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

EMBO J. 2013 Dec 11;32(24):3206-19. doi: 10.1038/emboj.2013.247. Epub 2013 Nov 22.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cytokines / genetics
  • Cytokines / metabolism
  • DNA Damage
  • Etoposide / pharmacology
  • HEK293 Cells / drug effects
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism*
  • Inflammation / metabolism
  • Mice
  • Mice, Mutant Strains
  • NF-kappa B / metabolism*
  • Ribonucleases
  • Signal Transduction
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Ubiquitin / metabolism
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitination

Substances

  • Cytokines
  • IKBKG protein, human
  • NF-kappa B
  • Transcription Factors
  • USP10 protein, human
  • Ubiquitin
  • Etoposide
  • I-kappa B Kinase
  • Ribonucleases
  • ZC3H12A protein, human
  • Ubiquitin Thiolesterase