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A calpain-like protease inhibits autophagic cell death

David T Madden1, Lotti Egger, Dale E Bredesen

  • 1Buck Institute for Age Research, Novato, California 94945, USA.

Autophagy
|April 4, 2007
PubMed

Insights

z-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD) triggers autophagic cell death by inhibiting both caspase-8 and a calpain-like protease. This reveals a novel protease that regulates programmed cell death.

Area of Science:

  • Cellular biology
  • Molecular mechanisms of cell death

Background:

  • Programmed cell death (PCD) is crucial in development and disease.
  • Autophagy, a cellular degradation process, can mediate PCD.
  • Caspase inhibition by zVAD was previously linked to autophagic cell death.

Purpose of the Study:

  • To elucidate the precise mechanism of zVAD-induced autophagic cell death.
  • To determine the specific molecular targets required for zVAD-induced autophagic cell death.

Main Methods:

  • Investigated phosphatidylserine exposure and membrane integrity loss during zVAD treatment.
  • Assessed the necessity of caspase-8 inhibition for zVAD-induced autophagic cell death.
  • Examined the role of calpain-like protease activity in regulating this cell death pathway.

Main Results:

  • zVAD-induced autophagic cell death involves phosphatidylserine exposure before membrane integrity loss, similar to apoptosis.
  • Caspase-8 inhibition alone is insufficient to induce autophagic cell death.
  • Blocking a calpain-like protease activity is also required for zVAD-induced autophagic cell death.

Conclusions:

  • zVAD induces autophagic cell death through a mechanism requiring both caspase-8 inhibition and the blockade of a calpain-like protease.
  • These findings identify a novel calpain-like cysteine protease that actively inhibits autophagic programmed cell death.

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