A calpain-like protease inhibits autophagic cell death

Abstract

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. ©2007 Landes Bioscience.