USP15 potentiates NF‐κB activation by differentially stabilizing TAB2 and TAB3
Qiaoqiao Zhou, Cheng Cheng, Yujuan Wei, Jing Yang, Wanzhu Zhou, Qiu‐yi Song, Mengxiang Ke, Wanyao Yan, Ling Zheng, Yu Zhang, Kun Huang
Abstract
Tumor necrosis factor α (TNFα)- and interleukin 1β (IL-1β)-induced nuclear factor-κB (NF-κB) activation play key roles in inflammation, immunity, and cancer development. Here, we identified one of the deubiquitinating enzymes (DUBs), ubiquitin-specific protease 15 (USP15), as a positive regulator in both TNFα- and IL-1β-induced NF-κB activation. Overexpression of USP15 potentiated TNFα- or IL-1β-triggered NF-κB activation and downstream gene transcription, whereas knockdown of USP15 had opposite effects. Mechanistically, upon TNFα stimulation, USP15 showed an enhanced interaction with transforming growth factor-β activated kinase-1 (TAK1)-TAK1 binding protein (TAB) complex to inhibit the proteolysis of TAB2/3 by different pathways. Apart from deubiquitination dependently inducing cleavage of lysine 48-linked TAB2 ubiquitination, USP15 also DUB independently inhibited lysosome-associated TAB2 degradation, thus enhanced TAB2 stabilization. For TAB3, USP15 inhibited NBR1-mediated selective autophagic TAB3 degradation independent of its deubiquitinating activity. Together, our results reveal a novel USP15-mediated mechanism through which efficient NF-κB activation is achieved by differentially maintaining the TAB2/3 stability.