期刊
CELL RESEARCH
卷 29, 期 6, 页码 474-485出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41422-019-0174-3
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资金
- National Institutes of Health [GM84459, AI64639, AI057555]
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.
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