Cyclodepsipeptide toxin promotes the degradation of Hsp90 client proteins through chaperone-mediated autophagy.
Promoting the degradation of Hsp90 client proteins by inhibiting Hsp90, an important protein chaperone, has been shown to be a promising new anticancer strategy. In this study, we show that an oxazoline analogue of apratoxin A (oz-apraA), a cyclodepsipeptide isolated from a marine cyanobacterium, promotes the degradation of Hsp90 clients through chaperone-mediated autophagy (CMA). We identify a KFERQ-like motif as a conserved pentapeptide sequence in the kinase domain of epidermal growth factor receptor (EGFR) necessary for recognition as a CMA substrate. Mutation of this motif prevents EGFR degradation by CMA and promotes the degradation of EGFR through the proteasomal pathway in oz-apraA-treated cells. Oz-apraA binds to Hsc70/Hsp70. We propose that apratoxin A inhibits Hsp90 function by stabilizing the interaction of Hsp90 client proteins with Hsc70/Hsp70 and thus prevents their interactions with Hsp90. Our study provides the first examples for the ability of CMA to mediate degradation of membrane receptors and cross talks of CMA and proteasomal degradation mechanisms.
Shanghai Institute of Materia Medica, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.
Shensi
S
Shen
Pengtao
P
Zhang
Martin A
MA
Lovchik
Ying
Y
Li
Liuya
L
Tang
Zhimin
Z
Chen
Rong
R
Zeng
Dawei
D
Ma
Junying
J
Yuan
Qiang
Q
Yu
D020816:Amino Acid Motifs; D001343:Autophagy; D001426:Bacterial Proteins; D002460:Cell Line; D047630:Depsipeptides / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism*; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors*; D006801:Humans; D018832:Molecular Chaperones; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
D001426:Bacterial Proteins; D047630:Depsipeptides; D018840:HSP70 Heat-Shock Proteins; D018841:HSP90 Heat-Shock Proteins; D018832:Molecular Chaperones; C442201:apratoxin A; D066246:ErbB Receptors; D046988:Proteasome Endopeptidase Complex