TRAF Family Member-Associated NF-{kappa}B Activator Inhibits Genotoxic NF-{kappa}B Activation by Facilitating USP10-Dependent Deubiquitination of TRAF6 [Molecular Bases of Disease]

April 10th, 2015 by Wang, W., Huang, X., Xin, H.-B., Fu, M., Xue, A., Wu, Z.-H.

DNA damage-induced NF-κB activation plays a critical role in regulating cellular response to genotoxic stress. However, the molecular mechanisms controlling the magnitude and duration of this genotoxic NF-κB signaling cascade are poorly understood. We recently demonstrated that genotoxic NF-κB activation is regulated by reversible ubiquitination of several essential mediators involved in this signaling pathway. Here we show that TRAF family member-associated NF-κB activator (TANK) negatively regulates NF-κB activation by DNA damage via inhibiting ubiquitination of TRAF6. Despite lack of a deubiquitination enzyme domain, TANK was shown to negatively regulate ubiquitination of TRAF proteins. We found TANK formed a complex with MCPIP1 (also known as ZC3H12A) and a deubiquitinase USP10, which was essential for USP10-dependent deubiquitination of TRAF6 and resolution of genotoxic NF-κB activation upon DNA damage. CRISPR/Cas9-mediated deletion of TANK in human cells significantly enhanced NF-κB activation by genotoxic treatments, resulting in enhanced cell survival and increased inflammatory cytokine production upon genotoxic drug treatment. Furthermore, we found that TANK-MCPIP1-USP10 complex also decreased TRAF6 ubiquitination in cells treated with IL-1β or LPS. In accordance, depletion of USP10 enhanced NF-κB activation induced by IL-1β or LPS. Collectively, our data demonstrate that TANK serves as an important negative regulator of NF-κB signaling cascades induced by genotoxic stress and IL-1R/TLR stimulation in a manner dependent on MCPIP1/USP10-mediated TRAF6 deubiquitination.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on TRAF Family Member-Associated NF-{kappa}B Activator Inhibits Genotoxic NF-{kappa}B Activation by Facilitating USP10-Dependent Deubiquitination of TRAF6 [Molecular Bases of Disease]