USP11 negatively regulates TNFα-induced NF-κB activation by targeting on IκBα

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