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Benzo(a)pyrene regulates chaperone-mediated autophagy via heat shock protein 90

Min Su1, Shuhong Zhou2, Jun Li3

  • 1School of Pharmacy, Inner Mongolia Medical University, Hohhot, China.

Toxicology Letters
|June 30, 2023
PubMed
Abstract

Insights

Benzo(a)pyrene (BaP) exposure causes DNA damage and autophagy via Heat Shock Protein 90 (HSP90). This study reveals BaP regulates Chaperone-Mediated Autophagy (CMA) through HSP90, clarifying its molecular mechanism.

Area of Science:

  • Environmental Toxicology
  • Molecular Biology
  • Cellular Biology

Background:

  • Benzo(a)pyrene (BaP) is a known environmental pollutant that induces oxidative damage, DNA damage, and autophagy.
  • The precise molecular mechanisms underlying BaP's effects on autophagy remain unclear.
  • Heat shock protein 90 (HSP90) plays a crucial role in cellular stress responses and autophagy, and is a target in cancer therapy.

Purpose of the Study:

  • To elucidate the novel mechanism by which BaP regulates Chaperone-Mediated Autophagy (CMA) through HSP90.
  • To investigate the role of HSP90 in BaP-induced DNA damage and autophagy.

Main Methods:

  • Mice were exposed to BaP, and A549 cells were treated with BaP.
  • Cell proliferation was assessed using MTT assay.
  • DNA damage was evaluated using alkaline comet assay and γ-H2AX immunofluorescence.
  • Expression levels of HSP90, HSC70, and Lamp-2a (mRNA and protein) were determined by qPCR and Western blot.
  • HSP90 expression was inhibited using NVP-AUY 922 or HSP90α shRNA lentivirus.

Main Results:

  • BaP exposure significantly increased the expression of HSP90, HSC70, and Lamp-2a in lung tissue and A549 cells.
  • BaP induced DNA double-strand breaks and activated DNA damage responses.
  • Knockdown of HSP90 using NVP-AUY 922 or HSP90α shRNA prevented the BaP-induced increase in HSC70 and Lamp-2a, indicating BaP-induced CMA is HSP90-dependent.
  • These findings suggest BaP regulates CMA and causes DNA damage via HSP90.

Conclusions:

  • BaP regulates CMA through HSP90.
  • HSP90 is implicated in mediating BaP-induced gene instability and promoting CMA.
  • This study clarifies the mechanism of BaP's effect on autophagy, enhancing understanding of BaP's action.
Keywords:
Benzo(a)pyreneChaperone-mediated autophagyHeat shock cognate 70Heat shock protein 90Lysosomal-associated membrane protein type 2 receptor

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