USP11 negatively regulates TNFa-induced NF-[kappa]B activation by targeting on I[kappa]Ba

I[kappa]Ba serves as a central anchoring molecule in the sequestration of NF-[kappa]B transcription factor in the cytoplasm. Ubiquitination-mediated I[kappa]Ba degradation immediately precedes and is required for NF-[kappa]B nuclear translocation and activation. However, the precise mechanism for the deubiquitination of I[kappa]Ba is still not fully understood. Using a proteomic approach, we have identified Ubiquitin Specific Peptidase 11 (USP11) as an I[kappa]Ba associated deubiquitinase. Overexpression of USP11 inhibits I[kappa]Ba ubiquitination. Recombinant USP11 catalyzes deubiquitination of I[kappa]Ba in vitro. Moreover, knockdown of USP11 expression enhances TNFa-induced I[kappa]Ba ubiquitination and NF-[kappa]B activation. These data demonstrate that USP11 plays an important role in the downregulation of TNFa-mediated NF-[kappa]B activation through modulating I[kappa]Ba stability. In addition, overexpression of a catalytically inactive USP11 mutant partially inhibits TNFa- and IKKb-induced NF-[kappa]B activation, suggesting that USP11 also exerts a non-catalytic function in its negative regulation of TNFa-mediated NF-[kappa]B activation. Thus, I[kappa]Ba ubiquitination and deubiquitination processes function as a Yin-Yang regulatory mechanism on TNFa-induced NF-[kappa]B activation.