title: USP4 targets TAK1 to downregulate TNFα-induced NF-κB activation.
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.
authors.affiliation: Texas Children's Cancer Center, Department of Pediatrics, Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX 77030, USA.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Fan
authors.forename: Y
authors.initials: Y
authors.lastname: Yu
authors.forename: R-F
authors.initials: RF
authors.lastname: Mao
authors.forename: X-J
authors.initials: XJ
authors.lastname: Tan
authors.forename: G-F
authors.initials: GF
authors.lastname: Xu
authors.forename: H
authors.initials: H
authors.lastname: Zhang
authors.forename: X-B
authors.initials: XB
authors.lastname: Lu
authors.forename: S-B
authors.initials: SB
authors.lastname: Fu
authors.forename: J
authors.initials: J
authors.lastname: Yang
mesh_terms: D004797:Enzyme-Linked Immunosorbent Assay; D006367:HeLa Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D016297:Mutagenesis, Site-Directed; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D043222:Ubiquitin Thiolesterase / Q000235:genetics / Q000378:metabolism*; D064570:Ubiquitin-Specific Proteases; D054875:Ubiquitination / Q000187:drug effects; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D020930:MAP Kinase Kinase Kinases; D016328:NF-kappa B; D014409:Tumor Necrosis Factor-alpha; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; D000099151:MAP Kinase Kinase Kinase 7; C486203:USP4 protein, human