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

Lys63-linked polyubiquitination of transforming growth factor-beta-activated kinase 1 (TAK1) has an important role in tumor necrosis factor-alpha (TNF alpha)-induced NF-kappa 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 alpha induces association of USP4 with TAK1 to deubiquitinate TAK1 and downregulate TAK1-mediated NF-kappa B activation. Overexpression of USP4 wild type, but not deuibiquitinase-deficient C311A mutant, inhibits both TNF alpha- and TAK1/TAB1 co-overexpression-induced TAK1 polyubiquitination and NF-kappa B activation. Notably, knockdown of USP4 in HeLa cells enhances TNF alpha-induced TAK1 polyubiquitination, I kappa B kinase phosphorylation, I kappa B alpha phosphorylation and ubiquitination, as well as NF-kappa B-dependent gene expression. Moreover, USP4 negatively regulates IL-1 beta-, LPS- and TGF beta-induced NF-kappa B activation. Together, our results demonstrate that USP4 serves as a critical control to downregulate TNFa-induced NF-kappa B activation through deubiquitinating TAK1. Cell Death and Differentiation (2011) 18, 1547-1560; doi:10.1038/cdd.2011.11; published online 18 February 2011