Journal
CELL RESEARCH
Volume 16, Issue 11, Pages 895-901Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.cr.7310109
Keywords
autophagy; geldanamycin; Hsp90; I kappa B kinase; NF-kappa B; proteasome; selective degradation; therapy
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Funding
- NCI NIH HHS [1R01 CA116616] Funding Source: Medline
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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 I kappa B kinase (IKK), an essential activator of NF-kappa B, 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-kappa B and autophagy.
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