Zhou Q, Cheng C, Wei Y, Yang J, Zhou W, Song Q, Ke M, Yan W, Zheng L, Zhang Y, Huang K

Tumor necrosis factor ? (TNF?)- and interleukin 1? (IL-1?)-induced nuclear factor-?B (NF-?B) 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 TNF?- and IL-1?-induced NF-?B activation. Overexpression of USP15 potentiated ...

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TNF?- or IL-1?-triggered NF-?B activation and downstream gene transcription, whereas knockdown of USP15 had opposite effects. Mechanistically, upon TNF? stimulation, USP15 showed an enhanced interaction with transforming growth factor-? 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-?B activation is achieved by differentially maintaining the TAB2/3 stability.

Date: Aug. 01, 2020

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