¹Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA

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

Received 26 April 2007; Revised 28 April 2007; Accepted 29 April 2007.

Abstract

NF-B-inducing kinase (NIK) is required for NF-B activation based on the processing of NF-B2 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 the subunit of IB 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-B regulation. These findings also suggest a new therapeutic strategy for diseases associated with p100 processing.