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

On the Lab. II building site

425 special CDSs in PCN033 (XLSX 29 kb

Additional file 2: Table S2. of Genome analysis and in vivo virulence of porcine extraintestinal pathogenic Escherichia coli strain PCN033

Core genome content used to construct phylogenetic tree (XLSX 225 kb

Additional file 1: Table S1. of Genome analysis and in vivo virulence of porcine extraintestinal pathogenic Escherichia coli strain PCN033

Genomes used for phylogenetic and Escherichia coli protein database construction (DOC 86 kb