A calpain-like protease inhibits autophagic cell death.
Programmed cell death (PCD) plays critical roles during development and in disease states. One form of programmed cell death utilizes autophagy--a cellular mechanism of degrading bulk cytosolic components--to destroy cells. Previously, the broad-spectrum caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD) was shown to induce autophagic cell death. The mechanism of Zvad-induced cell death was proposed to require caspase-8 inhibition. In our report, we extend these findings to show that--as is the case for apoptosis--induction of autophagic cell death in response to zVAD results in phosphatidylserine exposure prior to loss of membrane integrity. Additionally, we show that caspase-8 inhibition is insufficient to cause autophagic cell death. Rather, the activity of a calpain-like protease must also be blocked. These results reveal the existence of an autophagic PCD-inhibiting calpain-like cysteine protease.
Madden
David T
DT
Buck Institute for Age Research, Novato, California 94945, USA.
Egger
Lotti
L
Bredesen
Dale E
DE
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D001343:Autophagy / Q000187:drug effects* / Q000502:physiology; D053181:Caspase 8; D061945:Caspase Inhibitors; D002460:Cell Line; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D051379:Mice; D010718:Phosphatidylserines / Q000378:metabolism
D000590:Amino Acid Chloromethyl Ketones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D010718:Phosphatidylserines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C505526:Casp8 protein, mouse; D053181:Caspase 8