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

I kappa B alpha serves as a central anchoring molecule in the sequestration of NF-kappa B transcription factor in the cytoplasm. Ubiquitination-mediated I kappa B alpha degradation immediately precedes and is required for NF-kappa B nuclear translocation and activation. However, the precise mechanism for the deubiquitination Of I kappa B alpha is still not fully understood. Using a proteomic approach, we have identified Ubiquitin Specific Pepticlase 11 (USP11) as an I kappa B alpha associated deubiquitinase. Overexpression of USP11 inhibits I kappa B alpha ubiquitination. Recombinant USP11 catalyzes deubiquitination Of I kappa B alpha in vitro. Moreover, knockdown of USP11 expression enhances TNF alpha-induced I kappa B alpha ubiquitination and NF-kappa B activation. These data demonstrate that USP11 plays an important role in the downregulation of TNF alpha-mediated NF-kappa B activation through modulating I kappa B alpha stability. In addition, overexpression of a catalytically inactive USP11 mutant partially inhibits TNF alpha- and IKK beta-induced NF-kappa B activation, suggesting that USP11 also exerts a non-catalytic function in its negative regulation of TNF alpha-mediated NF-kappa B activation. Thus. I kappa B alpha ubiquitination and deubiquitination processes function as a Yin-Yang regulatory mechanism on TNF alpha-induced NF-kappa B activation. (C) 2009 Elsevier Inc. All rights reserved.