17684 MW; 469AC84306B0E280 CRC64;
MEKALKIDTP QQGSIQDINH RVWVLQDQTL IAVPRKDRMS PVTIALISCR HVETLEKDRG
NPIYLGLNGL NLCLMCAKVG DQPTLQLKEK DIMDLYNQPE PVKSFLFYHS QSGRNSTFES
VAFPGWFIAV SSEGGCPLIL TQELGKANTT DFGLTMLF
