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

Shensi Shen1, Pengtao Zhang, Martin A Lovchik

  • 1Shanghai Institute of Materia Medica, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 201203, China.

The Journal of Cell Biology
|May 13, 2009
PubMed

Insights

A novel marine compound, oz-apraA, triggers the degradation of cancer-promoting proteins via chaperone-mediated autophagy (CMA). This anticancer strategy targets Hsp90 clients, including EGFR, revealing new insights into protein degradation pathways.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Heat shock protein 90 (Hsp90) is a crucial chaperone for numerous client proteins, and its inhibition is a promising anticancer strategy.
  • Chaperone-mediated autophagy (CMA) is a cellular pathway responsible for degrading specific proteins.

Purpose of the Study:

  • To investigate the mechanism by which an oxazoline analogue of apratoxin A (oz-apraA) promotes the degradation of Hsp90 client proteins.
  • To identify the role of chaperone-mediated autophagy (CMA) in this process and its interplay with the proteasomal pathway.

Main Methods:

  • Treatment of cells with oz-apraA, a marine cyclodepsipeptide.
  • Identification of a KFERQ-like motif in epidermal growth factor receptor (EGFR) essential for CMA recognition.
  • Mutation analysis of the KFERQ-like motif.
  • Investigation of protein interactions with Hsc70/Hsp70 and Hsp90.

Main Results:

  • Oz-apraA promotes the degradation of Hsp90 client proteins through CMA.
  • A conserved KFERQ-like pentapeptide motif in EGFR is critical for its recognition as a CMA substrate.
  • Mutation of this motif redirects EGFR degradation to the proteasomal pathway.
  • Oz-apraA binds to Hsc70/Hsp70, suggesting it stabilizes client protein interaction with Hsc70/Hsp70, thereby inhibiting Hsp90 function.

Conclusions:

  • Oz-apraA acts as an inducer of CMA for Hsp90 client proteins, including membrane receptors like EGFR.
  • This study demonstrates cross-talk between CMA and proteasomal degradation pathways.
  • The findings provide a novel mechanism for anticancer drug development targeting protein degradation.

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