USP15 potentiates NF-kappa B activation by differentially stabilizing TAB2 and TAB3
USP15 potentiates NF-kappa B activation by differentially stabilizing TAB2 and TAB3
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USP15 通过差异稳定 TAB2 和 TAB3 来增强 NF-κB 激活
DOI：
10.1111/febs.15202
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发表时间：
2020
期刊：
影响因子：
5.4
通讯作者：
Huang Kun
中科院分区：
文献类型：
--
作者：
Zhou Qiaoqiao;Cheng Cheng;Wei Yujuan;Yang Jing;Zhou Wanzhu;Song Qiuyi;Ke Mengxiang;Yan Wanyao;Zheng Ling;Zhang Yu;Huang Kun
肿瘤坏死因子α-α和白介素1-β(IL-1β)诱导的核因子-κB(NF-κB)活化在炎症、免疫和肿瘤的发生发展中起关键作用。在此，我们鉴定了去泛素化酶(DUBS)之一，泛素特异性蛋白酶15(USP15)，在肿瘤坏死因子α和IL-1β诱导的NF-κB激活中起着积极的调节作用。USP15的过表达增强了肿瘤坏死因子α或IL-1β触发的NF-κB激活和下游基因转录，而USP15的过表达则相反。在机制上，在肿瘤坏死因子α刺激下，USP15通过不同途径与转化生长因子-β激活的蛋白-1-结合蛋白复合体相互作用，抑制TAB2/3的蛋白降解。除了去泛素化依赖地诱导赖氨酸48连接的TAB2泛素化的切割外，USP15还独立地抑制了溶酶体相关的TAB2的降解，从而增强了TAB2的稳定性。对于Tab3，USP15抑制NBR1介导的选择性自噬Tab3的降解，而不依赖于其去泛素化活性。综上所述，我们的结果揭示了一种新的USP15介导的机制，通过这种机制，通过差异化地维持TAB2/3的稳定性来实现有效的NF-κB激活。
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.