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Regulation of autophagy by ceramide-CD95-PERK signaling

Margaret A Park1, Guo Zhang, James Norris

  • 1Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia 23298-0035, USA.

Autophagy
|August 23, 2008
PubMed

Insights

Ceramide-CD95 signaling triggers both cell death via caspase-8 and cell survival via autophagy. This dual pathway, regulated by PERK, presents potential therapeutic targets for cancer and liver diseases.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Biochemistry

Background:

  • Understanding cell survival mechanisms in transformed and primary cells is crucial for developing targeted therapies.
  • Sorafenib, vorinostat, bile acids, and MEK1/2 inhibitors are used in treating various diseases, but their precise effects on cell fate require elucidation.

Purpose of the Study:

  • To investigate the regulation of cell survival and death pathways in response to specific drug treatments.
  • To elucidate the roles of ceramide, CD95 death receptor, and PERK signaling in determining cell fate.

Main Methods:

  • Utilized transformed and primary cell systems treated with sorafenib, vorinostat, bile acid, and MEK1/2 inhibitors.
  • Assessed ceramide generation, CD95 death receptor activation, pro-caspase 8 cleavage, and PERK/eIF2alpha phosphorylation.
  • Investigated autophagy markers (ATG5, LC3 processing, GFP-LC3 vesicularization) and employed ATG5 knockdown.

Main Results:

  • Ceramide generation and CD95 death receptor activation were key to drug-induced toxicity, leading to pro-caspase 8 activation.
  • CD95 signaling concurrently activated autophagy pathways, evidenced by increased ATG5, LC3 processing, and GFP-LC3 vesicularization.
  • PKR-like endoplasmic reticulum kinase (PERK) played a dual role, promoting apoptosis while also inducing protective autophagy.

Conclusions:

  • Ceramide-CD95 signaling orchestrates a balance between apoptosis and autophagy, dictating cell fate.
  • PERK signaling acts as a critical switch, influencing both cell death and survival pathways.
  • Targeting death receptor-induced apoptosis and autophagy offers potential therapeutic strategies for diseases involving aberrant cell survival.

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