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

• Published in: Cell death and differentiation 2011-10, Vol.18 (10), p.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: Article
• Language: English
• Subjects: 631/250/516/1909; 631/45/127/1220; 631/45/607; Apoptosis; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Cycle Analysis; Enzyme-Linked Immunosorbent Assay; HeLa Cells; Humans; Immunoblotting; Immunoprecipitation; Life Sciences; 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; Stem Cells; 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 (TNF α )-induced NF- κ B 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 . TNF α induces association of USP4 with TAK1 to deubiquitinate TAK1 and downregulate TAK1-mediated NF- κ B activation. Overexpression of USP4 wild type, but not deuibiquitinase-deficient C311A mutant, inhibits both TNF α - and TAK1/TAB1 co-overexpression-induced TAK1 polyubiquitination and NF- κ B activation. Notably, knockdown of USP4 in HeLa cells enhances TNF α -induced TAK1 polyubiquitination, I κ B kinase phosphorylation, I κ B α phosphorylation and ubiquitination, as well as NF- κ B-dependent gene expression. Moreover, USP4 negatively regulates IL-1 β -, LPS- and TGF β -induced NF- κ B activation. Together, our results demonstrate that USP4 serves as a critical control to downregulate TNF α -induced NF- κ B activation through deubiquitinating TAK1.