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USP10 inhibits genotoxic NF‐κB activation by MCPIP1‐facilitated deubiquitination of NEMO
Author(s) -
Niu Jixiao,
Shi Yuling,
Xue Jingyan,
Miao Ruidong,
Huang Shengping,
Wang Tianyi,
Wu Jiong,
Fu Mingui,
Wu ZhaoHui
Publication year - 2013
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/emboj.2013.247
Subject(s) - deubiquitinating enzyme , dna damage , microbiology and biotechnology , transcription factor , biology , ubiquitin , nf κb , downregulation and upregulation , zinc finger , dna , cancer research , signal transduction , gene , biochemistry
DNA damage‐induced activation of the transcription factor NF‐κB plays an important role in the cellular response to genotoxic stress. However, uncontrolled NF‐κB activation upon DNA damage may lead to deleterious consequences. Although the mechanisms mediating genotoxic NF‐κB activation have been elucidated, how this signalling is terminated remains poorly understood. Here, we show that the CCCH‐type zinc finger‐containing protein MCPIP1 (monocyte chemotactic protein‐1‐induced protein‐1; also known as ZC3H12A) is induced upon genotoxic treatment in an NF‐κB‐dependent manner. MCPIP1 upregulation reduces NEMO linear ubiquitylation, resulting in decreased activation of IKK and NF‐κB. NEMO ubiquitylation is decreased through the deubiquitinase USP10, which interacts with NEMO via MCPIP1 upon genotoxic stress. USP10 association with NEMO leads to removal of NEMO‐attached linear polyubiquitin chains and subsequent inhibition of the genotoxic NF‐κB signalling cascade. Consistently, USP10 is required for MCPIP1‐mediated inhibition of genotoxic NF‐κB activation and promotion of apoptosis. Thus, by mediating USP10‐dependent deubiquitination of NEMO, MCPIP1 induction serves as a negative feedback mechanism for attenuating genotoxic NF‐κB activation.