Otud7b controls noncanonical NF-κB activation via deubiquitination of TRAF3

The noncanonical NF-κB pathway forms a major arm of NF-κB signaling that mediates important biological functions, including lymphoid organogenesis, B lymphocyte function, and cell growth and survival(1-3). Activation of the noncanonical NF-κB pathway involves degradation of an inhibitory protein, TNF receptor associated factor 3 (TRAF3), but how this signaling event is controlled is still unknown(1,2). Here we have identified the deubiquitinase Otud7b as a pivotal regulator of the noncanonical NF-κB pathway. Otud7b deficiency in mice has no appreciable effect on canonical NF-κB activation but causes hyper-activation of noncanonical NF-κB. In response to noncanonical NF-κB stimuli, Otud7b binds and deubiquitinates TRAF3, thereby inhibiting TRAF3 proteolysis and preventing aberrant noncanonical NF-κB activation. Consequently, the Otud7b deficiency results in B-cell hyperresponsiveness to antigens, lymphoid follicular hyperplasia in the intestinal mucosa, and elevated host-defense ability against an intestinal bacterial pathogen, Citrobacter rodentium. These findings establish Otud7b as a crucial regulator of signal-induced noncanonical NF-κB activation and suggest a mechanism of immune regulation that involves Otud7b-mediated deubiquitination and stabilization of TRAF3.