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USP22 controls necroptosis by regulating receptor‐interacting protein kinase 3 ubiquitination
EMBO Reports ( IF 6.5 ) Pub Date : 2020-12-28 , DOI: 10.15252/embr.202050163
Jens Roedig 1 , Lisa Kowald 1 , Thomas Juretschke 2 , Rebekka Karlowitz 1 , Behnaz Ahangarian Abhari 3 , Heiko Roedig 4 , Simone Fulda 1 , Petra Beli 2 , Sjoerd Jl van Wijk 1
Affiliation  

Dynamic control of ubiquitination by deubiquitinating enzymes is essential for almost all biological processes. Ubiquitin‐specific peptidase 22 (USP22) is part of the SAGA complex and catalyzes the removal of mono‐ubiquitination from histones H2A and H2B, thereby regulating gene transcription. However, novel roles for USP22 have emerged recently, such as tumor development and cell death. Apart from apoptosis, the relevance of USP22 in other programmed cell death pathways still remains unclear. Here, we describe a novel role for USP22 in controlling necroptotic cell death in human tumor cell lines. Loss of USP22 expression significantly delays TNFα/Smac mimetic/zVAD.fmk (TBZ)‐induced necroptosis, without affecting TNFα‐mediated NF‐κB activation or extrinsic apoptosis. Ubiquitin remnant profiling identified receptor‐interacting protein kinase 3 (RIPK3) lysines 42, 351, and 518 as novel, USP22‐regulated ubiquitination sites during necroptosis. Importantly, mutation of RIPK3 K518 reduced necroptosis‐associated RIPK3 ubiquitination and amplified necrosome formation and necroptotic cell death. In conclusion, we identify a novel role of USP22 in necroptosis and further elucidate the relevance of RIPK3 ubiquitination as crucial regulator of necroptotic cell death.

中文翻译:


USP22 通过调节受体相互作用蛋白激酶 3 泛素化来控制坏死性凋亡



去泛素化酶对泛素化的动态控制对于几乎所有生物过程都是至关重要的。泛素特异性肽酶 22 (USP22) 是 SAGA 复合体的一部分,催化组蛋白 H2A 和 H2B 中单泛素化的去除,从而调节基因转录。然而,USP22 最近出现了新的作用,例如肿瘤发展和细胞死亡。除细胞凋亡外,USP22 在其他程序性细胞死亡途径中的相关性仍不清楚。在这里,我们描述了 USP22 在控制人类肿瘤细胞系坏死性细胞死亡中的新作用。 USP22 表达的丧失显着延迟 TNFα/Smac mimetic/zVAD.fmk (TBZ) 诱导的坏死性凋亡,而不影响 TNFα 介导的 NF-κB 激活或外源性细胞凋亡。泛素残基分析将受体相互作用蛋白激酶 3 (RIPK3) 赖氨酸 42、351 和 518 确定为坏死性凋亡期间新的、受 USP22 调节的泛素化位点。重要的是,RIPK3 K518 的突变减少了坏死性凋亡相关的 RIPK3 泛素化,并放大了坏死体形成和坏死性细胞死亡。总之,我们确定了 USP22 在坏死性凋亡中的新作用,并进一步阐明了 RIPK3 泛素化作为坏死性细胞死亡的关键调节因子的相关性。
更新日期:2021-02-03
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