SCFFbw7 Modulates the NFκB Signaling Pathway by Targeting NFκB2 for Ubiquitination and Destruction

The NF kappa B/Rel family of proteins play critical roles in a variety of cellular processes. Thus, their physiological activation is tightly controlled. Recently, the NF kappa B2/p100 precursor has been characterized as the fourth I kappa B type of suppressor for NF kappa B. However, the molecular mechanism(s) underlying regulated destruction of NF kappa B2 remains largely unknown. Here, we report that, unlike other I kappa Bs, ubiquitination and destruction of NF kappa B2 are governed by SCFFbw7 in a GSK3-dependent manner. In Fbw7(-/-) cells, elevated expression of NF kappa B2/p100 leads to a subsequent reduction in NF kappa B signaling pathways and elevated sensitivity to TNF alpha-induced cell death. Reintroducing wild-type Fbw7, but not disease-derived mutant forms of Fbw7, rescues NF kappa B activity. Furthermore, T cell-specific depletion of Fbw7 also leads to reduced NF kappa B activity and perturbed T cell differentiation. Therefore, our work identifies Fbw7 as a physiological E3 ligase controlling NF kappa B2's stability. It further implicates that Fbw7 might exert its tumor-suppressor function by regulating NF kappa B activity.