Hsp90 inhibition results in autophagy-mediated proteasome-independent degradation of IkappaB kinase (IKK).
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.
Qing
Guoliang
G
Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, 604 Allison Road, Piscataway, NJ 08854, USA.
Yan
Pengrong
P
Xiao
Gutian
G
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
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