TRAF6

Chr 11

TNF receptor associated factor 6

Also known as: MGC:3310, RNF85

NCBI Gene: 7189 ENSG00000175104 UniProt: Q9Y4K3

This highly constrained gene encodes an E3 ubiquitin ligase that mediates synthesis of polyubiquitin chains and serves as a critical adapter protein in TNF receptor, IL-1 receptor, and IL-17 receptor signaling pathways, ultimately activating NF-kappa-B and JUN to regulate immune responses and osteoclast differentiation. Mutations cause autosomal recessive immunodeficiency with recurrent infections due to impaired innate and adaptive immune function. The gene's extreme intolerance to loss-of-function variants (pLI 0.997, LOEUF 0.217) reflects its essential role in immune system development and function.

GeneReviews ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the TNF receptor associated factor (TRAF) protein family. TRAF proteins are associated with, and mediate signal transduction from, members of the TNF receptor superfamily. This protein has an amino terminal RING domain which is followed by four zinc-finger motifs, a central coiled-coil region and a highly conserved carboxyl terminal domain, known as the TRAF-C domain and mediates signaling from members of the TNF receptor superfamily as well as the Toll/IL-1 family. Signals from receptors such as CD40, TNFSF11/RANCE and IL-1 have been shown to be mediated by this protein. This protein also interacts with various protein kinases including IRAK1/IRAK, SRC and PKCzeta, which provides a link between distinct signaling pathways. This protein functions as a signal transducer in the NF-kappaB pathway that activates IkappaB kinase (IKK) in response to proinflammatory cytokines. The interaction of this protein with UBE2N/UBC13, and UBE2V1/UEV1A, which are ubiquitin conjugating enzymes catalyzing the formation of polyubiquitin chains, has been found to be required for IKK activation by this protein. This protein also interacts with the transforming growth factor (TGF) beta receptor complex and is required for Smad-independent activation of the JNK and p38 kinases. The protein encoded by this gene is a key molecule in antiviral innate and antigen-specific immune responses. [provided by RefSeq, Nov 2021]

GeneReviews ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

534

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.22

LOEUF· LoF intol.

LOF

Mechanism· predicted

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