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

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

SUBMITTER: Niu J

PROVIDER: S-EPMC3981146 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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

Niu Jixiao J Shi Yuling Y Xue Jingyan J Miao Ruidong R Huang Shengping S Wang Tianyi T Wu Jiong J Fu Mingui M Wu Zhao-Hui ZH

The EMBO journal 20131122 24

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 kn ...[more]

PMID: 24270572

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Project description:BackgroundUTP-glucose-1-phosphoryl transferase (UGPase) catalyzes the synthesis of UDP-glucose, which is essential for generating the glycogen needed for the synthesis of bacterial lipopolysaccharide (LPS) and capsular polysaccharide, which play important roles in bacterial virulence. However, the molecular function of UGPase in Brucella is still unknown.ResultsIn this study, the ubiquitination modification of host immune-related protein in cells infected with UGPase-deleted or wild-type Brucella was analyzed using ubiquitination proteomics technology. The ubiquitination modification level and type of NF-κB Essential Modulator (NEMO or Ikbkg), a molecule necessary for NF-κB signal activation, was evaluated using Coimmunoprecipitation, Western blot, and dual-Luciferase Assay. We found 80 ubiquitin proteins were upregulated and 203 ubiquitin proteins were downregulated in cells infected with B. melitensis 16 M compared with those of B. melitensis UGPase-deleted strain (16 M-UGPase-). Moreover, the ubiquitin-modified proteins were mostly enriched in the categories of regulation of kinase/NF-κB signaling and response to a bacterium, suggesting Brucella UGPase inhibits ubiquitin modification of related proteins in the host NF-κB signaling pathway. Further analysis showed that the ubiquitination levels of NEMO K63 (K63-Ub) and Met1 (Met1-Ub) were significantly increased in the 16 M-UGPase--infected cells compared with that of the 16 M-infected cells, further confirming that the ubiquitination levels of NF-κB signaling-related proteins were regulated by the bacterial UGPase. Besides, the expression level of IκBα was decreased, but the level of p-P65 was significantly increased in the 16 M-UGPase--infected cells compared with that of the 16 M- and mock-infected cells, demonstrating that B. melitensis UGPase can significantly inhibit the degradation of IκBα and the phosphorylation of p65, and thus suppressing the NF-κB pathway.ConclusionsThe results of this study showed that Brucella melitensis UGPase inhibits the activation of NF-κB by modulating the ubiquitination of NEMO, which will provide a new scientific basis for the study of immune mechanisms induced by Brucella.

Dataset Information

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

Publications

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

Similar Datasets

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