TRAF3 (TNF Receptor Associated Factor 3)

2002-08-01   Valérie Kedinger 

IGBMC - BP 10142, 67404 ILLKIRCH cedex, France

Identity

HGNC
LOCATION
14q32.32
LOCUSID
ALIAS
CAP-1,CAP1,CD40bp,CRAF1,IIAE5,LAP1,RNF118
FUSION GENES

DNA/RNA

Description

13 exons spanning approximately 130 kb

Transcription

Three alternatively spliced transcript variants encoding two distinct isoforms have been reported.

Proteins

Atlas Image

Description

Isoform 1: 568 amino acids Isoform 2: 543 amino acids

Expression

TRAF3 protein is detected in the skin, with a stronger intensity in more differentiated cells in the upper layers of the complex epithelium. TRAF3 is also expressed in the cartilage, in the cardiovascular system, in the trachea, in the salivary gland, in the liver, in the pancreas, in the prostate gland, in the pituitary gland. A gradient of TRAF3 expression appears to exist along the nephron, with progressively higher expression from proximal tubule to collecting duct. In the central nervous system, many but not most neurons in the cerebral cortex, basal ganglia, and brain stem contain at least low levels of TRAF3 protein. In contrast, almost no expression of TRAF3 is detected in the immune system.

Localisation

mainly cytoplasmic

Function

The TRAF family proteins act at least in part as adapter proteins that recruit other signaling molecules to ligand-bound TNF family receptors. TRAF3 was first described as a molecule that binds the cytoplasmic tail of CD40. Signaling through CD40 in B cells induces rescue from apoptosis, proliferation, differentiation, Ig production, class switching and expression of co-stimulatory molecules. Insights into the in vivo functions of TRAF3 have come from generation of mice deficient for TRAF3. These mice are depleted in all lineages of peripheral leucocytes, and die shortly after birth. However, B cells from TRAF3-/- upregulate CD23 and proliferate normally in response to CD40 ligand stimulation. Moreover, fetal liver cells from TRAF3 deficient mice can reconstitute the immune system of irradiated wild type mice, although isotype switching in response to T-dependent antigens is defective. Thus, TRAF3 is not required for CD40 signaling, but appears important in T cell-dependent immune responses. These effects of TRAF3 may be mediated through other TNF receptor family members : TRAF3 can bind directly to the cytosolic domains of CD27, CD30, LTbR, LMP-1, and also binds indirectly TNF-R2.

Homology

TRAF3 belongs to a family of six proteins (TRAF1 to 6), sharing a common structural organization. TRAF3 counterparts are found in mouse, fly and worm.

Implicated in

Disease
Hodgkin disease, Lymphomas.

Bibliography

Pubmed IDLast YearTitleAuthors
110235202000Hodgkin disease: pharmacologic intervention of the CD40-NF kappa B pathway by a protease inhibitor.Annunziata CM et al
116078472001Tumor necrosis factor receptor-associated factors (TRAFs).Bradley JR et al
75333271995Involvement of CRAF1, a relative of TRAF, in CD40 signaling.Cheng G et al
106447112000Membrane localization of TRAF 3 enables JNK activation.Dadgostar H et al
95503801997Immunohistochemical analysis of in vivo patterns of TRAF-3 expression, a member of the TNF receptor-associated factor family.Krajewski S et al
95806481998Epstein-Barr virus and a cellular signaling pathway in lymphomas from immunosuppressed patients.Liebowitz D et al
89345681996Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses.Xu Y et al
101993931998A single gene for human TRAF-3 at chromosome 14q32.3 encodes a variety of mRNA species by alternative polyadenylation, mRNA splicing and transcription initiation.van Eyndhoven WG et al

Other Information

Locus ID:

NCBI: 7187
MIM: 601896
HGNC: 12033
Ensembl: ENSG00000131323

Variants:

dbSNP: 7187
ClinVar: 7187
TCGA: ENSG00000131323
COSMIC: TRAF3

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000131323ENST00000347662A6NHG8
ENSG00000131323ENST00000351691A6NHG8
ENSG00000131323ENST00000392745Q13114
ENSG00000131323ENST00000539721Q13114
ENSG00000131323ENST00000558700H0YL25
ENSG00000131323ENST00000559734H0YL26
ENSG00000131323ENST00000560371Q13114
ENSG00000131323ENST00000560463H0YMI8

Expression (GTEx)

0
10
20
30
40
50
60

Pathways

PathwaySourceExternal ID
Toll-like receptor signaling pathwayKEGGko04620
Small cell lung cancerKEGGko05222
Toll-like receptor signaling pathwayKEGGhsa04620
Pathways in cancerKEGGhsa05200
Small cell lung cancerKEGGhsa05222
RIG-I-like receptor signaling pathwayKEGGko04622
RIG-I-like receptor signaling pathwayKEGGhsa04622
NOD-like receptor signaling pathwayKEGGko04621
NOD-like receptor signaling pathwayKEGGhsa04621
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Herpes simplex infectionKEGGko05168
Herpes simplex infectionKEGGhsa05168
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
NF-kappa B signaling pathwayKEGGhsa04064
NF-kappa B signaling pathwayKEGGko04064
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Metabolism of proteinsREACTOMER-HSA-392499
Post-translational protein modificationREACTOMER-HSA-597592
DiseaseREACTOMER-HSA-1643685
Diseases of Immune SystemREACTOMER-HSA-5260271
Diseases associated with the TLR signaling cascadeREACTOMER-HSA-5602358
TRAF3 deficiency - HSEREACTOMER-HSA-5602571
Immune SystemREACTOMER-HSA-168256
Innate Immune SystemREACTOMER-HSA-168249
Toll-Like Receptors CascadesREACTOMER-HSA-168898
Toll Like Receptor 3 (TLR3) CascadeREACTOMER-HSA-168164
MyD88-independent TLR3/TLR4 cascadeREACTOMER-HSA-166166
TRIF-mediated TLR3/TLR4 signalingREACTOMER-HSA-937061
Activation of IRF3/IRF7 mediated by TBK1/IKK epsilonREACTOMER-HSA-936964
Toll Like Receptor 4 (TLR4) CascadeREACTOMER-HSA-166016
Activated TLR4 signallingREACTOMER-HSA-166054
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathwaysREACTOMER-HSA-168928
TRAF3-dependent IRF activation pathwayREACTOMER-HSA-918233
Negative regulators of RIG-I/MDA5 signalingREACTOMER-HSA-936440
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
TNFR2 non-canonical NF-kB pathwayREACTOMER-HSA-5668541
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathwayREACTOMER-HSA-5676594
DeubiquitinationREACTOMER-HSA-5688426
Ovarian tumor domain proteasesREACTOMER-HSA-5689896
IL-17 signaling pathwayKEGGko04657
IL-17 signaling pathwayKEGGhsa04657

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
176928052007Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma.369
150846082004Regulation of the NF-kappaB-inducing kinase by tumor necrosis factor receptor-associated factor 3-induced degradation.180
168584092006Regulation of antiviral responses by a direct and specific interaction between TRAF3 and Cardif.153
216600532011Expanding TRAF function: TRAF3 as a tri-faced immune regulator.136
208323412010Human TRAF3 adaptor molecule deficiency leads to impaired Toll-like receptor 3 response and susceptibility to herpes simplex encephalitis.114
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
157089702005TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-kappaB pathway by TRAF-binding TNFRs.74
198936242009The E3 ubiquitin ligase Triad3A negatively regulates the RIG-I/MAVS signaling pathway by targeting TRAF3 for degradation.74
199960942010Regulation of virus-triggered signaling by OTUB1- and OTUB2-mediated deubiquitination of TRAF3 and TRAF6.71
176087432007YopJ targets TRAF proteins to inhibit TLR-mediated NF-kappaB, MAPK and IRF3 signal transduction.61

Citation

Valérie Kedinger

TRAF3 (TNF Receptor Associated Factor 3)

Atlas Genet Cytogenet Oncol Haematol. 2002-08-01

Online version: http://atlasgeneticsoncology.org/gene/271/traf3