Reviewed, UniProtKB/Swiss-Prot P29460 (IL12B_HUMAN)

Names and origin

Protein names

Recommended name:
    Interleukin-12 subunit beta
      Short name=IL-12B
Alternative name(s):
    IL-12 subunit p40
    Cytotoxic lymphocyte maturation factor 40 kDa subunit
      Short name=CLMF p40
    NK cell stimulatory factor chain 2
      Short name=NKSF2

Gene names

Name:	IL12B
Synonyms:	NKSF2

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	328 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Cytokine that can act as a growth factor for activated T and NK cells, enhance the lytic activity of NK/lymphokine-activated killer cells, and stimulate the production of IFN-gamma by resting PBMC. Ref.12 Associates with IL23A to form the IL-23 interleukin, an heterodimeric cytokine which functions in innate and adaptive immunity. IL-23 may constitute with IL-17 an acute response to infection in peripheral tissues. IL-23 binds to an heterodimeric receptor complex composed of IL12RB1 and IL23R, activates the Jak-Stat signaling cascade, stimulates memory rather than naive T-cells and promotes production of proinflammatory cytokines. IL-23 induces autoimmune inflammation and thus may be responsible for autoimmune inflammatory diseases and may be important for tumorigenesis. Ref.12
Subunit structure	Heterodimer with IL12A; disulfide-linked. The heterodimer is known as interleukin IL-12. Heterodimer with IL23A; disulfide-linked. The heterodimer is known as interleukin IL-23. Also secreted as a monomer. Ref.9 Ref.14 Ref.16
Subcellular location	Secreted.
Post-translational modification	Known to be C-mannosylated in the recombinant protein; it is not yet known for sure if the wild-type protein is also modified.
Involvement in disease	Defects in IL12B are a cause of mendelian susceptibility to mycobacterial disease (MSMD) [MIM:209950]; also known as familial disseminated atypical mycobacterial infection. This rare condition confers predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guerin (BCG) vaccine and environmental non-tuberculous mycobacteria, and by the more virulent Mycobacterium tuberculosis. Other microorganisms rarely cause severe clinical disease in individuals with susceptibility to mycobacterial infections, with the exception of Salmonella which infects less than 50% of these individuals. The pathogenic mechanism underlying MSMD is the impairment of interferon-gamma mediated immunity, whose severity determines the clinical outcome. Some patients die of overwhelming mycobacterial disease with lepromatous-like lesions in early childhood, whereas others develop, later in life, disseminated but curable infections with tuberculoid granulomas. MSMD is a genetically heterogeneous disease with autosomal recessive, autosomal dominant or X-linked inheritance. Ref.11 Ref.13
Sequence similarities	Belongs to the type I cytokine receptor family. Type 3 subfamily. Contains 1 fibronectin type-III domain. Contains 1 Ig-like C2-type (immunoglobulin-like) domain.

Ontologies

Keywords
Cellular component	Secreted
Coding sequence diversity	Polymorphism
Domain	Immunoglobulin domain Signal
Molecular function	Cytokine
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	T-helper 1 type immune response Ref.2 Traceable author statement. Source: UniProtKB T-helper cell differentiation Ref.2 Inferred from direct assay. Source: UniProtKB cell cycle arrest Inferred from direct assay. Source: UniProtKB cell migration Inferred from direct assay. Source: UniProtKB interferon-gamma biosynthetic process Ref.2 Traceable author statement. Source: UniProtKB negative regulation of smooth muscle cell proliferation Inferred from direct assay. Source: UniProtKB positive regulation of activated T cell proliferation Ref.1 Inferred from direct assay. Source: UniProtKB positive regulation of cell adhesion Inferred from direct assay. Source: UniProtKB positive regulation of interferon-gamma biosynthetic process Ref.2 Traceable author statement. Source: UniProtKB positive regulation of interferon-gamma production Ref.1 Inferred from direct assay. Source: UniProtKB positive regulation of natural killer cell activation Ref.1 Inferred from direct assay. Source: UniProtKB positive regulation of natural killer cell mediated cytotoxicity directed against tumor cell target Inferred from direct assay. Source: UniProtKB positive regulation of smooth muscle cell apoptosis Inferred from direct assay. Source: UniProtKB response to UV-B Inferred from direct assay. Source: UniProtKB
Cellular component	interleukin-12 complex Ref.1 Inferred from direct assay. Source: UniProtKB membrane Inferred from electronic annotation. Source: InterPro
Molecular function	cytokine activity Ref.1 Inferred from electronic annotation. Source: UniProtKB-KW cytokine receptor activity Inferred from electronic annotation. Source: InterPro interleukin-12 receptor binding Ref.1 Traceable author statement. Source: UniProtKB protein heterodimerization activity Ref.1 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
IL12A	P29459	1	EBI-1029614,EBI-1029636

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 22

22

Ref.7

Chain

23 – 328

306

Interleukin-12 subunit beta

PRO_0000010930

Regions

Domain

23 – 106

84

Ig-like C2-type

Domain

235 – 327

93

Fibronectin type-III

Amino acid modifications

Glycosylation

135

1

N-linked (GlcNAc...) Potential

Glycosylation

222

1

N-linked (GlcNAc...) Ref.14

Glycosylation

319

1

C-linked (Man) Ref.10

CAR_000187

Disulfide bond

50 ↔ 90

Ref.14

Disulfide bond

131 ↔ 142

Ref.14

Disulfide bond

170 ↔ 193

Ref.14

Disulfide bond

199

Interchain (with C-96 in IL12A) Ref.14

Disulfide bond

300 ↔ 327

Ref.14

Natural variations

Natural variant

33

1

V → I: dbSNP rs3213096.

VAR_020001

Natural variant

298

1

V → F: dbSNP rs3213119.

VAR_049170

Experimental info

Sequence conflict

239

1

K → N in AAA59938. Ref.2

Secondary structure

1

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328

Helix Strand Turn

Details...

Beta strand

24 – 27

4

Beta strand

30 – 36

7

Beta strand

44 – 49

6

Beta strand

59 – 62

4

Beta strand

70 – 79

10

Helix

82 – 84

3

Beta strand

86 – 92

7

Beta strand

95 – 108

14

Turn

122 – 124

3

Beta strand

130 – 147

18

Beta strand

150 – 160

11

Beta strand

168 – 170

3

Beta strand

174 – 181

8

Beta strand

184 – 195

12

Beta strand

208 – 216

9

Beta strand

219 – 227

9

Helix

229 – 232

4

Beta strand

239 – 245

7

Beta strand

250 – 257

8

Turn

266 – 268

3

Beta strand

271 – 278

8

Beta strand

289 – 299

11

Beta strand

305 – 312

8

Beta strand

323 – 326

4

Sequences

	Sequence		Length	Mass (Da)
	P29460-1 [UniParc]. Last modified April 1, 1993. Version 1. Checksum: 118FA801B8F5BB2F	FASTA	328	37,169
	10 20 30 40 50 60 MCHQQLVISW FSLVFLASPL VAIWELKKDV YVVELDWYPD APGEMVVLTC DTPEEDGITW 70 80 90 100 110 120 TLDQSSEVLG SGKTLTIQVK EFGDAGQYTC HKGGEVLSHS LLLLHKKEDG IWSTDILKDQ 130 140 150 160 170 180 KEPKNKTFLR CEAKNYSGRF TCWWLTTIST DLTFSVKSSR GSSDPQGVTC GAATLSAERV 190 200 210 220 230 240 RGDNKEYEYS VECQEDSACP AAEESLPIEV MVDAVHKLKY ENYTSSFFIR DIIKPDPPKN 250 260 270 280 290 300 LQLKPLKNSR QVEVSWEYPD TWSTPHSYFS LTFCVQVQGK SKREKKDRVF TDKTSATVIC 310 320 RKNASISVRA QDRYYSSSWS EWASVPCS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Coexpression of two distinct genes is required to generate secreted bioactive cytotoxic lymphocyte maturation factor." Gubler U., Chua A.O., Schoenhaut D.S., Dwyer C.M., McComas W., Motyka R., Nabavi N., Wolitzky A.G., Quinn P.M., Familletti P.C., Gately M.K. Proc. Natl. Acad. Sci. U.S.A. 88:4143-4147(1991) [PubMed: 1674604] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells." Wolf S.F., Temple P.A., Kobayashi M., Young D., Dicig M., Lowe L., Dzialo R., Fitz L., Ferenz C., Hewick R.M., Kelleher K., Herrmann S.H., Clark S.C., Azzoni L., Chan S.H., Trinchieri G., Perussia B. J. Immunol. 146:3074-3081(1991) [PubMed: 1673147] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[3]	"Complete primary structure, chromosomal localization, and definition of polymorphisms of the gene encoding the human interleukin 12 p40 subunit." Huang D., Cancilla M.R., Morahan G. Genes Immun. 1:515-520(2000) [PubMed: 11197695] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]	"Cloning and sequence analysis of IL-12 cDNA from Chinese." Hongyuan J., Meiyun Z. Submitted (AUG-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	SeattleSNPs variation discovery resource Submitted (MAY-2002) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS ILE-33 AND PHE-298.
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Brain.
[7]	"Purification to homogeneity and partial characterization of cytotoxic lymphocyte maturation factor from human B-lymphoblastoid cells." Stern A.S., Podlaski F.J., Hulmes J.D., Pan Y.C.E., Quinn P.M., Wolitzky A.G., Familletti P.C., Stremlo D.L., Truitt T., Chizzonite R., Gately M.K. Proc. Natl. Acad. Sci. U.S.A. 87:6808-6812(1990) [PubMed: 2204066] [Abstract] Cited for: PROTEIN SEQUENCE OF 23-45.
[8]	"Homology of the p40 subunit of natural killer cell stimulatory factor (NKSF) with the extracellular domain of the interleukin-6 receptor." Gearing D.P., Cosman D. Cell 66:9-10(1991) [PubMed: 2070420] [Abstract] Cited for: SIMILARITY TO IL-6 RECEPTOR.
[9]	"Stimulatory and inhibitory effects of interleukin (IL)-4 and IL-13 on the production of cytokines by human peripheral blood mononuclear cells: priming for IL-12 and tumor necrosis factor alpha production." D'Andrea A., Ma X., Aste-Amezaga M., Paganin C., Trinchieri G. J. Exp. Med. 181:537-546(1995) [PubMed: 7836910] [Abstract] Cited for: SUBUNIT.
[10]	"Recombinant human interleukin-12 is the second example of a C-mannosylated protein." Doucey M.A., Hess D., Blommers M.J., Hofsteenge J. Glycobiology 9:435-441(1999) [PubMed: 10207176] [Abstract] Cited for: GLYCOSYLATION AT TRP-319.
[11]	"Inherited interleukin 12 deficiency in a child with bacille Calmette-Guerin and Salmonella enteritidis disseminated infection." Altare F., Lammas D., Revy P., Jouanguy E., Doeffinger R., Lamhamedi-Cherradi S.-E., Drysdale P., Scheel-Toellner D., Girdlestone J., Darbyshire P., Wadhwa M., Dockrell H., Salmon M., Fischer A., Durandy A., Casanova J.-L., Kumararatne D.S. J. Clin. Invest. 102:2035-2040(1998) [PubMed: 9854038] [Abstract] Cited for: INVOLVEMENT IN MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL DISEASE.
[12]	"Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12." Oppmann B., Lesley R., Blom B., Timans J.C., Xu Y., Hunte B., Vega F., Yu N., Wang J., Singh K.P., Zonin F., Vaisberg E., Churakova T., Liu M.-R., Gorman D., Wagner J., Zurawski S., Liu Y.-J. , Abrams J.S., Moore K.W., Rennick D.M., de Waal-Malefyt R., Hannum C., Bazan J.F., Kastelein R.A. Immunity 13:715-725(2000) [PubMed: 11114383] [Abstract] Cited for: FUNCTION, INTERACTION WITH IL23A.
[13]	"Inherited interleukin-12 deficiency: IL12B genotype and clinical phenotype of 13 patients from six kindreds." Picard C., Fieschi C., Altare F., Al-Jumaah S., Al-Hajjar S., Feinberg J., Dupuis S., Soudais C., Al-Mohsen I.Z., Genin E., Lammas D., Kumararatne D.S., Leclerc T., Rafii A., Frayha H., Murugasu B., Wah L.B., Sinniah R. , Loubser M., Okamoto E., Al-Ghonaium A., Tufenkeji H., Abel L., Casanova J.-L. Am. J. Hum. Genet. 70:336-348(2002) [PubMed: 11753820] [Abstract] Cited for: INVOLVEMENT IN MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL DISEASE.
[14]	"Charged residues dominate a unique interlocking topography in the heterodimeric cytokine interleukin-12." Yoon C., Johnston S.C., Tang J., Stahl M., Tobin J.F., Somers W.S. EMBO J. 19:3530-3541(2000) [PubMed: 10899108] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS) OF 23-328 ALONE AND IN COMPLEX WITH IL12A, GLYCOSYLATION AT ASN-222, DISULFIDE BONDS.
[15]	"Crystal structures of the pro-inflammatory cytokine interleukin-23 and its complex with a high-affinity neutralizing antibody." Beyer B.M., Ingram R., Ramanathan L., Reichert P., Le H.V., Madison V., Orth P. J. Mol. Biol. 382:942-955(2008) [PubMed: 18708069] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF 23-328 IN COMPLEX WITH IL23A AND ANTIBODY.
[16]	"The structure of interleukin-23 reveals the molecular basis of p40 subunit sharing with interleukin-12." Lupardus P.J., Garcia K.C. J. Mol. Biol. 382:931-941(2008) [PubMed: 18680750] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) OF 23-328 IN COMPLEX WITH IL23A, SUBUNIT.
+	Additional computationally mapped references.

Web resources

IL12Bbase

IL12B mutation db

GeneReviews

SeattleSNPs

Cross-references

Sequence databases

EMBLGenBankDDBJ

M65272 mRNA. Translation: AAA35695.1.
M65290 mRNA. Translation: AAA59938.1.
AY008847 Genomic DNA. Translation: AAG32620.1.
AF180563 mRNA. Translation: AAD56386.1.
AF512686 Genomic DNA. Translation: AAM34792.1.
BC067498 mRNA. Translation: AAH67498.1.
BC067499 mRNA. Translation: AAH67499.1.
BC067500 mRNA. Translation: AAH67500.1.
BC067501 mRNA. Translation: AAH67501.1.
BC067502 mRNA. Translation: AAH67502.1.
BC074723 mRNA. Translation: AAH74723.1.

IPI

IPI00021798.

PIR

A38957.

RefSeq

NP_002178.2.

UniGene

Hs.674

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1F42	X-ray	2.50	A	23-328	[»]
1F45	X-ray	2.80	A	23-328	[»]
3D85	X-ray	1.90	D	23-328	[»]
3D87	X-ray	2.90	B/D	23-328	[»]
3DUH	X-ray	2.30	A/B	23-328	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:3774N.

IntAct

P29460. 1 interaction.

PTM databases

GlycoSuiteDB

P29460.

PhosphoSite

P29460.

Proteomic databases

PRIDE

P29460.

Genome annotation databases

Ensembl

ENSG00000113302. Homo sapiens. [Contig view]

GeneID

3593.

KEGG

hsa:3593.

Organism-specific databases

GeneCards

GC05M158674.

H-InvDB

HIX0031989.

HGNC

HGNC:5970. IL12B.

MIM

161561. gene.
209950. phenotype.

Orphanet

748. Mendelian susceptibility to atypical mycobacteria.

PharmGKB

PA29785.

GenAtlas

Search...

Phylogenomic databases

HOGENOM

P29460.

HOVERGEN

P29460.

OMA

P29460. STPHSYF.

Enzyme and pathway databases

Pathway_Interaction_DB

il12_2pathway. IL12-mediated signaling events.
il23pathway. IL23-mediated signaling events.
il27pathway. IL27-mediated signaling events.

Gene expression databases

ArrayExpress

P29460.

Bgee

P29460.

CleanEx

HS_IL12B.

GermOnline

ENSG00000113302. Homo sapiens.

Family and domain databases

InterPro

IPR008957. Fibronectin_typ-III-like_fold.
IPR003961. FN_III.
IPR003530. Hematopoietin_rcpt_L_F3_CS.
IPR007110. Ig-like.
IPR013783. Ig-like_fold.
IPR003598. Ig_sub2.
IPR015528. IL_12_beta.
IPR019482. Interleukin-12_bsu_cen-dom.
[Graphical view]

Gene3D

G3DSA:2.60.40.30. FN_III-like. 2 hits.
G3DSA:2.60.40.10. Ig-like_fold. 1 hit.

PANTHER

PTHR11321. IL_12_beta. 1 hit.

Pfam

PF00041. fn3. 1 hit.
PF10420. IL12p40_C. 1 hit.
[Graphical view]

PIRSF

PIRSF038007. IL_12_beta. 1 hit.

SMART

SM00408. IGc2. 1 hit.
[Graphical view]

PROSITE

PS50853. FN3. 1 hit.
PS01354. HEMATOPO_REC_L_F3. 1 hit.
PS50835. IG_LIKE. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

14039.

PMAP-CutDB

P29460.

SOURCE

Search...

Entry information

Entry name

IL12B_HUMAN

Accession

Primary (citable) accession number: P29460

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 1, 1993
Last sequence update:	April 1, 1993
Last modified:	June 16, 2009
This is version 116 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)