ID IL21_HUMAN Reviewed; 162 AA. AC Q9HBE4; A5J0L4; DT 23-NOV-2004, integrated into UniProtKB/Swiss-Prot. DT 10-APR-2019, sequence version 3. DT 27-MAR-2024, entry version 165. DE RecName: Full=Interleukin-21 {ECO:0000305}; DE Short=IL-21; DE AltName: Full=Za11; DE Flags: Precursor; GN Name=IL21 {ECO:0000312|HGNC:HGNC:6005}; 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), FUNCTION, SUBCELLULAR LOCATION, AND RP 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., Conklin D., RA Presnell S.R., Berry J., Shiota F., Bort S., Hambly K., Mudri S., Clegg C., RA Moore M., Grant F.J., Lofton-Day C., Gilbert T., Raymond F., Ching A., RA Yao L., Smith D., Webster P., Whitmore T., Maurer M., Kaushansky K., RA 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., 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 [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 project: RT 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 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 and RT cell-mediated anti-tumour responses."; RL Immunology 112:177-182(2004). RN [8] RP STRUCTURE BY NMR OF 30-162, 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 engineering RT of a superpotent analogue."; RL J. Biol. Chem. 282:23326-23336(2007). RN [9] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 30-162 IN COMPLEX WITH IL21R, AND RP 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 of RT IL-21R."; RL J. Biol. Chem. 287:9454-9460(2012). RN [10] RP VARIANT CVID11 PRO-56, AND CHARACTERIZATION OF VARIANT CVID11 PRO-56. 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 production CC of IgG(1) and IgG(3) in B-cells (By similarity). Implicated in the CC generation and maintenance of T follicular helper (Tfh) cells and the CC formation of germinal-centers. Together with IL6, control the early CC generation of Tfh cells and are critical for an effective antibody CC response to acute viral infection (By similarity). May play a role in CC proliferation and maturation of natural killer (NK) cells in synergy CC with IL15. May regulate proliferation of mature B- and T-cells in CC response to activating stimuli. In synergy with IL15 and IL18 CC stimulates interferon gamma production in T-cells and NK cells CC (PubMed:11081504, PubMed:15178704). During T-cell mediated immune CC response may inhibit dendritic cells (DC) activation and maturation (By CC similarity). {ECO:0000250|UniProtKB:Q9ES17, CC ECO:0000269|PubMed:11081504, ECO:0000269|PubMed:15178704}. CC -!- INTERACTION: CC Q9HBE4; Q12797-6: ASPH; NbExp=3; IntAct=EBI-6595560, EBI-12092171; 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 but not CC in CD8-positive T-cells, B-cells, or monocytes. CC {ECO:0000269|PubMed:11081504}. CC -!- DISEASE: Immunodeficiency, common variable, 11 (CVID11) [MIM:615767]: A CC primary immunodeficiency characterized by antibody deficiency, CC hypogammaglobulinemia, recurrent bacterial infections and an inability CC to mount an antibody response to antigen. The defect results from a CC failure of B-cell differentiation and impaired secretion of CC immunoglobulins; the numbers of circulating B-cells is usually in the CC normal range, but can be low. {ECO:0000269|PubMed:24746753}. Note=The CC disease is caused by variants affecting the gene represented in this CC entry. CC -!- SIMILARITY: Belongs to the IL-15/IL-21 family. {ECO:0000305}. CC -!- CAUTION: It is uncertain whether Met-1 or Met-8 is the initiator. CC {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; -; mRNA. DR EMBL; DQ645417; ABG36529.1; -; mRNA. DR EMBL; AY763518; AAU88182.1; -; Genomic_DNA. DR EMBL; AC053545; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC066258; AAH66258.1; -; mRNA. DR EMBL; BC066259; AAH66259.1; -; mRNA. DR EMBL; BC066260; AAH66260.1; -; mRNA. DR EMBL; BC066261; AAH66261.1; -; mRNA. DR EMBL; BC066262; AAH66262.1; -; mRNA. DR EMBL; BC069124; AAH69124.1; -; mRNA. DR CCDS; CCDS3727.1; -. [Q9HBE4-1] DR CCDS; CCDS75189.1; -. [Q9HBE4-2] DR RefSeq; NP_001193935.1; NM_001207006.2. [Q9HBE4-2] DR RefSeq; NP_068575.1; NM_021803.3. [Q9HBE4-1] DR PDB; 2OQP; NMR; -; A=30-162. DR PDB; 3TGX; X-ray; 2.80 A; B/D/F/H/J/L/N/P=30-162. DR PDB; 8ENT; X-ray; 2.83 A; A/D/G/J=30-162. DR PDBsum; 2OQP; -. DR PDBsum; 3TGX; -. DR PDBsum; 8ENT; -. DR AlphaFoldDB; Q9HBE4; -. DR EMDB; EMD-28278; -. DR SMR; Q9HBE4; -. DR BioGRID; 121857; 10. DR IntAct; Q9HBE4; 4. DR MINT; Q9HBE4; -. DR STRING; 9606.ENSP00000497915; -. DR BindingDB; Q9HBE4; -. DR ChEMBL; CHEMBL4665586; -. DR GlyCosmos; Q9HBE4; 1 site, No reported glycans. DR GlyGen; Q9HBE4; 1 site. DR iPTMnet; Q9HBE4; -. DR PhosphoSitePlus; Q9HBE4; -. DR BioMuta; IL21; -. DR DMDM; 55976599; -. DR MassIVE; Q9HBE4; -. DR PaxDb; 9606-ENSP00000264497; -. DR PeptideAtlas; Q9HBE4; -. DR ProteomicsDB; 81533; -. [Q9HBE4-1] DR ProteomicsDB; 81534; -. [Q9HBE4-2] DR ABCD; Q9HBE4; 14 sequenced antibodies. DR Antibodypedia; 15937; 961 antibodies from 45 providers. DR DNASU; 59067; -. DR Ensembl; ENST00000611104.2; ENSP00000477555.1; ENSG00000138684.9. [Q9HBE4-2] DR Ensembl; ENST00000648588.1; ENSP00000497915.1; ENSG00000138684.9. [Q9HBE4-1] DR GeneID; 59067; -. DR KEGG; hsa:59067; -. DR MANE-Select; ENST00000648588.1; ENSP00000497915.1; NM_021803.4; NP_068575.1. DR UCSC; uc003ies.4; human. [Q9HBE4-1] DR AGR; HGNC:6005; -. DR CTD; 59067; -. DR DisGeNET; 59067; -. DR GeneCards; IL21; -. DR HGNC; HGNC:6005; IL21. DR HPA; ENSG00000138684; Tissue enriched (lymphoid). DR MalaCards; IL21; -. DR MIM; 605384; gene. DR MIM; 615767; phenotype. DR neXtProt; NX_Q9HBE4; -. DR OpenTargets; ENSG00000138684; -. DR Orphanet; 477661; IL21-related infantile inflammatory bowel disease. DR PharmGKB; PA29820; -. DR VEuPathDB; HostDB:ENSG00000138684; -. DR eggNOG; ENOG502SES1; Eukaryota. DR GeneTree; ENSGT00390000010494; -. DR HOGENOM; CLU_127182_1_0_1; -. DR InParanoid; Q9HBE4; -. DR OMA; MIHQHLR; -. DR OrthoDB; 4440444at2759; -. DR PhylomeDB; Q9HBE4; -. DR TreeFam; TF336380; -. DR PathwayCommons; Q9HBE4; -. DR Reactome; R-HSA-9020958; Interleukin-21 signaling. DR SignaLink; Q9HBE4; -. DR SIGNOR; Q9HBE4; -. DR BioGRID-ORCS; 59067; 13 hits in 1135 CRISPR screens. DR EvolutionaryTrace; Q9HBE4; -. DR GeneWiki; Interleukin_21; -. DR GenomeRNAi; 59067; -. DR Pharos; Q9HBE4; Tbio. DR PRO; PR:Q9HBE4; -. DR Proteomes; UP000005640; Chromosome 4. DR RNAct; Q9HBE4; Protein. DR Bgee; ENSG00000138684; Expressed in male germ line stem cell (sensu Vertebrata) in testis and 19 other cell types or tissues. DR ExpressionAtlas; Q9HBE4; baseline and differential. DR GO; GO:0005576; C:extracellular region; TAS:Reactome. DR GO; GO:0005615; C:extracellular space; NAS:UniProtKB. DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW. 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:0098586; P:cellular response to virus; ISS:UniProtKB. DR GO; GO:0051607; P:defense response to virus; TAS:ARUK-UCL. DR GO; GO:0002314; P:germinal center B cell differentiation; ISS:UniProtKB. DR GO; GO:0030890; P:positive regulation of B cell proliferation; IDA:MGI. DR GO; GO:0008284; P:positive regulation of cell population proliferation; IDA:MGI. DR GO; GO:0001819; P:positive regulation of cytokine production; IDA:CACAO. DR GO; GO:0002639; P:positive regulation of immunoglobulin production; ISS:UniProtKB. DR GO; GO:0050729; P:positive regulation of inflammatory response; IC:BHF-UCL. DR GO; GO:0032740; P:positive regulation of interleukin-17 production; IDA:BHF-UCL. 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:0032729; P:positive regulation of type II interferon production; NAS:UniProtKB. DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IDA:MGI. DR GO; GO:0007165; P:signal transduction; NAS:UniProtKB. DR GO; GO:0061470; P:T follicular helper cell differentiation; ISS:UniProtKB. DR GO; GO:0007260; P:tyrosine phosphorylation of STAT protein; IDA:CACAO. DR Gene3D; 1.20.1250.70; Interleukin-15/Interleukin-21; 1. DR InterPro; IPR009079; 4_helix_cytokine-like_core. DR InterPro; IPR003443; IL-15/IL-21_fam. DR PANTHER; PTHR14356; INTERLEUKIN-15-RELATED; 1. DR PANTHER; PTHR14356:SF2; INTERLEUKIN-21; 1. DR Pfam; PF02372; IL15; 1. DR SUPFAM; SSF47266; 4-helical cytokines; 1. DR Genevisible; Q9HBE4; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Cytokine; Disease variant; KW Disulfide bond; Glycoprotein; Reference proteome; Secreted; Signal. FT SIGNAL 1..24 FT /evidence="ECO:0000250|UniProtKB:Q76LU5" FT CHAIN 25..162 FT /note="Interleukin-21" FT /id="PRO_0000015505" FT REGION 105..126 FT /note="Disordered" FT /evidence="ECO:0000256|SAM:MobiDB-lite" FT CARBOHYD 97 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000255" FT DISULFID 71..122 FT /evidence="ECO:0000269|PubMed:17565991, FT ECO:0000269|PubMed:22235133, ECO:0000312|PDB:2OQP, FT ECO:0000312|PDB:3TGX" FT DISULFID 78..125 FT /evidence="ECO:0000269|PubMed:17565991, FT ECO:0000269|PubMed:22235133, ECO:0000312|PDB:2OQP, FT ECO:0000312|PDB:3TGX" FT VAR_SEQ 147..162 FT /note="MIHQHLSSRTHGSEDS -> VSTLSFI (in isoform 2)" FT /evidence="ECO:0000303|PubMed:17673207" FT /id="VSP_030129" FT VARIANT 56 FT /note="L -> P (in CVID11; interferes with binding to FT IL21R)" FT /evidence="ECO:0000269|PubMed:24746753" FT /id="VAR_071292" FT HELIX 32..49 FT /evidence="ECO:0007829|PDB:3TGX" FT HELIX 50..55 FT /evidence="ECO:0007829|PDB:3TGX" FT HELIX 69..71 FT /evidence="ECO:0007829|PDB:3TGX" FT HELIX 72..81 FT /evidence="ECO:0007829|PDB:3TGX" FT HELIX 92..103 FT /evidence="ECO:0007829|PDB:3TGX" FT STRAND 108..112 FT /evidence="ECO:0007829|PDB:2OQP" FT HELIX 113..115 FT /evidence="ECO:0007829|PDB:8ENT" FT STRAND 120..122 FT /evidence="ECO:0007829|PDB:3TGX" FT TURN 125..127 FT /evidence="ECO:0007829|PDB:3TGX" FT HELIX 133..149 FT /evidence="ECO:0007829|PDB:3TGX" SQ SEQUENCE 162 AA; 18653 MW; 54EFD4EED3AB97FE CRC64; MRSSPGNMER IVICLMVIFL GTLVHKSSSQ GQDRHMIRMR QLIDIVDQLK NYVNDLVPEF LPAPEDVETN CEWSAFSCFQ KAQLKSANTG NNERIINVSI KKLKRKPPST NAGRRQKHRL TCPSCDSYEK KPPKEFLERF KSLLQKMIHQ HLSSRTHGSE DS //