Serine proteases mediate apoptosis-like cell death and phagocytosis under caspase-inhibiting conditions

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L Egger1, J Schneider, C Rhême

  • 1Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Zentrale Klinische Forschung, Breisacherstrasse 66, D-79106 Freiburg, Germany.

Cell Death and Differentiation
|September 23, 2003
PubMed

Insights

Even with caspase inhibitors, cells undergo apoptosis-like death via serine proteases. This process involves mitochondrial damage and phagocytosis, revealing alternative cell death pathways.

Area of Science:

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Background:

  • Apoptosis execution relies on caspases.
  • Caspase inhibitors (e.g., Z-VAD.fmk) often fail to block cell death due to basal caspase activity or caspase-independent pathways.
  • Physiological relevance of death mediators under caspase inhibition is unclear.

Purpose of the Study:

  • To determine if caspase-independent cell death pathways exhibit hallmarks of apoptosis.
  • To identify the mediators of apoptosis-like cell death under caspase inhibition.
  • To investigate the role of serine proteases in this process.

Main Methods:

  • Treatment of cells with ER stress drugs or IL-3 deprivation.
  • Application of caspase inhibitor Z-VAD.fmk and serine protease inhibitor Pefabloc (AEBSF).
  • Assessment of apoptosis hallmarks: cell shrinkage, membrane blebbing, cytochrome c release, phosphatidylserine (PS) exposure, and phagocytosis.

Main Results:

  • Cells exhibited apoptosis hallmarks (cell shrinkage, membrane blebbing, cytochrome c release, PS exposure, phagocytosis) despite Z-VAD.fmk treatment.
  • Co-treatment with Z-VAD.fmk and AEBSF abolished these events, implicating serine proteases.
  • Serine proteases acted upstream of mitochondrial membrane permeability increase.
  • Omi/HtrA2, a mitochondrial serine protease, was released later.

Conclusions:

  • Cells undergo apoptosis-like death and phagocytosis mediated by serine proteases, even when caspases are inhibited.
  • This serine protease-driven pathway damages the mitochondrial membrane.
  • Identifies a critical caspase-independent cell death mechanism relevant to apoptosis.

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