ORIGINAL ARTICLE

Cell Research (2007): 520-530
© 2007 IBCB, SIBS, CAS All rights reserved 1001-0602/06 $ 30.00
www.nature.com/cr

Hsp90 regulates processing of NF-κB2 p100 involving protection of NF-κB-inducing kinase (NIK) from autophagy-mediated degradation

Guoliang Qing, Pengrong Yan, Zhaoxia Qu, Hudan Liu and Gutian Xiao

Correspondence: Gutian Xiao Tel: +1-732-445-2839; Fax: +1-732-445-5870 E-mail: xiao@biology.rutgers.edu

Download as printable (PDF) file Full Text (html)file Search Medline for articles by: Guoliang Qing

NF-κB-inducing kinase (NIK) is required for NF-κB activation based on the processing of NF-κB2 p100. Here we report a novel mechanism of NIK regulation involving the chaperone 90 kDa heat shock protein (Hsp90) and autophagy. Functional inhibition of Hsp90 by the anti-tumor agent geldanamycin (GA) efficiently disrupts its interaction with NIK, resulting in NIK degradation and subsequent blockage of p100 processing. Surprisingly, GA-induced NIK degradation is mediated by autophagy, but largely independent of the ubiquitin-proteasome system. Hsp90 seems to be specifically involved in the folding/stabilization of NIK protein, because GA inhibition does not affect NIK mRNA transcription and translation. Furthermore, Hsp90 is not required for NIK-mediated recruitment of α the subunit of IκB kinase to p100, a key step in induction of p100 processing. These findings define an alternative mechanism for Hsp90 client degradation and identify a novel function of autophagy in NF-κB regulation. These findings also suggest a new therapeutic strategy for diseases associated with p100 processing.

Cell Research (2007) 17:520–530. doi: 10.1038/cr.2007.47; published online 12 June 2007

Keywords: autophagy, geldanamycin, Hsp90; NF-κB2, NIK, proteasome-independent degradation