Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Box 902, Houston, TX, 77030, USA.
Center for Reproductive Medicine, Henan Key Laboratory of Reproduction and Genetics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, 450052, China.
Cell Res. 2019 Jun;29(6):474-485. doi: 10.1038/s41422-019-0174-3. Epub 2019 May 13.
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.
NF-κB 是一个转录因子家族，调节包括免疫反应在内的多种生物过程，其激活途径分为经典途径和非经典途径，分别基于 IκBα 的降解和 IκB 样蛋白 p100 的加工。尽管 p100 对非经典 NF-κB 刺激作出反应进行加工，但它不会像经典 NF-κB 激活那样发生降解，而是与经典 NF-κB 激活一起被积累。我们在这里表明，去泛素化酶 Otub1 可严格控制 p100 的稳定性。Otub1 缺陷不仅促进信号诱导的 p100 加工和非经典 NF-κB 激活，还导致稳态 p100 降解，从而导致经典途径中 NF-κB 的异常激活。B 细胞条件性缺失 Otub1 会导致 B 细胞增生、抗体过度产生和狼疮样自身免疫。Otub1 缺陷的 B 细胞显示出异常激活的表型，并过度产生细胞因子 IL-6，导致自身免疫的诱导。因此，Otub1 维持 p100 的稳定性是 NF-κB 调节的一种异常机制，可防止自身免疫。
