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Detection of Inflammasome Activation and Pyroptotic Cell Death in Murine Bone Marrow-derived Macrophages
Published on: May 21, 2018
Proteasome activity is required for anthrax lethal toxin to kill macrophages
1Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA.
Infection and Immunity
|May 25, 1999
Summary
Proteasome inhibitors block anthrax lethal toxin (LeTx) cytotoxicity by preventing ATP depletion, indicating the proteasome mediates an early toxic LeTx process. This suggests LeTx intoxication involves proteasome-dependent degradation of essential macrophage molecules.
Area of Science:
- Cell Biology
- Toxicology
- Molecular Biology
Background:
- Anthrax lethal toxin (LeTx), composed of protective antigen (PA) and lethal factor (LF), is cytotoxic to macrophages.
- LF is translocated into the cytosol by PA, where it cleaves substrates like MEK1.
Purpose of the Study:
- To investigate the role of the proteasome in LeTx-induced cytotoxicity.
- To determine the mechanism by which proteasome inhibitors affect LeTx toxicity.
Main Methods:
- Treatment of macrophage cell lines with LeTx and various protease/proteasome inhibitors.
- Assessment of cytotoxicity, MEK1 cleavage, ATP levels, and proteasome activity.
- Analysis of IkappaB-alpha degradation.
Main Results:
- Proteasome inhibitors, but not other protease inhibitors, blocked LeTx cytotoxicity.
- Inhibitors prevented LeTx-induced ATP depletion but did not inhibit LF's MEK1 cleavage activity.
- No overall activation of the proteasome by LeTx was observed.
Conclusions:
- The proteasome mediates an early, toxic process in LeTx intoxication downstream of MEK1 cleavage.
- This process likely involves the degradation of essential macrophage homeostasis molecules.
- Proteasome inhibition offers a potential strategy to counteract LeTx toxicity.
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