IL12A_HUMAN
ID IL12A_HUMAN Reviewed; 219 AA.
AC P29459; Q96QZ1;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2002, sequence version 2.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Interleukin-12 subunit alpha;
DE Short=IL-12A;
DE AltName: Full=Cytotoxic lymphocyte maturation factor 35 kDa subunit;
DE Short=CLMF p35;
DE AltName: Full=IL-12 subunit p35;
DE AltName: Full=NK cell stimulatory factor chain 1;
DE Short=NKSF1;
DE Flags: Precursor;
GN Name=IL12A; Synonyms=NKSF1;
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], AND FUNCTION.
RX PubMed=1673147;
RA Wolf S.F., Temple P.A., Kobayashi M., Young D., Dicig M., Lowe L.,
RA Dzialo R., Fitz L., Ferenz C., Hewick R.M., Kelleher K., Herrmann S.H.,
RA Clark S.C., Azzoni L., Chan S.H., Trinchieri G., Perussia B.;
RT "Cloning of cDNA for natural killer cell stimulatory factor, a
RT heterodimeric cytokine with multiple biologic effects on T and natural
RT killer cells.";
RL J. Immunol. 146:3074-3081(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBUNIT, AND SUBCELLULAR LOCATION.
RX PubMed=1674604; DOI=10.1073/pnas.88.10.4143;
RA Gubler U., Chua A.O., Schoenhaut D.S., Dwyer C.M., McComas W., Motyka R.,
RA Nabavi N., Wolitzky A.G., Quinn P.M., Familletti P.C., Gately M.K.;
RT "Coexpression of two distinct genes is required to generate secreted
RT bioactive cytotoxic lymphocyte maturation factor.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:4143-4147(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RG SeattleSNPs variation discovery resource;
RL Submitted (JUL-2001) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16641997; DOI=10.1038/nature04728;
RA Muzny D.M., Scherer S.E., Kaul R., Wang J., Yu J., Sudbrak R., Buhay C.J.,
RA Chen R., Cree A., Ding Y., Dugan-Rocha S., Gill R., Gunaratne P.,
RA Harris R.A., Hawes A.C., Hernandez J., Hodgson A.V., Hume J., Jackson A.,
RA Khan Z.M., Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Morgan M.B., Nazareth L.V., Scott G.,
RA Sodergren E., Song X.-Z., Steffen D., Wei S., Wheeler D.A., Wright M.W.,
RA Worley K.C., Yuan Y., Zhang Z., Adams C.Q., Ansari-Lari M.A., Ayele M.,
RA Brown M.J., Chen G., Chen Z., Clendenning J., Clerc-Blankenburg K.P.,
RA Chen R., Chen Z., Davis C., Delgado O., Dinh H.H., Dong W., Draper H.,
RA Ernst S., Fu G., Gonzalez-Garay M.L., Garcia D.K., Gillett W., Gu J.,
RA Hao B., Haugen E., Havlak P., He X., Hennig S., Hu S., Huang W.,
RA Jackson L.R., Jacob L.S., Kelly S.H., Kube M., Levy R., Li Z., Liu B.,
RA Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V., Okwuonu G.O.,
RA Palmeiri A., Pasternak S., Perez L.M., Phelps K.A., Plopper F.J., Qiang B.,
RA Raymond C., Rodriguez R., Saenphimmachak C., Santibanez J., Shen H.,
RA Shen Y., Subramanian S., Tabor P.E., Verduzco D., Waldron L., Wang J.,
RA Wang J., Wang Q., Williams G.A., Wong G.K.-S., Yao Z., Zhang J., Zhang X.,
RA Zhao G., Zhou J., Zhou Y., Nelson D., Lehrach H., Reinhardt R.,
RA Naylor S.L., Yang H., Olson M., Weinstock G., Gibbs R.A.;
RT "The DNA sequence, annotation and analysis of human chromosome 3.";
RL Nature 440:1194-1198(2006).
RN [5]
RP PROTEIN SEQUENCE OF 23-48, AND FUNCTION.
RX PubMed=2204066; DOI=10.1073/pnas.87.17.6808;
RA Stern A.S., Podlaski F.J., Hulmes J.D., Pan Y.C.E., Quinn P.M.,
RA Wolitzky A.G., Familletti P.C., Stremlo D.L., Truitt T., Chizzonite R.,
RA Gately M.K.;
RT "Purification to homogeneity and partial characterization of cytotoxic
RT lymphocyte maturation factor from human B-lymphoblastoid cells.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:6808-6812(1990).
RN [6]
RP SIMILARITY TO IL-6.
RX PubMed=1374259; DOI=10.1016/0167-5699(92)90140-3;
RA Merberg D.M., Wolf S.F., Clark S.C.;
RT "Sequence similarity between NKSF and the IL-6/G-CSF family.";
RL Immunol. Today 13:77-78(1992).
RN [7]
RP FUNCTION.
RX PubMed=7528775; DOI=10.1084/jem.181.1.399;
RA Bacon C.M., McVicar D.W., Ortaldo J.R., Rees R.C., O'Shea J.J.,
RA Johnston J.A.;
RT "Interleukin 12 (IL-12) induces tyrosine phosphorylation of JAK2 and TYK2:
RT differential use of Janus family tyrosine kinases by IL-2 and IL-12.";
RL J. Exp. Med. 181:399-404(1995).
RN [8]
RP FUNCTION IN STAT4 ACTIVATION.
RX PubMed=7638186; DOI=10.1073/pnas.92.16.7307;
RA Bacon C.M., Petricoin E.F. III, Ortaldo J.R., Rees R.C., Larner A.C.,
RA Johnston J.A., O'Shea J.J.;
RT "Interleukin 12 induces tyrosine phosphorylation and activation of STAT4 in
RT human lymphocytes.";
RL Proc. Natl. Acad. Sci. U.S.A. 92:7307-7311(1995).
RN [9]
RP FUNCTION.
RX PubMed=8605935; DOI=10.1002/eji.1830260323;
RA Heufler C., Koch F., Stanzl U., Topar G., Wysocka M., Trinchieri G.,
RA Enk A., Steinman R.M., Romani N., Schuler G.;
RT "Interleukin-12 is produced by dendritic cells and mediates T helper 1
RT development as well as interferon-gamma production by T helper 1 cells.";
RL Eur. J. Immunol. 26:659-668(1996).
RN [10]
RP FUNCTION.
RX PubMed=8943050; DOI=10.1073/pnas.93.24.14002;
RA Presky D.H., Yang H., Minetti L.J., Chua A.O., Nabavi N., Wu C.-Y.,
RA Gately M.K., Gubler U.;
RT "A functional interleukin 12 receptor complex is composed of two beta-type
RT cytokine receptor subunits.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:14002-14007(1996).
RN [11]
RP SUBUNIT, SUBCELLULAR LOCATION, AND FUNCTION.
RX PubMed=9342359; DOI=10.1073/pnas.94.22.12041;
RA Devergne O., Birkenbach M., Kieff E.;
RT "Epstein-Barr virus-induced gene 3 and the p35 subunit of interleukin 12
RT form a novel heterodimeric hematopoietin.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:12041-12046(1997).
RN [12]
RP INDUCTION (MICROBIAL INFECTION), AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=16548883; DOI=10.1111/j.1462-5822.2005.00644.x;
RA Leong W.F., Chow V.T.;
RT "Transcriptomic and proteomic analyses of rhabdomyosarcoma cells reveal
RT differential cellular gene expression in response to enterovirus 71
RT infection.";
RL Cell. Microbiol. 8:565-580(2006).
RN [13]
RP FUNCTION.
RX PubMed=22306691; DOI=10.1038/ni.2227;
RA Collison L.W., Delgoffe G.M., Guy C.S., Vignali K.M., Chaturvedi V.,
RA Fairweather D., Satoskar A.R., Garcia K.C., Hunter C.A., Drake C.G.,
RA Murray P.J., Vignali D.A.;
RT "The composition and signaling of the IL-35 receptor are unconventional.";
RL Nat. Immunol. 13:290-299(2012).
RN [14]
RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 23-219, SUBUNIT, AND DISULFIDE
RP BONDS.
RX PubMed=10899108; DOI=10.1093/emboj/19.14.3530;
RA Yoon C., Johnston S.C., Tang J., Stahl M., Tobin J.F., Somers W.S.;
RT "Charged residues dominate a unique interlocking topography in the
RT heterodimeric cytokine interleukin-12.";
RL EMBO J. 19:3530-3541(2000).
CC -!- FUNCTION: Heterodimerizes with IL12B to form the IL-12 cytokine or with
CC EBI3/IL27B to form the IL-35 cytokine (PubMed:8943050, PubMed:8605935).
CC IL-12 is primarily produced by professional antigen-presenting cells
CC (APCs) such as B-cells and dendritic cells (DCs) as well as macrophages
CC and granulocytes and regulates T-cell and natural killer-cell
CC responses, induces the production of interferon-gamma (IFN-gamma),
CC favors the differentiation of T-helper 1 (Th1) cells and is an
CC important link between innate resistance and adaptive immunity
CC (PubMed:1673147, PubMed:1674604, PubMed:8605935). Mechanistically,
CC exerts its biological effects through a receptor composed of IL12R1 and
CC IL12R2 subunits (PubMed:8943050). Binding to the receptor results in
CC the rapid tyrosine phosphorylation of a number of cellular substrates
CC including the JAK family kinases TYK2 and JAK2 (PubMed:7528775). In
CC turn, recruited STAT4 gets phosphorylated and translocates to the
CC nucleus where it regulates cytokine/growth factor responsive genes
CC (PubMed:7638186). As part of IL-35, plays essential roles in
CC maintaining the immune homeostasis of the liver microenvironment and
CC functions also as an immune-suppressive cytokine (By similarity).
CC Mediates biological events through unconventional receptors composed of
CC IL12RB2 and gp130/IL6ST heterodimers or homodimers (PubMed:22306691).
CC Signaling requires the transcription factors STAT1 and STAT4, which
CC form a unique heterodimer that binds to distinct DNA sites
CC (PubMed:22306691). {ECO:0000250|UniProtKB:P43431,
CC ECO:0000269|PubMed:1673147, ECO:0000269|PubMed:1674604,
CC ECO:0000269|PubMed:2204066, ECO:0000269|PubMed:22306691,
CC ECO:0000269|PubMed:7528775, ECO:0000269|PubMed:7638186,
CC ECO:0000269|PubMed:8605935, ECO:0000269|PubMed:8943050}.
CC -!- SUBUNIT: Heterodimer with IL12B; disulfide-linked (PubMed:1674604,
CC PubMed:10899108). This heterodimer is known as interleukin IL-12
CC (PubMed:1674604). Heterodimer with EBI3/IL27B; not disulfide-linked
CC (PubMed:9342359). This heterodimer is known as interleukin IL-35
CC (PubMed:9342359). {ECO:0000269|PubMed:10899108,
CC ECO:0000269|PubMed:1674604, ECO:0000269|PubMed:9342359}.
CC -!- INTERACTION:
CC P29459; P29460: IL12B; NbExp=2; IntAct=EBI-1029636, EBI-1029614;
CC -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:1674604,
CC ECO:0000269|PubMed:9342359}.
CC -!- INDUCTION: (Microbial infection) By pathogenic organisms, including
CC Gram- positive and Gram-negative bacteria, parasites, viruses, and
CC fungi.Down-regulated in response to enterovirus 71 (EV71) infection.
CC {ECO:0000269|PubMed:16548883}.
CC -!- SIMILARITY: Belongs to the IL-6 superfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAA59937.1; Type=Erroneous initiation; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Interleukin-12 entry;
CC URL="https://en.wikipedia.org/wiki/Interleukin_12";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/il12a/";
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DR EMBL; M65291; AAA59937.1; ALT_INIT; mRNA.
DR EMBL; M65271; AAA35694.1; -; mRNA.
DR EMBL; AF404773; AAK84425.1; -; Genomic_DNA.
DR EMBL; AC010370; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR RefSeq; NP_000873.2; NM_000882.3.
DR PDB; 1F45; X-ray; 2.80 A; B=23-219.
DR PDB; 3HMX; X-ray; 3.00 A; B=23-219.
DR PDBsum; 1F45; -.
DR PDBsum; 3HMX; -.
DR AlphaFoldDB; P29459; -.
DR SMR; P29459; -.
DR BioGRID; 109806; 15.
DR ComplexPortal; CPX-381; Interleukin-12 complex.
DR ComplexPortal; CPX-382; Interleukin-12-receptor complex.
DR CORUM; P29459; -.
DR DIP; DIP-3772N; -.
DR IntAct; P29459; 8.
DR STRING; 9606.ENSP00000303231; -.
DR ChEMBL; CHEMBL2364153; -.
DR DrugCentral; P29459; -.
DR GlyGen; P29459; 2 sites.
DR iPTMnet; P29459; -.
DR PhosphoSitePlus; P29459; -.
DR BioMuta; IL12A; -.
DR DMDM; 20141534; -.
DR PaxDb; P29459; -.
DR PeptideAtlas; P29459; -.
DR PRIDE; P29459; -.
DR ABCD; P29459; 1 sequenced antibody.
DR Antibodypedia; 853; 1001 antibodies from 45 providers.
DR DNASU; 3592; -.
DR Ensembl; ENST00000305579.7; ENSP00000303231.2; ENSG00000168811.7.
DR GeneID; 3592; -.
DR KEGG; hsa:3592; -.
DR UCSC; uc003fcx.4; human.
DR CTD; 3592; -.
DR DisGeNET; 3592; -.
DR GeneCards; IL12A; -.
DR HGNC; HGNC:5969; IL12A.
DR HPA; ENSG00000168811; Tissue enhanced (esophagus).
DR MalaCards; IL12A; -.
DR MIM; 161560; gene.
DR neXtProt; NX_P29459; -.
DR Orphanet; 117; Behcet disease.
DR Orphanet; 186; Primary biliary cholangitis.
DR PharmGKB; PA29784; -.
DR VEuPathDB; HostDB:ENSG00000168811; -.
DR eggNOG; ENOG502S8JN; Eukaryota.
DR InParanoid; P29459; -.
DR OrthoDB; 1409826at2759; -.
DR PhylomeDB; P29459; -.
DR TreeFam; TF330814; -.
DR PathwayCommons; P29459; -.
DR Reactome; R-HSA-6783783; Interleukin-10 signaling.
DR Reactome; R-HSA-6785807; Interleukin-4 and Interleukin-13 signaling.
DR Reactome; R-HSA-8984722; Interleukin-35 Signalling.
DR Reactome; R-HSA-9020591; Interleukin-12 signaling.
DR SignaLink; P29459; -.
DR SIGNOR; P29459; -.
DR BioGRID-ORCS; 3592; 18 hits in 1075 CRISPR screens.
DR EvolutionaryTrace; P29459; -.
DR GeneWiki; IL12A; -.
DR GenomeRNAi; 3592; -.
DR Pharos; P29459; Tclin.
DR PRO; PR:P29459; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; P29459; protein.
DR Bgee; ENSG00000168811; Expressed in lower esophagus mucosa and 97 other tissues.
DR ExpressionAtlas; P29459; baseline and differential.
DR Genevisible; P29459; HS.
DR GO; GO:0005788; C:endoplasmic reticulum lumen; TAS:Reactome.
DR GO; GO:0005576; C:extracellular region; TAS:Reactome.
DR GO; GO:0005615; C:extracellular space; IDA:ComplexPortal.
DR GO; GO:0043514; C:interleukin-12 complex; IDA:UniProtKB.
DR GO; GO:0042022; C:interleukin-12 receptor complex; IC:ComplexPortal.
DR GO; GO:0031906; C:late endosome lumen; TAS:Reactome.
DR GO; GO:0005886; C:plasma membrane; IC:ComplexPortal.
DR GO; GO:0005125; F:cytokine activity; IEA:UniProtKB-KW.
DR GO; GO:0008083; F:growth factor activity; IEA:UniProtKB-KW.
DR GO; GO:0042163; F:interleukin-12 beta subunit binding; IPI:AgBase.
DR GO; GO:0005143; F:interleukin-12 receptor binding; NAS:UniProtKB.
DR GO; GO:0045513; F:interleukin-27 binding; IPI:UniProtKB.
DR GO; GO:0046982; F:protein heterodimerization activity; IPI:UniProtKB.
DR GO; GO:0016477; P:cell migration; IDA:UniProtKB.
DR GO; GO:0098586; P:cellular response to virus; IMP:UniProtKB.
DR GO; GO:0050830; P:defense response to Gram-positive bacterium; IEP:UniProtKB.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IDA:BHF-UCL.
DR GO; GO:0006955; P:immune response; TAS:UniProtKB.
DR GO; GO:1903588; P:negative regulation of blood vessel endothelial cell proliferation involved in sprouting angiogenesis; IGI:ARUK-UCL.
DR GO; GO:0032700; P:negative regulation of interleukin-17 production; IDA:BHF-UCL.
DR GO; GO:0050709; P:negative regulation of protein secretion; IGI:ARUK-UCL.
DR GO; GO:0048662; P:negative regulation of smooth muscle cell proliferation; IDA:BHF-UCL.
DR GO; GO:1900747; P:negative regulation of vascular endothelial growth factor signaling pathway; IGI:ARUK-UCL.
DR GO; GO:0045785; P:positive regulation of cell adhesion; IDA:UniProtKB.
DR GO; GO:2000510; P:positive regulation of dendritic cell chemotaxis; IMP:UniProtKB.
DR GO; GO:0032729; P:positive regulation of interferon-gamma production; IDA:ComplexPortal.
DR GO; GO:0050671; P:positive regulation of lymphocyte proliferation; IDA:UniProtKB.
DR GO; GO:0032946; P:positive regulation of mononuclear cell proliferation; IMP:AgBase.
DR GO; GO:0032816; P:positive regulation of natural killer cell activation; IDA:UniProtKB.
DR GO; GO:0045954; P:positive regulation of natural killer cell mediated cytotoxicity; IDA:UniProtKB.
DR GO; GO:0002860; P:positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target; IDA:UniProtKB.
DR GO; GO:0032819; P:positive regulation of natural killer cell proliferation; IDA:ComplexPortal.
DR GO; GO:0051135; P:positive regulation of NK T cell activation; IDA:BHF-UCL.
DR GO; GO:0051142; P:positive regulation of NK T cell proliferation; IDA:ComplexPortal.
DR GO; GO:0046427; P:positive regulation of receptor signaling pathway via JAK-STAT; IDA:ComplexPortal.
DR GO; GO:0034393; P:positive regulation of smooth muscle cell apoptotic process; IDA:BHF-UCL.
DR GO; GO:0001916; P:positive regulation of T cell mediated cytotoxicity; IDA:UniProtKB.
DR GO; GO:0042102; P:positive regulation of T cell proliferation; IDA:ComplexPortal.
DR GO; GO:0042531; P:positive regulation of tyrosine phosphorylation of STAT protein; IDA:UniProtKB.
DR GO; GO:0032496; P:response to lipopolysaccharide; IDA:UniProtKB.
DR GO; GO:0010224; P:response to UV-B; IDA:UniProtKB.
DR GO; GO:0009615; P:response to virus; IEP:UniProtKB.
DR Gene3D; 1.20.1250.10; -; 1.
DR InterPro; IPR009079; 4_helix_cytokine-like_core.
DR InterPro; IPR004281; IL-12_alpha.
DR Pfam; PF03039; IL12; 1.
DR SUPFAM; SSF47266; SSF47266; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Cytokine; Direct protein sequencing; Disulfide bond;
KW Glycoprotein; Growth factor; Host-virus interaction; Reference proteome;
KW Secreted; Signal.
FT SIGNAL 1..22
FT /evidence="ECO:0000269|PubMed:2204066"
FT CHAIN 23..219
FT /note="Interleukin-12 subunit alpha"
FT /id="PRO_0000015604"
FT CARBOHYD 93
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 107
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT DISULFID 64..196
FT /evidence="ECO:0000269|PubMed:10899108"
FT DISULFID 85..123
FT /evidence="ECO:0000269|PubMed:10899108"
FT DISULFID 96
FT /note="Interchain (with C-199 in IL12B)"
FT /evidence="ECO:0000269|PubMed:10899108"
FT CONFLICT 213
FT /note="M -> T (in Ref. 2; AAA35694)"
FT /evidence="ECO:0000305"
FT HELIX 43..58
FT /evidence="ECO:0007829|PDB:1F45"
FT HELIX 59..61
FT /evidence="ECO:0007829|PDB:1F45"
FT TURN 74..78
FT /evidence="ECO:0007829|PDB:3HMX"
FT HELIX 81..84
FT /evidence="ECO:0007829|PDB:1F45"
FT HELIX 88..92
FT /evidence="ECO:0007829|PDB:1F45"
FT STRAND 107..109
FT /evidence="ECO:0007829|PDB:3HMX"
FT TURN 114..116
FT /evidence="ECO:0007829|PDB:3HMX"
FT HELIX 118..145
FT /evidence="ECO:0007829|PDB:1F45"
FT HELIX 155..169
FT /evidence="ECO:0007829|PDB:1F45"
FT HELIX 190..217
FT /evidence="ECO:0007829|PDB:1F45"
SQ SEQUENCE 219 AA; 24874 MW; 7C658AB7716112B2 CRC64;
MCPARSLLLV ATLVLLDHLS LARNLPVATP DPGMFPCLHH SQNLLRAVSN MLQKARQTLE
FYPCTSEEID HEDITKDKTS TVEACLPLEL TKNESCLNSR ETSFITNGSC LASRKTSFMM
ALCLSSIYED LKMYQVEFKT MNAKLLMDPK RQIFLDQNML AVIDELMQAL NFNSETVPQK
SSLEEPDFYK TKIKLCILLH AFRIRAVTID RVMSYLNAS
