USP4 targets TAK1 to downregulate TNFα-induced NF-κB activation.
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.
Mesh Terms:
Enzyme-Linked Immunosorbent Assay, HeLa Cells, Humans, Immunoblotting, Immunoprecipitation, MAP Kinase Kinase Kinases, Mutagenesis, Site-Directed, NF-kappa B, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, Ubiquitin Thiolesterase, Ubiquitination
Enzyme-Linked Immunosorbent Assay, HeLa Cells, Humans, Immunoblotting, Immunoprecipitation, MAP Kinase Kinase Kinases, Mutagenesis, Site-Directed, NF-kappa B, Protein Binding, Reverse Transcriptase Polymerase Chain Reaction, Tumor Necrosis Factor-alpha, Ubiquitin Thiolesterase, Ubiquitination
Cell Death Differ.
Date: Oct. 01, 2011
PubMed ID: 21331078
View in: Pubmed Google Scholar
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