| First Author | Niu J | Year | 2013 |
| Journal | EMBO J | Volume | 32 |
| Issue | 24 | Pages | 3206-19 |
| PubMed ID | 24270572 | Mgi Jnum | J:206842 |
| Mgi Id | MGI:5553034 | Doi | 10.1038/emboj.2013.247 |
| Citation | Niu J, et al. (2013) USP10 inhibits genotoxic NF-kappaB activation by MCPIP1-facilitated deubiquitination of NEMO. EMBO J 32(24):3206-19 |
| abstractText | DNA damage-induced activation of the transcription factor NF-kappaB plays an important role in the cellular response to genotoxic stress. However, uncontrolled NF-kappaB activation upon DNA damage may lead to deleterious consequences. Although the mechanisms mediating genotoxic NF-kappaB 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-kappaB-dependent manner. MCPIP1 upregulation reduces NEMO linear ubiquitylation, resulting in decreased activation of IKK and NF-kappaB. 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-kappaB signalling cascade. Consistently, USP10 is required for MCPIP1-mediated inhibition of genotoxic NF-kappaB 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-kappaB activation. |
