ID IL21_HUMAN Reviewed; 155 AA. AC Q9HBE4; A5J0L4; DT 23-NOV-2004, integrated into UniProtKB/Swiss-Prot. DT 23-NOV-2004, sequence version 2. DT 11-NOV-2015, entry version 114. DE RecName: Full=Interleukin-21; DE Short=IL-21; DE AltName: Full=Za11; DE Flags: Precursor; GN Name=IL21; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION, SUBCELLULAR RP LOCATION, AND TISSUE SPECIFICITY. RX PubMed=11081504; DOI=10.1038/35040504; RA Parrish-Novak J., Dillon S.R., Nelson A., Hammond A., Sprecher C., RA Gross J.A., Johnston J., Madden K., Xu W., West J., Schrader S., RA Burkhead S., Heipel M., Brandt C., Kuijper J.L., Kramer J., RA Conklin D., Presnell S.R., Berry J., Shiota F., Bort S., Hambly K., RA Mudri S., Clegg C., Moore M., Grant F.J., Lofton-Day C., Gilbert T., RA Raymond F., Ching A., Yao L., Smith D., Webster P., Whitmore T., RA Maurer M., Kaushansky K., Holly R.D., Foster D.; RT "Interleukin 21 and its receptor are involved in NK cell expansion and RT regulation of lymphocyte function."; RL Nature 408:57-63(2000). RN [2] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2). RX PubMed=17673207; DOI=10.1016/j.febslet.2007.07.034; RA Rahman M., Nara H., Onoda T., Araki A., Li J., Hoshino T., Asao H.; RT "Cloning and characterization of an isoform of interleukin-21."; RL FEBS Lett. 581:4001-4009(2007). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA]. RG SeattleSNPs variation discovery resource; RL Submitted (SEP-2004) to the EMBL/GenBank/DDBJ databases. RN [4] 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., RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J., RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., RA 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., RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., RA 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., RA Waterston R.H., Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 RT and 4."; RL Nature 434:724-731(2005). RN [5] 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP FUNCTION. RX PubMed=15178704; DOI=10.1189/jlb.1003488; RA Strengell M., Julkunen I., Matikainen S.; RT "IFN-alpha regulates IL-21 and IL-21R expression in human NK and T RT cells."; RL J. Leukoc. Biol. 76:416-422(2004). RN [7] RP REVIEW. RX PubMed=15147560; DOI=10.1111/j.1365-2567.2004.01886.x; RA Sivakumar P.V., Foster D.C., Clegg C.H.; RT "Interleukin-21 is a T-helper cytokine that regulates humoral immunity RT and cell-mediated anti-tumour responses."; RL Immunology 112:177-182(2004). RN [8] RP STRUCTURE BY NMR OF 23-155, AND DISULFIDE BONDS. RX PubMed=17565991; DOI=10.1074/jbc.M701313200; RA Bondensgaard K., Breinholt J., Madsen D., Omkvist D.H., Kang L., RA Worsaae A., Becker P., Schioedt C.B., Hjorth S.A.; RT "The existence of multiple conformers of interleukin-21 directs RT engineering of a superpotent analogue."; RL J. Biol. Chem. 282:23326-23336(2007). RN [9] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 23-155 IN COMPLEX WITH IL21R, RP AND DISULFIDE BONDS. RX PubMed=22235133; DOI=10.1074/jbc.M111.311084; RA Hamming O.J., Kang L., Svensson A., Karlsen J.L., Rahbek-Nielsen H., RA Paludan S.R., Hjorth S.A., Bondensgaard K., Hartmann R.; RT "Crystal structure of interleukin-21 receptor (IL-21R) bound to IL-21 RT reveals that sugar chain interacting with WSXWS motif is integral part RT of IL-21R."; RL J. Biol. Chem. 287:9454-9460(2012). RN [10] RP VARIANT CVID11 PRO-49, AND CHARACTERIZATION OF VARIANT CVID11 PRO-49. RX PubMed=24746753; DOI=10.1016/j.jaci.2014.02.034; RA Salzer E., Kansu A., Sic H., Majek P., Ikinciogullari A., Dogu F.E., RA Prengemann N.K., Santos-Valente E., Pickl W.F., Bilic I., Ban S.A., RA Kuloglu Z., Demir A.M., Ensari A., Colinge J., Rizzi M., Eibel H., RA Boztug K.; RT "Early-onset inflammatory bowel disease and common variable RT immunodeficiency-like disease caused by IL-21 deficiency."; RL J. Allergy Clin. Immunol. 133:1651-1660(2014). CC -!- FUNCTION: Cytokine with immunoregulatory activity. May promote the CC transition between innate and adaptive immunity. Induces the CC production of IgG(1) and IgG(3) in B-cells (By similarity). May CC play a role in proliferation and maturation of natural killer (NK) CC cells in synergy with IL15. May regulate proliferation of mature CC B- and T-cells in response to activating stimuli. In synergy with CC IL15 and IL18 stimulates interferon gamma production in T-cells CC and NK cells. During T-cell mediated immune response may inhibit CC dendritic cells (DC) activation and maturation. {ECO:0000250, CC ECO:0000269|PubMed:11081504, ECO:0000269|PubMed:15178704}. CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:11081504}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=Q9HBE4-1; Sequence=Displayed; CC Name=2; Synonyms=IL-21iso; CC IsoId=Q9HBE4-2; Sequence=VSP_030129; CC -!- TISSUE SPECIFICITY: Expressed in activated CD4-positive T-cells CC but not in CD8-positive T-cells, B-cells, or monocytes. CC {ECO:0000269|PubMed:11081504}. CC -!- DISEASE: Immunodeficiency, common variable, 11 (CVID11) CC [MIM:615767]: A primary immunodeficiency characterized by antibody CC deficiency, hypogammaglobulinemia, recurrent bacterial infections CC and an inability to mount an antibody response to antigen. The CC defect results from a failure of B-cell differentiation and CC impaired secretion of immunoglobulins; the numbers of circulating CC B-cells is usually in the normal range, but can be low. CC {ECO:0000269|PubMed:24746753}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the IL-15/IL-21 family. {ECO:0000305}. CC -!- SEQUENCE CAUTION: CC Sequence=AAG29348.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC Sequence=AAH66258.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC Sequence=AAH66259.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC Sequence=AAH66260.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC Sequence=AAH66261.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC Sequence=AAH66262.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC Sequence=AAH69124.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC Sequence=AAU88182.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC Sequence=ABG36529.1; Type=Erroneous initiation; Note=Translation N-terminally shortened.; Evidence={ECO:0000305}; CC -!- WEB RESOURCE: Name=SeattleSNPs; CC URL="http://pga.gs.washington.edu/data/il21/"; 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; AF254069; AAG29348.1; ALT_INIT; mRNA. DR EMBL; DQ645417; ABG36529.1; ALT_INIT; mRNA. DR EMBL; AY763518; AAU88182.1; ALT_INIT; Genomic_DNA. DR EMBL; AC053545; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC066258; AAH66258.1; ALT_INIT; mRNA. DR EMBL; BC066259; AAH66259.1; ALT_INIT; mRNA. DR EMBL; BC066260; AAH66260.1; ALT_INIT; mRNA. DR EMBL; BC066261; AAH66261.1; ALT_INIT; mRNA. DR EMBL; BC066262; AAH66262.1; ALT_INIT; mRNA. DR EMBL; BC069124; AAH69124.1; ALT_INIT; mRNA. DR RefSeq; NP_001193935.1; NM_001207006.2. DR RefSeq; NP_068575.1; NM_021803.3. DR UniGene; Hs.567559; -. DR PDB; 2OQP; NMR; -; A=23-155. DR PDB; 3TGX; X-ray; 2.80 A; B/D/F/H/J/L/N/P=23-155. DR PDBsum; 2OQP; -. DR PDBsum; 3TGX; -. DR ProteinModelPortal; Q9HBE4; -. DR SMR; Q9HBE4; 23-155. DR BioGrid; 121857; 3. DR IntAct; Q9HBE4; 2. DR MINT; MINT-8201759; -. DR STRING; 9606.ENSP00000264497; -. DR BioMuta; IL21; -. DR DMDM; 55976599; -. DR PaxDb; Q9HBE4; -. DR PRIDE; Q9HBE4; -. DR DNASU; 59067; -. DR Ensembl; ENST00000264497; ENSP00000264497; ENSG00000138684. DR Ensembl; ENST00000611104; ENSP00000477555; ENSG00000138684. DR GeneID; 59067; -. DR KEGG; hsa:59067; -. DR UCSC; uc003ies.3; human. [Q9HBE4-1] DR UCSC; uc010int.4; human. [Q9HBE4-2] DR CTD; 59067; -. DR GeneCards; IL21; -. DR H-InvDB; HIX0031753; -. DR HGNC; HGNC:6005; IL21. DR MIM; 605384; gene. DR MIM; 615767; phenotype. DR neXtProt; NX_Q9HBE4; -. DR Orphanet; 238569; Autosomal recessive early-onset inflammatory bowel disease. DR PharmGKB; PA29820; -. DR eggNOG; ENOG410IWTD; Eukaryota. DR eggNOG; ENOG411198G; LUCA. DR HOGENOM; HOG000113039; -. DR HOVERGEN; HBG052106; -. DR InParanoid; Q9HBE4; -. DR KO; K05434; -. DR OrthoDB; EOG7M98JN; -. DR PhylomeDB; Q9HBE4; -. DR TreeFam; TF336380; -. DR SignaLink; Q9HBE4; -. DR EvolutionaryTrace; Q9HBE4; -. DR GeneWiki; Interleukin_21; -. DR GenomeRNAi; 59067; -. DR NextBio; 65134; -. DR PRO; PR:Q9HBE4; -. DR Proteomes; UP000005640; Chromosome 4. DR Bgee; Q9HBE4; -. DR CleanEx; HS_IL21; -. DR Genevisible; Q9HBE4; HS. DR GO; GO:0005615; C:extracellular space; NAS:UniProtKB. DR GO; GO:0005622; C:intracellular; IDA:GOC. DR GO; GO:0005126; F:cytokine receptor binding; TAS:UniProtKB. DR GO; GO:0005134; F:interleukin-2 receptor binding; IPI:UniProtKB. DR GO; GO:0048469; P:cell maturation; IDA:UniProtKB. DR GO; GO:0006955; P:immune response; IEA:InterPro. DR GO; GO:0030890; P:positive regulation of B cell proliferation; IDA:MGI. DR GO; GO:0008284; P:positive regulation of cell proliferation; IDA:MGI. DR GO; GO:0001819; P:positive regulation of cytokine production; IDA:CACAO. DR GO; GO:0050729; P:positive regulation of inflammatory response; IC:BHF-UCL. DR GO; GO:0045078; P:positive regulation of interferon-gamma biosynthetic process; NAS:UniProtKB. DR GO; GO:0032733; P:positive regulation of interleukin-10 production; IEA:Ensembl. DR GO; GO:0032740; P:positive regulation of interleukin-17 production; IDA:BHF-UCL. DR GO; GO:0002729; P:positive regulation of natural killer cell cytokine production; IEA:Ensembl. DR GO; GO:0032825; P:positive regulation of natural killer cell differentiation; IEA:Ensembl. DR GO; GO:0045954; P:positive regulation of natural killer cell mediated cytotoxicity; IDA:CACAO. DR GO; GO:0042102; P:positive regulation of T cell proliferation; IDA:UniProtKB. DR GO; GO:0034105; P:positive regulation of tissue remodeling; IC:BHF-UCL. DR GO; GO:0042511; P:positive regulation of tyrosine phosphorylation of Stat1 protein; IDA:MGI. DR GO; GO:0042517; P:positive regulation of tyrosine phosphorylation of Stat3 protein; IDA:MGI. DR GO; GO:0007165; P:signal transduction; NAS:UniProtKB. DR GO; GO:0042503; P:tyrosine phosphorylation of Stat3 protein; IDA:CACAO. DR InterPro; IPR009079; 4_helix_cytokine-like_core. DR InterPro; IPR003443; IL-15/IL-21_fam. DR InterPro; IPR028151; IL-21. DR PANTHER; PTHR14356; PTHR14356; 1. DR Pfam; PF02372; IL15; 1. DR SUPFAM; SSF47266; SSF47266; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Complete proteome; Cytokine; KW Disease mutation; Disulfide bond; Glycoprotein; Reference proteome; KW Secreted; Signal. FT SIGNAL 1 22 {ECO:0000255}. FT CHAIN 23 155 Interleukin-21. FT /FTId=PRO_0000015505. FT CARBOHYD 90 90 N-linked (GlcNAc...). {ECO:0000255}. FT DISULFID 64 115 FT DISULFID 71 118 FT VAR_SEQ 140 155 MIHQHLSSRTHGSEDS -> VSTLSFI (in isoform FT 2). {ECO:0000303|PubMed:17673207}. FT /FTId=VSP_030129. FT VARIANT 49 49 L -> P (in CVID11; interferes with FT binding to IL21R). FT {ECO:0000269|PubMed:24746753}. FT /FTId=VAR_071292. FT HELIX 25 42 {ECO:0000244|PDB:3TGX}. FT HELIX 43 48 {ECO:0000244|PDB:3TGX}. FT HELIX 62 64 {ECO:0000244|PDB:3TGX}. FT HELIX 65 74 {ECO:0000244|PDB:3TGX}. FT HELIX 85 96 {ECO:0000244|PDB:3TGX}. FT STRAND 101 105 {ECO:0000244|PDB:2OQP}. FT STRAND 107 109 {ECO:0000244|PDB:2OQP}. FT STRAND 113 115 {ECO:0000244|PDB:3TGX}. FT TURN 118 120 {ECO:0000244|PDB:3TGX}. FT HELIX 126 142 {ECO:0000244|PDB:3TGX}. SQ SEQUENCE 155 AA; 17923 MW; E994A3D19029B914 CRC64; MERIVICLMV IFLGTLVHKS SSQGQDRHMI RMRQLIDIVD QLKNYVNDLV PEFLPAPEDV ETNCEWSAFS CFQKAQLKSA NTGNNERIIN VSIKKLKRKP PSTNAGRRQK HRLTCPSCDS YEKKPPKEFL ERFKSLLQKM IHQHLSSRTH GSEDS //