Calpain activates caspase-8 in neuron-like differentiated PC12 cells via the amyloid-beta-peptide and CD95 pathways.
The neurotoxic amyloid-beta-peptide (Abeta) is important in the pathogenesis of Alzheimer's disease (AD). Calpain (Ca(2+)-dependent protease) and caspase-8 (the initiating caspase for the extrinsic, receptor-mediated apoptosis pathway) have been implicated in AD/Abeta toxicity. We previously found that Abeta promoted degradation of calpastatin (the specific endogenous calpain inhibitor); calpastatin degradation was prevented by inhibitors of either calpain or caspase-8. The results implied a cross-talk between the two proteases and suggested that one protease was responsible for the activity of the other one. We now report on the previously unrecognized caspase-8 activation by calpain. In neuron-like differentiated PC12 cells, calpain promotes active caspase-8 formation from procaspase-8 via the Abeta and CD95 pathways, along with degradation of the procaspase-8 processing inhibitor caspase-8 (FLICE)-like inhibitory protein, short isoform (FLIP(S)). Inhibition of calpain (by pharmacological inhibitors and by overexpression of calpastatin) prevents the cleavage of procaspase-8 to mature, active caspase-8, and inhibits FLIP(S) degradation in the Abeta-treated and CD95-triggered cells. Increased cellular Ca(2+) per se results in calpain activation but does not lead to caspase-8 activation or FLIP(S) degradation. The results suggest that procaspase-8 and FLIP(S) association with cell membrane receptor complexes is required for calpain-induced caspase-8 activation. The results presented here add to the understanding of the roles of calpain, caspase-8, and CD95 pathway in AD/Abeta toxicity. Calpain-promoted activation of caspase-8 may have implications for other types of CD95-induced cell damage, and for nonapoptotic functions of caspase-8. Inhibition of calpain may be useful for modulating certain caspase-8-dependent processes.
Vaisid
Tali
T
Department of Human Molecular Genetics and Biochemistry, Sackler School of Medicine, Tel-Aviv University, Ramat-Aviv, Tel-Aviv 69978, Israel.
Barnoy
Sivia
S
Kosower
Nechama S
NS
D000544:Alzheimer Disease / Q000276:immunology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001667:Binding, Competitive; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000494:pharmacology; D002154:Calpain / Q000378:metabolism*; D053181:Caspase 8 / Q000276:immunology / Q000378:metabolism*; D002454:Cell Differentiation; D004195:Disease Models, Animal; D053200:Fas-Associated Death Domain Protein / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D019014:fas Receptor / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002135:Calcium-Binding Proteins; D053200:Fas-Associated Death Domain Protein; D010446:Peptide Fragments; D019014:fas Receptor; C033668:calpastatin; D002154:Calpain; D053181:Caspase 8