TRAF3

TRAF3 is a cytoplasmic RING-type E3 ubiquitin ligase (EC 2.3.2.27) and signalling adaptor of the TNF receptor-associated factor family. Its C-terminal MATH/TRAF-C domain binds the cytoplasmic tails of TNF receptor superfamily members - CD40, LTBR, BAFF-R, BCMA, CD30, OX40, EDAR, Fn14 - and the Epstein-Barr virus oncoprotein LMP1, while its N-terminal RING and zinc fingers provide ubiquitin ligase activity; the protein acts as a homotrimer and also forms heterotrimers with TRAF2 and TRAF5. TRAF3 is distinctive among TRAFs in having two functions of opposite sign. It is the constitutive brake on the non-canonical NF-kappaB pathway: within a TRAF2-cIAP1/2 assembly it recruits the kinase NIK/MAP3K14 and drives its continuous proteasomal degradation, so that p100/NFKB2 remains unprocessed until receptor engagement destroys TRAF3 itself; this restrains B-cell survival and lymphoid organ development, and TRAF3 inactivation is a recurrent driver event in multiple myeloma. Conversely, TRAF3 is a non-redundant positive component of type I interferon induction, bridging the TLR adaptors TRIF and MyD88 and the mitochondrial RIG-I adaptor MAVS to the IRF3/IRF7 kinases TBK1 and IKK-epsilon; autosomal dominant human TRAF3 deficiency, caused by a dominant-negative R118W allele, causes herpes simplex encephalitis through impaired TLR3-dependent interferon induction. Which output is produced is set by the ubiquitin chain TRAF3 carries: TRIF-driven K63-linked self-ubiquitination activates the interferon arm, whereas MyD88/cIAP-driven K48-linked ubiquitination degrades TRAF3 and licenses MAPK activation and pro-inflammatory cytokine production. As an enzyme TRAF3 builds K63-linked chains, most clearly on ASC, where the modification is required for inflammasome speck formation. TRAF3 acts in the cytosol and at the cytoplasmic face of the plasma membrane, on endosomes carrying internalised TLR4/TRAM, and on mitochondria at the MAVS platform.

Disorders

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