TRAF3

The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins associate with, and mediate the signal transduction from, members of the TNF receptor (TNFR) superfamily. This protein participates in the signal transduction of CD40, a TNFR family member important for the activation of the immune response. This protein is found to be a critical component of the lymphotoxin-beta receptor (LTbetaR) signaling complex, which induces NF-kappaB activation and cell death initiated by LTbeta ligation. Epstein-Barr virus encoded latent infection membrane protein-1 (LMP1) can interact with this and several other members of the TRAF family, which may be essential for the oncogenic effects of LMP1. Several alternatively spliced transcript variants encoding three distinct isoforms have been reported. [provided by RefSeq, Dec 2010]

TRAF3 Gene(Protein Coding) TNF Receptor Associated Factor 3

Cytoplasmic E3 ubiquitin ligase that regulates various signaling pathways, such as the NF-kappa-B, mitogen-activated protein kinase (MAPK) and interferon regulatory factor (IRF) pathways, and thus controls a lot of biological processes in both immune and non-immune cell types (PubMed:33148796, PubMed:33608556).
In TLR and RLR signaling pathways, acts as an E3 ubiquitin ligase promoting the synthesis of 'Lys-63'-linked polyubiquitin chains on several substrates such as ASC that lead to the activation of the type I interferon response or the inflammasome (PubMed:25847972, PubMed:27980081).
Following the activation of certain TLRs such as TLR4, acts as a negative NF-kappa-B regulator, possibly to avoid unregulated inflammatory response, and its degradation via 'Lys-48'-linked polyubiquitination is required for MAPK activation and production of inflammatory cytokines. Alternatively, when TLR4 orchestrates bacterial expulsion, TRAF3 undergoes 'Lys-33'-linked polyubiquitination and subsequently binds to RALGDS, mobilizing the exocyst complex to rapidly expel intracellular bacteria back for clearance (PubMed:27438768).
Acts also as a constitutive negative regulator of the alternative NF-kappa-B pathway, which controls B-cell survival and lymphoid organ development. Required for normal antibody isotype switching from IgM to IgG. Plays a role T-cell dependent immune responses. Down-regulates proteolytic processing of NFKB2, and thereby inhibits non-canonical activation of NF-kappa-B. Promotes ubiquitination and proteasomal degradation of MAP3K14.

Biological Process apoptotic process Source:ProtInc1 Publication
Biological Process defense response to virus Source:ComplexPortal2 Publications
Biological Process negative regulation of NF-kappaB transcription factor activity Source:UniProtKB1 Publication
Biological Process positive regulation of JNK cascade Source:GO_Central1 Publication
Biological Process protein K63-linked ubiquitination Source:GO_Central1 Publication
Biological Process regulation of apoptotic process Source:InterPro
Biological Process regulation of cytokine production Source:UniProtKB
Biological Process regulation of defense response to virus Source:UniProtKB
Biological Process regulation of I-kappaB kinase/NF-kappaB signaling Source:GO_Central1 Publication
Biological Process regulation of interferon-beta production Source:UniProtKB
Biological Process regulation of proteolysis Source:UniProtKB1 Publication
Biological Process signal transduction Source:ProtInc1 Publication
Biological Process Toll signaling pathway Source:InterPro
Biological Process toll-like receptor signaling pathway Source:UniProtKB
Biological Process TRIF-dependent toll-like receptor signaling pathway Source:Reactome
Biological Process tumor necrosis factor-mediated signaling pathway Source:UniProtKB1 Publication
Biological Process type I interferon signaling pathway Source:ComplexPortal1 Publication

Cytoplasm
Endosome
Mitochondrion
Undergoes endocytosis together with TLR4 upon LPS signaling (By similarity).
Co-localized to mitochondria with TRIM35 (PubMed:32562145).

Encephalopathy, acute, infection-induced, 5, herpes-specific (IIAE5):
A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. It is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome.

Undergoes 'Lys-48'-linked polyubiquitination, leading to its proteasomal degradation in response to signaling by TNFSF13B, TLR4 or through CD40. 'Lys-48'-linked polyubiquitinated form is deubiquitinated by OTUD7B, preventing TRAF3 proteolysis and over-activation of non-canonical NF-kappa-B. Undergoes 'Lys-63'-linked ubiquitination during early stages of virus infection, and 'Lys-48'-linked ubiquitination during later stages. Undergoes both 'Lys-48'-linked and 'Lys-63'-linked ubiquitination in response to TLR3 and TLR4 signaling. 'Lys-63'-linked ubiquitination can be mediated by TRIM35. Deubiquitinated by OTUB1, OTUB2 and OTUD5. Undergoes 'Lys-63'-linked deubiquitination by MYSM1 to terminate the pattern-recognition receptors/PRRs pathways (By similarity).
Undergoes also 'Lys-29'-linked ubiquitination on Cys-56 and Cys-124 by NEDD4L; leading to increased 'Lys-48'- and 'Lys-63'-linked ubiquitination as well as increased binding to TBK1 (PubMed:33608556).
TLR4 signals emanating from bacteria containing vesicles trigger 'Lys-33'-linked polyubiquitination that promotes the assembly of the exocyst complex thereby connecting innate immune signaling to the cellular trafficking apparatus (PubMed:27438768).
Deubiquitinated by USP25 during viral infection, leading to TRAF3 stabilization and type I interferon production (By similarity).
(Microbial infection) Cleaved by enterovirus D68 protease 2A; leading to inhibition of NF-kappa-B or IFN-beta triggered by TRAF3.