西亚试剂：Cyclodepsipeptide toxin promotes the degradation of Hsp90 c

Cyclodepsipeptide toxin promotes the degradation of Hsp90 client proteins through chaperone-mediated autophagy

Shensi Shen1, Pengtao Zhang2, Martin A. Lovchik2, Ying Li2, Liuya Tang3, Zhimin Chen1, Rong Zeng3, Dawei Ma2, Junying Yuan4, and Qiang Yu1

1 Shanghai Institute of Materia Medica, 2 State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, and 3 Key Laboratory of Systems Biology, Institute of Biochemistry and Cell Biology, Shanghai Institue of Biological Sciences, Chinese Academy of Sciences, Shanghai 201203, China
4 Department of Cell Biology, Harvard Medical School, Boston, MA 02115

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.

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