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

• DOI: 10.1038/s41422-019-0174-3
• Publication Date: 2019-05-13T22:32:56Z
• Authors: Yanchuan Li; Jin-Young Yang; Xiaoping Xie; Zuliang Jie; Lingyun Zhang; Jianhong Shi; Daniel Lin; Meidi Gu; Xiaofei Zhou; Haiyan S. Li; Stephanie S. Wato...; Antrix Jain; Sung Yun Jung; Jun Qin; Xuhong Cheng; Shao-Cong Sun
• Keywords: Mice, Knockout; 0303 health sciences; Deubiquitinating Enzymes; Protein Stability; NF-kappa B; Autoimmunity; Mice, Transgenic; Mice, Inbred C57BL; Cysteine Endopeptidases; Mice; 03 medical and health sciences; HEK293 Cells; Animals; Humans; I-kappa B Proteins; Cells, Cultured

NF-κB, a family of transcription factors regulating diverse biological processes including immune responses, is activated by canonical and noncanonical pathways based on degradation of IκBα and processing of the IκB-like protein p100, respectively. Although p100 responds to noncanonical NF-κB stimuli for processing, it does not undergo degradation, but rather becomes accumulated, along with canonical NF-κB 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-κB activation but also causes steady-state p100 degradation, leading to aberrant NF-κB 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-κB regulation that prevents autoimmunity.