Xiao N, Li H, Luo J, Wang R, Chen H, Chen J, Wang P

Tumor necrosis factor (TNF) receptor- associated factor (TRAF) 2 and 6 are essential adaptor proteins for NF-kB signaling pathway, which play important roles in inflammation and immune response. Polyubiquitination of TRAF2 and TRAF6 is critical to their activities and functions in TNFa and IL-1b-induced NF-κB activation. However, the regulation of ...

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TRAF2 and TRAF6 by deubiquitination remains not completely understood. In this study, we identified ubiquitin-specific protease USP4 as a novel deubiquitinase targeting TRAF2 and TRAF6 for deubiquitination. We found that USP4 specifically interacts with TRAF2 and TRAF6, but not TRAF3. Moreover, USP4 associates with TRAF6 both in vitro and in vivo independent of its deubiquitinase activity. The USP domain is responsible for USP4 to interact with TRAF6. Ectopic expression of USP4 inhibits the TRAF2 and TRAF6-stimulated NF-κB reporter gene and negatively regulates the TNFa-induced IkBa degradation and NF-kB activation. Knockdown of USP4 significantly increased TNFa-induced cytokine expression. Furthermore, we found that USP4 deubiquitinates both TRAF2 and TRAF6 in vivo and in vitro in a deubiquitinase activity-dependent manner. Importantly, our data showed that USP4 is a negative regulator of TNFa and IL-1b-induced cancer cell migration. Together, our study provides a novel insight into the regulation of NF-kB signaling pathway and uncovers a previously unknown function of USP4 in cancer.

Date: Oct. 27, 2011

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