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Live-cell Imaging of Lysosomal Membrane Permeabilization During Necroptosis
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Live-cell Imaging of Lysosomal Membrane Permeabilization During Necroptosis

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Anthrax lethal toxin induced lysosomal membrane permeabilization and cytosolic cathepsin release is

Kathleen M Averette1, Matthew R Pratt, Yanan Yang

  • 1Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, Los Angeles, California, USA.

Plos One
|November 20, 2009
PubMed

Insights

Bacillus anthracis lethal toxin (LT) triggers cell death by causing lysosomal membrane permeabilization (LMP). This process requires Nlrp1b and releases cathepsin B into the cytosol, impacting cell death pathways.

Area of Science:

  • Immunology
  • Cell Biology
  • Microbiology

Background:

  • NOD-like receptors (NLRs) are intracellular sensors detecting microbial components and danger signals.
  • NLR activation can lead to pyroptosis (caspase-1 dependent) or pyronecrosis (caspase-1 independent) cell death.
  • Bacillus anthracis lethal toxin (LT) activates specific Nlrp1b alleles, inducing pyroptosis in immune cells.

Purpose of the Study:

  • To investigate the mechanism of Bacillus anthracis lethal toxin (LT)-induced cell death.
  • To determine the role of lysosomal membrane permeabilization (LMP) in LT-mediated cell death.
  • To elucidate the involvement of cathepsins in LT-induced cell death pathways.

Main Methods:

  • Macrophage and dendritic cell cultures treated with Bacillus anthracis lethal toxin (LT).
  • Assessment of lysosomal membrane permeabilization (LMP) using specific dyes and microscopy.
  • Inhibition studies using proteasome inhibitors, heat shock, and cathepsin B inhibitors.
  • Analysis of cathepsin B release into the cell cytosol.

Main Results:

  • LT induces lysosomal membrane permeabilization (LMP) in a manner dependent on the Nlrp1b sensor.
  • LMP induction by LT is blocked by proteasome inhibitors and heat shock, similar to pyroptosis.
  • The lysosomal protease cathepsin B is released into the cytosol following LT treatment.
  • Cathepsin inhibitors effectively block LT-mediated cell death.

Conclusions:

  • Lysosomal membrane permeabilization (LMP) is a critical event in the cellular response to Bacillus anthracis lethal toxin (LT).
  • The cytosolic relocalization of cathepsins is a shared mechanism in both pyroptosis and pyronecrosis induced by LT.
  • These findings reveal a novel role for lysosomes in innate immunity against bacterial toxins.

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