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

DNA damage-induced activation of the transcription factor NF-kappa B plays an important role in the cellular response to genotoxic stress. However, uncontrolled NF-kappa B activation upon DNA damage may lead to deleterious consequences. Although the mechanisms mediating genotoxic NF-kappa B 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-kappa B-dependent manner. MCPIP1 upregulation reduces NEMO linear ubiquitylation, resulting in decreased activation of IKK and NF-kappa B. 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-kappa B signalling cascade. Consistently, USP10 is required for MCPIP1-mediated inhibition of genotoxic NF-kappa B 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-kappa B activation.