title: USP10 inhibits genotoxic NF-κB activation by MCPIP1-facilitated deubiquitination of NEMO.
abstract: 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.
authors.affiliation: 1] Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA [2] Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA.
authors.forename: Jixiao
authors.initials: J
authors.lastname: Niu
authors.forename: Yuling
authors.initials: Y
authors.lastname: Shi
authors.forename: Jingyan
authors.initials: J
authors.lastname: Xue
authors.forename: Ruidong
authors.initials: R
authors.lastname: Miao
authors.forename: Shengping
authors.initials: S
authors.lastname: Huang
authors.forename: Tianyi
authors.initials: T
authors.lastname: Wang
authors.forename: Jiong
authors.initials: J
authors.lastname: Wu
authors.forename: Mingui
authors.initials: M
authors.lastname: Fu
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage; D005047:Etoposide / Q000494:pharmacology; D057809:HEK293 Cells / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D016328:NF-kappa B / Q000378:metabolism*; D012260:Ribonucleases; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D016207:Cytokines; C491731:IKBKG protein, human; D016328:NF-kappa B; D014157:Transcription Factors; C431363:USP10 protein, human; D025801:Ubiquitin; D005047:Etoposide; D051550:I-kappa B Kinase; D012260:Ribonucleases; C510646:ZC3H12A protein, human; D043222:Ubiquitin Thiolesterase