USP4 targets TAK1 to downregulate TNFα-induced NF-κB activation

Cell Death Differ. 2011 Oct;18(10):1547-60. doi: 10.1038/cdd.2011.11. Epub 2011 Feb 18.

Abstract

Lys63-linked polyubiquitination of transforming growth factor-β-activated kinase 1 (TAK1) has an important role in tumor necrosis factor-α (TNFα)-induced NF-κB activation. Using a functional genomic approach, we have identified ubiquitin-specific peptidase 4 (USP4) as a deubiquitinase for TAK1. USP4 deubiquitinates TAK1 in vitro and in vivo. TNFα induces association of USP4 with TAK1 to deubiquitinate TAK1 and downregulate TAK1-mediated NF-κB activation. Overexpression of USP4 wild type, but not deuibiquitinase-deficient C311A mutant, inhibits both TNFα- and TAK1/TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-κB activation. Notably, knockdown of USP4 in HeLa cells enhances TNFα-induced TAK1 polyubiquitination, IκB kinase phosphorylation, IκBα phosphorylation and ubiquitination, as well as NF-κB-dependent gene expression. Moreover, USP4 negatively regulates IL-1β-, LPS- and TGFβ-induced NF-κB activation. Together, our results demonstrate that USP4 serves as a critical control to downregulate TNFα-induced NF-κB activation through deubiquitinating TAK1.

Publication types

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

MeSH terms

  • Enzyme-Linked Immunosorbent Assay
  • HeLa Cells
  • Humans
  • Immunoblotting
  • Immunoprecipitation
  • MAP Kinase Kinase Kinases / genetics
  • MAP Kinase Kinase Kinases / metabolism*
  • Mutagenesis, Site-Directed
  • NF-kappa B / metabolism*
  • Protein Binding / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Necrosis Factor-alpha / pharmacology*
  • Ubiquitin Thiolesterase / genetics
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Specific Proteases
  • Ubiquitination / drug effects

Substances

  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • USP4 protein, human
  • MAP Kinase Kinase Kinases
  • MAP kinase kinase kinase 7
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases