USP10 inhibits genotoxic NF-κB activation by MCPIP1-facilitated deubiquitination of NEMO.

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.
Mesh Terms:
Animals, Apoptosis, Cytokines, DNA Damage, Etoposide, HEK293 Cells, Humans, I-kappa B Kinase, Inflammation, Mice, Mice, Mutant Strains, NF-kappa B, Signal Transduction, Transcription Factors, Ubiquitin, Ubiquitin Thiolesterase, Ubiquitination
EMBO J.
Date: Dec. 11, 2013
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