The deubiquitinating enzyme USP11 controls an IκB kinase α(IKKα)-p53 signaling pathway in response to tumor necrosis factor α(TNFα)

Post-translational modification and degradation of proteins by the ubiquitin-proteasome system are key regulatory events in cellular responses to various stimuli. The NF-kappa B B signaling pathway is controlled by the ubiquitin-mediated proteolysis. Although mechanisms of ubiquitination in the NF-kappa B pathway have been extensively studied, deubiquitination-mediated regulation of the NF-kappa B signaling remains poorly understood. The present studies show that a deubiquitinating enzyme, USP11, specifically regulates I kappa B kinase alpha (IKK alpha) among the NF-kappa B signaling molecules. Knocking down USP11 attenuates expression of IKK alpha in the transcriptional, but not the post- translational, level. However, down-regulation of USP11 dramatically enhances NF-kappa B activity in response to tumor necrosis factor-alpha, indicating that IKK alpha does not require activation of NF-kappa B. Instead, knock down of USP11 or IKK alpha is associated with abrogation of p53 expression upon exposure to tumor necrosis factor-alpha. In concert with these results, silencing of USP11 is associated with transcriptional attenuation of the p53- responsive genes, such as p21 or Bax. Importantly, the ectopic expression of IKK alpha into cells silenced for USP11 restores p53 expression, demonstrating that USP11 functions as an upstream regulator of an IKK alpha-p53 signaling pathway.