Preventing abnormal NF-κB activation and autoimmunity by Otub1-mediated p100 stabilization

NF-kappa B, a family of transcription factors regulating diverse biological processes including immune responses, is activated by canonical and noncanonical pathways based on degradation of I kappa Ba and processing of the I kappa B-like protein p100, respectively. Although p100 responds to noncanonical NF-kappa B stimuli for processing, it does not undergo degradation, but rather becomes accumulated, along with canonical NF-kappa B activation. We show here that the stability of p100 is tightly controlled by a deubiquitinase, Otub1. Otub1 deficiency not only promotes signal-induced p100 processing and noncanonical NF-kappa B activation but also causes steady-state p100 degradation, leading to aberrant NF-kappa B activation in the canonical pathway. B-cell-conditional deletion of Otub1 results in B-cell hyperplasia, antibody hyper-production, and lupus-like autoimmunity. Otub1-deficient B cells display aberrantly activated phenotypes and overproduce the cytokine IL-6, contributing to autoimmunity induction. Thus, maintenance of p100 stability by Otub1 serves as an unusual mechanism of NF-kappa B regulation that prevents autoimmunity.