Regulation of autophagy by ceramide-CD95-PERK signaling.
The manuscripts by Park et al. and Zhang et al. were initially planned as studies to understand the regulation of cell survival in transformed cells treated with sorafenib and vorinostat, and in primary hepatocytes treated with a bile acid+MEK1/2 inhibitor. In both cell systems we discovered that the toxicity of sorafenib and vorinostat or bile acid+MEK1/2 inhibitor exposure depended on the generation of ceramide and the ligand-independent activation of the CD95 death receptor, with subsequent activation of pro-caspase 8. We noted, however, in these systems that, in parallel with death receptor-induced activation of the extrinsic pathway, CD95 signaling also promoted increased phosphorylation of PKR-like endoplasmic reticulum kinase (PERK) and eIF2alpha, increased expression of ATG5, and increased processing of LC3 and vesicularization of a GFP-LC3 construct. The knockdown of ATG5 expression blocked GFP-LC3 vesicularization and enhanced cell killing. Thus ceramide-CD95 signaling promoted cell death via activation of pro-caspase 8 and cell survival via autophagy. PERK was shown to signal in a switch-hitting fashion; PERK promoted CD95-DISC formation and an eIF2alpha-dependent reduction in c-FLIP-s levels that were essential for cell killing to proceed, but in parallel it also promoted autophagy that was protective. The death receptor-induced apoptosis and autophagy occur proximal to the receptor rather than the mitochondrion, and the relative flow of death receptor signaling into either pathway may determine cell fate. Finally, death receptor induced apoptosis and autophagy could be potential targets for therapeutic intervention.
Park
Margaret A
MA
Department of Biochemistry, Virginia Commonwealth University, Richmond, Virginia 23298-0035, USA.
Zhang
Guo
G
Norris
James
J
Hylemon
Philip B
PB
Fisher
Paul B
PB
Grant
Steven
S
Dent
Paul
P
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D001343:Autophagy / Q000187:drug effects*; D053181:Caspase 8 / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism*; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy*; D015398:Signal Transduction; D019892:eIF-2 Kinase / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
D000970:Antineoplastic Agents; D053181:Caspase 8; D002518:Ceramides; D019892:eIF-2 Kinase; D019014:fas Receptor