Li JM, Wu H, Zhang W, Blackburn MR, Jin J

IκBα is an inhibitor of NF-κB, a family of transcription factors that transactivate genes related to inflammation. Upon inflammatory stimuli, IκBα is rapidly degraded via the ubiquitin-proteasome pathway. While it is very clear that the SCF(β-TRCP) ubiquitin ligase ubiquitinates IκBα upon stimulation, little is known about the post-ubiquitinational events of ...

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IκBα proteolysis. Here we report that p97, a valosin-containing protein (also called VCP), plays an essential role in the post-ubiquitinational regulation of IκBα turnover after TNFα or IL-1β treatment. The ATPase activity of p97 is essential for its role in IκBα proteolysis. Moreover, we found that UFD1L and NPL4, two cofactors of p97, assist p97 to control the post-ubiquitinational regulation of IκBα. The p97-UFD1L-NPL4 protein complex specifically associates with ubiquitinated IκBα via the interactions between p97 and the SCF(β-TRCP) ubiquitin ligase, and between the polyubiquitin binding domain of UFD1L and polyubiquitinated IκBα. Furthermore, we observed that the post-ubiquitinational regulation of IκBα by the p97-UFD1L-NPL4 complex is important for NF-κB activation under stimuli.

Date: Nov. 18, 2013

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