title: Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IkappaB kinase (IKK).
abstract: 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 IkappaB kinase (IKK), an essential activator of NF-kappaB, 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-kappaB and autophagy.
authors.affiliation: Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Qing
authors.forename: Pengrong
authors.initials: P
authors.lastname: Yan
authors.forename: Gutian
authors.initials: G
authors.lastname: Xiao
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D016227:Benzoquinones / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism*; D020672:I-kappa B Proteins / Q000378:metabolism; D015151:Immunoblotting; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D051379:Mice; D008954:Models, Biological; D016133:Polymerase Chain Reaction; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D020672:I-kappa B Proteins; D047029:Lactams, Macrocyclic; D025801:Ubiquitin; D051550:I-kappa B Kinase; D046988:Proteasome Endopeptidase Complex; C001277:geldanamycin