IL21_HUMAN
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 03-AUG-2022, entry version 157.
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/";
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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 PDBsum; 2OQP; -.
DR PDBsum; 3TGX; -.
DR AlphaFoldDB; Q9HBE4; -.
DR SMR; Q9HBE4; -.
DR BioGRID; 121857; 8.
DR IntAct; Q9HBE4; 4.
DR MINT; Q9HBE4; -.
DR STRING; 9606.ENSP00000264497; -.
DR BindingDB; Q9HBE4; -.
DR ChEMBL; CHEMBL4665586; -.
DR GlyGen; Q9HBE4; 1 site.
DR iPTMnet; Q9HBE4; -.
DR PhosphoSitePlus; Q9HBE4; -.
DR BioMuta; IL21; -.
DR DMDM; 55976599; -.
DR PaxDb; Q9HBE4; -.
DR PeptideAtlas; Q9HBE4; -.
DR PRIDE; Q9HBE4; -.
DR ProteomicsDB; 81533; -. [Q9HBE4-1]
DR ProteomicsDB; 81534; -. [Q9HBE4-2]
DR ABCD; Q9HBE4; 14 sequenced antibodies.
DR Antibodypedia; 15937; 842 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 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; 1439856at2759; -.
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 1059 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 lymph node and 19 other tissues.
DR ExpressionAtlas; Q9HBE4; baseline and differential.
DR Genevisible; Q9HBE4; HS.
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:0032729; P:positive regulation of interferon-gamma production; NAS:UniProtKB.
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: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; -; 1.
DR InterPro; IPR009079; 4_helix_cytokine-like_core.
DR InterPro; IPR003443; IL-15/IL-21_fam.
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; 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 STRAND 114..116
FT /evidence="ECO:0007829|PDB:2OQP"
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
