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

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• 作者：Wenjing Sun ; Xiaojie Tan ; Yi Shi ; Gufeng Xu ; Renfang Mao ; Xue Gu ; Yihui Fan ; Yang Yu ; Susan Burlingame ; Hong Zhang ; Surya P. Rednam ; Xiongbin Lu ; Ting Zhang ; Songbin Fu ; Guangwen Cao ; Jun Qin ; Jianhua
• 关键词：I&#x3ba ; B&#x3b1 ; NF-&#x3ba ; B ; USP11 ; IKK&#x3b2 ; TNF&#x3b1
• 刊名：Cellular Signalling
• 出版年：2010
• 出版时间：March 2010
• 年：2010
• 卷：22
• 期：3
• 页码：386-394
• 全文大小：1040 K

文摘

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.