The role of tumor necrosis factor receptor -associated factor 3 (TRAF3) in regulating the type I and type II NF-kappaB pathways

Proper activation of NF-kappaB transcription factors is critical in regulating fundamental biological processes such as cell survival and proliferation, as well as inflammatory and immune responses. Recently, the NF-kappaB signaling pathways have been categorized into the classical or type I pathway, which activates the degradation of IkappaBalpha and the release of active NF-kappaB complexes consisting mainly of p50, and the alternative or type II pathway, which involves the induced processing of p100 to p52 and the formation of NF-kappaB complexes consisting of p52. Numerous receptors that can activate both the NF-kappaB pathways have been found to associate with TRAF3. To understand the role of TRAF3 in regulating the NF-kappaB pathways, we have investigated NF-kappaB activity in both TRAF3-/- tissues and cells. Here we demonstrated that TRAF3-/- cells have constitutive p52 activity as well as enhanced classical NF-kappaB activity. TRAF3 deficient B cells also displayed ligand-independent enhanced survival. Moreover, TRAF3 null tissues and cells displayed enhanced expression of NF-kappaB regulated pro-inflammatory genes. More significantly, the postnatal death of TRAF3 null mice was rescued by the additional deletion of the p100 gene, indicating that the constitutive p52 activity contributes to the lethal phenotype of the TRAF3 deficient mice. We concluded from these genetic data that TRAF3 is a novel negative regulator of both the classical and the alternative NF-kappaB pathways and, hence, may serve as an inhibitor of pro-inflammatory and autoimmune diseases.