Post-translational modification and degradation of proteins by the ubiquitin-proteasome system are key regulatory events in cellular responses to various stimuli. The NF-B signaling pathway is controlled by the ubiquitin-mediated proteolysis. Whereas mechanisms of ubiquitination in the NF-B pathway have been extensively studied, deubiquitination-mediated regulation of the NF-B signaling remains poorly understood. The present studies show that a deubiquitinating enzyme, USP11, specifically regulates IB kinase a (IKKa) among the NF-B signaling molecules. Knocking down USP11 attenuates expression of IKKa in the transcriptional, but not the post-translational level. However, down-regulation of USP11 dramatically enhances NF-B activity in response to TNFa, indicating that IKKa does not require activation of NF-B. Instead, knock down of USP11 or IKKa is associated with abrogation of p53 expression upon exposure to TNFa. 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 IKKa into cells silenced for USP11 restores p53 expression, demonstrating that USP11 functions as an upstream regulator of an IKKa-p53 signaling pathway.