Regulation of the NF-kappaB alternative pathway: implication for B cell transformation

The NF-?B2 gene is recurrently mutated and over-expressed in human lymphoid malignancies. However, a casual relationship between NF-?B2 mutation and lymphomagenesis has not been established. It is also unclear how the mutation may lead to lymphoid malignancies. Recent studies suggest that nuclear factor ?B inducing kinase (NIK) is suppressed through constitutive proteasome-mediated degradation regulated by TRAF3, thus preventing processing of the NF-?B2 precursor protein p100 to release p52. Here we demonstrate that BAFF Receptor, a member of the TNF Receptor family, interact with TRAF1, a member of TRAF family. This interaction activates NF-?B2 via increased degradation of TRAF3 and stabilization of NIK. Indeed, interference of TRAF1 in lymphoma B cell line downregulates p100 processing and lead to decreased survival of B cells.