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

• Published in: Cell death and differentiation Vol. 18; no. 10; pp. 1547 - 1560
• Main Authors: Fan, Y-H, Yu, Y, Mao, R-F, Tan, X-J, Xu, G-F, Zhang, H, Lu, X-B, Fu, S-B, Yang, J
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.10.2011
• Subjects: 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; Original Paper; 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
• ISSN: 1350-9047; 1476-5403
• DOI: 10.1038/cdd.2011.11

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.