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Open Access

Open Access

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

Jixiao Niu, Yuling Shi, Jingyan Xue, Ruidong Miao, Shengping Huang, Tianyi Wang, Jiong Wu, Mingui Fu, Zhao‐Hui Wu

Author Affiliations

  1. Jixiao Niu1,2,
  2. Yuling Shi1,2,
  3. Jingyan Xue2,3,
  4. Ruidong Miao4,
  5. Shengping Huang4,
  6. Tianyi Wang5,
  7. Jiong Wu3,
  8. Mingui Fu4 and
  9. Zhao‐Hui Wu*,1,2
  1. 1 Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA
  2. 2 Center for Cancer Research, University of Tennessee Health Science Center, Memphis, TN, USA
  3. 3 Department of Breast Surgery, Cancer Hospital/Institute, Fudan University, Shanghai, China
  4. 4 Department of Basic Medical Science, University of Missouri Kansas City, Kansas City, MO, USA
  5. 5 Department of Infectious Disease and Microbiology, University of Pittsburgh, Pittsburgh, PA, USA
  1. * Department of Pathology and Laboratory Medicine, Center for Cancer Research, University of Tennessee Health Science Center, 19 South Manassas Street, Memphis, TN 38163, USA Tel.:+1 901 448 2612; Fax:+1 901 448 3910; E-mail: zwu6{at}uthsc.edu

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.

  • Received January 23, 2013.
  • Accepted October 31, 2013.

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