CD40 CD40 molecule [Homo sapiens (human)] - Gene

Summary

Official Symbol: CD40provided by HGNC
Official Full Name: CD40 moleculeprovided by HGNC
Primary source: HGNC:HGNC:11919
See related: Ensembl:ENSG00000101017 MIM:109535
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: p50; Bp50; CDW40; TNFRSF5
Summary: This gene is a member of the TNF-receptor superfamily. The encoded protein is a receptor on antigen-presenting cells of the immune system and is essential for mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory B cell development, and germinal center formation. AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. Adaptor protein TNFR2 interacts with this receptor and serves as a mediator of the signal transduction. The interaction of this receptor and its ligand is found to be necessary for amyloid-beta-induced microglial activation, and thus is thought to be an early event in Alzheimer disease pathogenesis. Mutations affecting this gene are the cause of autosomal recessive hyper-IgM immunodeficiency type 3 (HIGM3). Multiple alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Nov 2014]
Expression: Broad expression in lymph node (RPKM 19.2), appendix (RPKM 13.7) and 23 other tissues See more
Orthologs: mouse all

Genomic context

Location:: 20q13.12

Exon count:: 9

Annotation release	Status	Assembly	Chr	Location
109.20200815	current	GRCh38.p13 (GCF_000001405.39)	20	NC_000020.11 (46118242..46129858)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	20	NC_000020.10 (44746899..44758384)

Chromosome 20 - NC_000020.11 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

CRISPR/Cas9 Screens Reveal Multiple Layers of B cell CD40 Regulation.
Title: CRISPR/Cas9 Screens Reveal Multiple Layers of B cell CD40 Regulation.
Results illustrated significant CD40 hypermethylation in GC samples compared to normal specimens which was significantly correlated with the clinical stage of malignancy.
Title: CD40 DNA hypermethylation in primary gastric tumors; as a novel diagnostic biomarker.
The CD40 polymorphisms -1 C > T and 6,048 G > T were associated with systemic lupus erythematosus (SLE) susceptibility. There was no difference between CD40 mRNA expression and CD40 polymorphisms. The sCD40 levels were lower SLE patients with TT haplotype, whereas higher sCD40 levels were associated with damage and impaired renal function according to SLICC and KDIGO. The sCD40 levels were negatively correlated with eGFR.
Title: Association of soluble CD40 levels with -1 C > T CD40 polymorphism and chronic kidney disease in systemic lupus erythematosus.
Association between CD40 polymorphisms and systemic lupus erythematosus susceptibility and significantly higher sCD40 and sCD40L levels in patients with systemic lupus erythematosus than in controls (meta-analysis).
Title: Association between CD40 polymorphisms and systemic lupus erythematosus and correlation between soluble CD40 and CD40 ligand levels in the disease: a meta-analysis.
Results found no alterations regarding CD40 mRNA expression in rheumatoid arthritis patients.
Title: Assessment of CD40 and CD40L expression in rheumatoid arthritis patients, association with clinical features and DAS28.
High CD40 expression showed a significant correlation with poor outcomes for both low-grade gliomas and glioblastoma (GBM) and was overexpressed in isocitrate dehydrogenase wild-type GBM.
Title: Expression of CD40 Correlates Negatively with Overall and Progression-Free Survival of Low- and High-Grade Gliomas.
The work showed a significant association between the -1 C>T (rs1883832) polymorphism of the CD40 gene and myocardial infarction in the Tunisians.
Title: Associations of rs1883832 and rs4810485 polymorphisms of CD40 gene with myocardial infarction in the Tunisian population.
these results do not suggest a functional role of CD40 genetic variants in acute coronary syndrome
Title: Analysis of Genetic Variation in CD40 and CD40L: Relationship with mRNA Relative Expression and Soluble Proteins in Acute Coronary Syndrome.
The rs1535045 and rs1883832 on CD40 were remained in various subgroups and the heterogeneity test showed no pronounced heterogeneity in any pairwise comparison. In addition, the results of the cumulative effects showed a tendency of that the more risk alleles (rs1535045 T and rs1883832 T) subjects carried, the more possibility of HCV infection exhibited.
Title: CD40 polymorphisms were associated with HCV infection susceptibility among Chinese population.
anti-CD40 and IL-21 induced normal and even higher levels of Bcl-XL, respectively, in CD27(+) B cells from AP-CVID, which was accompanied by cell viability increase. Thus low-survival memory B cells from AP-CVID can overcome their cell death regulation defects through pro-survival signals provided by T cells. In conclusion, we identify apoptosis regulation defects as disease-contributing factors in CVID.
Title: IL-21 and anti-CD40 restore Bcl-2 family protein imbalance in vitro in low-survival CD27<sup>+</sup> B cells from CVID patients.

Submit: New GeneRIF Correction See all GeneRIFs (427)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
A genome-wide association study identifies three new risk loci for Kawasaki disease. GeneReviews: Not available
Common variants at CD40 and other loci confer risk of rheumatoid arthritis. GeneReviews: Not available
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. GeneReviews: Not available
Genetics of rheumatoid arthritis contributes to biology and drug discovery. GeneReviews: Not available
Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20. GeneReviews: Not available
Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. GeneReviews: Not available
Genome-wide meta-analysis identifies novel multiple sclerosis susceptibility loci. GeneReviews: Not available
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. GeneReviews: Not available
Hyper-IgM syndrome type 3 MedGen: C1720957 OMIM: 606843 GeneReviews: Not available	Compare labs
Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis. GeneReviews: Not available

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Protein interactions

Protein	Gene	Interaction	Pubs
Envelope surface glycoprotein gp120	env	The low mannose-level gp120 induces higher activation of plasmacytoid dendritic cells by upregulation of IFN-alpha, PD-L1, CD40, CCR7, CD80, and CD86 than the high mannose-level gp120 does	PubMed
	env	Inhibition of CpG-B-induced maturation of plasmacytoid dendritic cells by HIV-1 gp120 results in downregulation of CD40, CD83, CCR7, and HLA-DR expression	PubMed
	env	The binding of HIV-1 gp120 to CD4 molecules on T cells interrupts the sequential cascade of intercellular interactions involving antigen/MHC class II-TCR/CD4, CD40L-CD40, and B71-CD28	PubMed
	env	HIV-1 gp120-induced reduction of IL-12 parallels IL-10 induction and inhibits translocation of CD40 to the surface of monocytes	PubMed
	env	Upregulation of apoptosis genes such as NCK-associated protein 1, PTB domain adaptor protein CED-6, and TNF receptor superfamily 5 are induced by HIV-1 gp120 in human neurons	PubMed
Pr55(Gag)	gag	CD40L expression on the surface of virus-like particles (VLPs) is to target HIV-1 Gag antigens to the CD40 receptor on dendritic cell (DCs)	PubMed
Tat	tat	Depletion of ARMS abrogates HIV-1 Tat-induced upregulation of CD40 expression in primary human microglia	PubMed
	tat	Recombinant CD40L synergizes with HIV-1 Tat to increase TNF-alpha release from primary human monocytes and microglia in an NF-kappaB-dependent manner. This synergism is attributed to a Tat-mediated up-regulation of CD40.	PubMed
	tat	HIV-1 Tat upregulates the expression of MHC and co-stimulatory molecules CD40, CD80, CD83 and CD86 in monocyte-derived dendritic cells, thereby driving T cell-mediated immune responses	PubMed
Vpr	vpr	HIV-1 Vpr downregulates the expression of several immunologically important molecules including CD40, CD80, CD83, and CD86 co-stimulatory molecules on monocyte-derived macrophage (MDM) and monocyte-derived dendritic cells (MDDC)	PubMed
Vpu	vpu	HIV-1 Vpu upregulates CD40 expression, which enhances efficient expression of VCAM-1 in endothelial cells	PubMed
matrix	gag	Treatment of human PBMCs with HIV-1 MA upregulates the expression of MCP-1, ICAM-1, CD40, CD86 and CD36 and downregulates the expression of nuclear receptors FXR and PPARgamma	PubMed

Go to the HIV-1, Human Interaction Database

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

RH93708 (e-PCR)
- UniSTS:91489

CD40_s5 (e-PCR)
- UniSTS:510346

PMC259134P3 (e-PCR)
- UniSTS:272293

STS-R49884 (e-PCR)
- UniSTS:33205

PMC60102P1 (e-PCR)
- UniSTS:273387

PMC60102P10 (e-PCR)
- UniSTS:273388

PMC60102P11 (e-PCR)
- UniSTS:273389

PMC60102P2 (e-PCR)
- UniSTS:273390

PMC60102P3 (e-PCR)
- UniSTS:273391

PMC60102P4 (e-PCR)
- UniSTS:273392

PMC60102P5 (e-PCR)
- UniSTS:273393

PMC60102P6 (e-PCR)
- UniSTS:273394

PMC60102P7 (e-PCR)
- UniSTS:273395

PMC60102P9 (e-PCR)
- UniSTS:273396

Homology

Homologs of the CD40 gene: The CD40 gene is conserved in chimpanzee, Rhesus monkey, dog, cow, mouse, rat, chicken, and frog.
Orthologs from Annotation Pipeline: 234 organisms have orthologs with human gene CD40
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
antigen binding	IBA Inferred from Biological aspect of Ancestor more info	PubMed
enzyme binding	IPI Inferred from Physical Interaction more info	PubMed
protein binding	IPI Inferred from Physical Interaction more info	PubMed
protein domain specific binding	IEA Inferred from Electronic Annotation more info
signaling receptor activity	IEA Inferred from Electronic Annotation more info
ubiquitin protein ligase binding	IPI Inferred from Physical Interaction more info	PubMed

Process	Evidence Code	Pubs
B cell activation	IBA Inferred from Biological aspect of Ancestor more info	PubMed
B cell proliferation	NAS Non-traceable Author Statement more info	PubMed
CD40 signaling pathway	IBA Inferred from Biological aspect of Ancestor more info	PubMed
CD40 signaling pathway	IDA Inferred from Direct Assay more info	PubMed
TRIF-dependent toll-like receptor signaling pathway	IBA Inferred from Biological aspect of Ancestor more info	PubMed
cellular calcium ion homeostasis	IMP Inferred from Mutant Phenotype more info	PubMed
cellular response to erythropoietin	IEA Inferred from Electronic Annotation more info
cellular response to interleukin-1	IBA Inferred from Biological aspect of Ancestor more info	PubMed
cellular response to lipopolysaccharide	IEA Inferred from Electronic Annotation more info
cellular response to mechanical stimulus	IEP Inferred from Expression Pattern more info	PubMed
cellular response to tumor necrosis factor	IBA Inferred from Biological aspect of Ancestor more info	PubMed
defense response to protozoan	IBA Inferred from Biological aspect of Ancestor more info	PubMed
defense response to virus	IBA Inferred from Biological aspect of Ancestor more info	PubMed
immune response-regulating cell surface receptor signaling pathway	IBA Inferred from Biological aspect of Ancestor more info	PubMed
inflammatory response	IBA Inferred from Biological aspect of Ancestor more info	PubMed
platelet activation	NAS Non-traceable Author Statement more info	PubMed
positive regulation of B cell proliferation	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of GTPase activity	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of I-kappaB kinase/NF-kappaB signaling	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of I-kappaB kinase/NF-kappaB signaling	IEP Inferred from Expression Pattern more info	PubMed
positive regulation of MAP kinase activity	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of NF-kappaB transcription factor activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of NF-kappaB transcription factor activity	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of angiogenesis	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of angiogenesis	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of blood vessel endothelial cell migration	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of blood vessel endothelial cell migration	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of endothelial cell apoptotic process	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of endothelial cell apoptotic process	IDA Inferred from Direct Assay more info	PubMed
positive regulation of interleukin-12 production	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of isotype switching to IgG isotypes	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of protein kinase C signaling	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of protein phosphorylation	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of transcription by RNA polymerase II	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of transcription by RNA polymerase II	IMP Inferred from Mutant Phenotype more info	PubMed
positive regulation of tyrosine phosphorylation of STAT protein	IBA Inferred from Biological aspect of Ancestor more info	PubMed
positive regulation of tyrosine phosphorylation of STAT protein	IMP Inferred from Mutant Phenotype more info	PubMed
protein kinase B signaling	IEA Inferred from Electronic Annotation more info
protein-containing complex assembly	TAS Traceable Author Statement more info	PubMed
regulation of immune response	TAS Traceable Author Statement more info
regulation of immunoglobulin secretion	IBA Inferred from Biological aspect of Ancestor more info	PubMed
response to cobalamin	IEA Inferred from Electronic Annotation more info
response to interferon-gamma	IBA Inferred from Biological aspect of Ancestor more info	PubMed
response to peptide	IEA Inferred from Electronic Annotation more info
tumor necrosis factor-mediated signaling pathway	TAS Traceable Author Statement more info

Component	Evidence Code	Pubs
CD40 receptor complex	IBA Inferred from Biological aspect of Ancestor more info	PubMed
CD40 receptor complex	ISS Inferred from Sequence or Structural Similarity more info
cell surface	HDA more info	PubMed
cytoplasm	IEA Inferred from Electronic Annotation more info
external side of plasma membrane	IBA Inferred from Biological aspect of Ancestor more info	PubMed
extracellular exosome	HDA more info	PubMed
integral component of plasma membrane	TAS Traceable Author Statement more info	PubMed
intracellular membrane-bounded organelle	IEA Inferred from Electronic Annotation more info
neuronal cell body	IEA Inferred from Electronic Annotation more info
plasma membrane	ISS Inferred from Sequence or Structural Similarity more info
plasma membrane	TAS Traceable Author Statement more info
varicosity	IEA Inferred from Electronic Annotation more info

General protein information

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Preferred Names: tumor necrosis factor receptor superfamily member 5

Names: B cell surface antigen CD40; B cell-associated molecule; CD40 molecule, TNF receptor superfamily member 5; CD40L receptor

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_007279.1 RefSeqGene

Range

4988..16479

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_40

mRNA and Protein(s)

NM_001250.6 → NP_001241.1 tumor necrosis factor receptor superfamily member 5 isoform 1 precursor

See identical proteins and their annotated locations for NP_001241.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).

Source sequence(s)

AL035662, BC012419, BC064518, BM761221, BX364284

Consensus CDS

CCDS13393.1

UniProtKB/Swiss-Prot

P25942

UniProtKB/TrEMBL

A0A0S2Z3C7, Q6P2H9

Related

ENSP00000361359.3, ENST00000372285.8

Conserved Domains (1) summary

cd13407
Location:26 → 186

TNFRSF5; Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), also known as CD40
NM_001302753.2 → NP_001289682.1 tumor necrosis factor receptor superfamily member 5 isoform 3 precursor

Status: REVIEWED

Description

Transcript Variant: This variant (3) uses an alternate splice site in the 3' coding region, which results in a frameshift, compared to variant 1. It encodes isoform 3, which has a shorter and distinct C-terminus, compared to isoform 1.

Source sequence(s)

AL035662, BC012419, BC064518, BM761221, BX364284, BX364285

UniProtKB/Swiss-Prot

P25942

UniProtKB/TrEMBL

Q6P2H9

Conserved Domains (1) summary

cd13407
Location:26 → 186

TNFRSF5; Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), also known as CD40
NM_001322421.2 → NP_001309350.1 tumor necrosis factor receptor superfamily member 5 isoform 4 precursor

Status: REVIEWED

Source sequence(s)

AL035662, BX364284, HY063089

Conserved Domains (1) summary

cd13407
Location:26 → 186

TNFRSF5; Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), also known as CD40
NM_001322422.2 → NP_001309351.1 tumor necrosis factor receptor superfamily member 5 isoform 5 precursor

Status: REVIEWED

Source sequence(s)

AK222896, AL035662, BX364284, HY063089

UniProtKB/Swiss-Prot

P25942

UniProtKB/TrEMBL

A0A0S2Z349

Conserved Domains (2) summary

cd00185
Location:62 → 103

TNFRSF; CRD2 [structural motif]

cl22855
Location:26 → 135

TNFRSF; Tumor necrosis factor receptor superfamily (TNFRSF)
NM_001362758.2 → NP_001349687.1 tumor necrosis factor receptor superfamily member 5 isoform 6 precursor

Status: REVIEWED

Source sequence(s)

AL035662

Conserved Domains (1) summary

cd13407
Location:26 → 186

TNFRSF5; Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), also known as CD40
NM_152854.4 → NP_690593.1 tumor necrosis factor receptor superfamily member 5 isoform 2 precursor

See identical proteins and their annotated locations for NP_690593.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an exon in the 3' coding region, which results in a frameshift, compared to variant 1. The resulting isoform (2) contains a shorter and distinct C-terminus, compared to isoform 1.

Source sequence(s)

AL035662, BC012419, BC064518, BM761221, BX364284

Consensus CDS

CCDS13394.1

UniProtKB/Swiss-Prot

P25942

UniProtKB/TrEMBL

Q6P2H9

Related

ENSP00000361350.3, ENST00000372276.7

Conserved Domains (1) summary

cd13407
Location:26 → 166

TNFRSF5; Tumor necrosis factor receptor superfamily member 5 (TNFRSF5), also known as CD40

RNA

NR_126502.2 RNA Sequence

Status: REVIEWED

Description

Transcript Variant: This variant (4) lacks two internal exons and uses an alternate splice site in the 3' region, compared to variant 1. This variant is represented as non-coding because the use of the 5'-most supported translational start codon, as used in variant 1, renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).

Source sequence(s)

AK222896, AL035662, BC012419, BC064518, BX364284

Related

ENST00000620709.4
NR_136327.2 RNA Sequence

Status: REVIEWED

Source sequence(s)

AL035662, BX364284, HY063089

RefSeqs of Annotated Genomes: Homo sapiens Updated Annotation Release 109.20200815

The following sections contain reference sequences that belong to a specific genome build. Explain

Reference GRCh38.p13 Primary Assembly

Genomic

NC_000020.11 Reference GRCh38.p13 Primary Assembly

Range

46118242..46129858

Download

GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

XM_017028135.1 → XP_016883624.1 tumor necrosis factor receptor superfamily member 5 isoform X1
XM_005260619.3 → XP_005260676.1 tumor necrosis factor receptor superfamily member 5 isoform X3

Conserved Domains (2) summary

cd00185
Location:62 → 103

TNFRSF; CRD2 [structural motif]

cl22855
Location:26 → 135

TNFRSF; Tumor necrosis factor receptor superfamily (TNFRSF)
XM_011529109.2 → XP_011527411.1 tumor necrosis factor receptor superfamily member 5 isoform X5

See identical proteins and their annotated locations for XP_011527411.1

Related

ENSP00000434825.1, ENST00000466205.5

Conserved Domains (2) summary

cd00185
Location:62 → 103

TNFRSF; CRD2 [structural motif]

cl22855
Location:26 → 135

TNFRSF; Tumor necrosis factor receptor superfamily (TNFRSF)
XM_017028136.1 → XP_016883625.1 tumor necrosis factor receptor superfamily member 5 isoform X2