ORIGINAL ARTICLE

Cell Research (2006)16: 895-901
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Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IkB kinase (IKK)

Guoliang Qing, Pengrong Yan, Gutian Xiao

¹Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA

Correspondence:Gutian Xiao Tel.: +1-732-445-2839; Fax: +1-732-445-5870; E-mail:xiao@biology.rutgers.edu Received 28 September 2006; revised 9 October 2006; accepted 10 October 2006; published online 7 November 2006

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Autophagic and proteasomal proteolysis are two major pathways for degradation of cellular constituents. Current models suggest that autophagy is responsible for the nonselective bulk degradation of long-lived proteins and organelles while the proteasome specifically degrades short-lived proteins including misfolded proteins caused by the absence of Hsp90 function. Here, we show that the IkB kinase (IKK), an essential activator of NF-kB, is selectively degraded by autophagy when Hsp90 is inhibited by geldanamycin (GA), a specific Hsp90 inhibitor showing highly effective anti-tumor activity. We find that in this case inactivation of ubiquitination or proteasome fails to block IKK degradation. However, inhibition of autophagy by an autophagy inhibitor or knockout of Atg5, a key component of the autophagy pathway, significantly rescues IKK from GA-induced degradation. These findings provide the first evidence that an Hsp90 client may be degraded by a mechanism different from the proteasome pathway and establish a molecular link among Hsp90, NF-kB and autophagy

Cell Research (2006) 16:895-901. doi:10.1038/sj.cr.7310109; published online 7 November 2006

Keywords: autophagy, geldanamycin, Hsp90, IkB kinase, NF-kB, proteasome, selective degradation, therapy