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A Calpain-Like Protease Inhibits Autophagic Cell Death

David T. Madden, Lotti Egger and Dale E. Bredesen

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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.

Authors

David T. Madden

Buck Institute for Age Research

Lotti Egger

Buck Institute for Age Research

Dale E. Bredesen

Buck Institute for Age Research

This is an open-access article

 Download PDF

If the document does not open, please right-click on the link (control-click on a Macintosh) and select the option to save the file to disk.