CA-074Me Protection against Anthrax Lethal Toxin
- 1 October 2009
- journal article
- Published by American Society for Microbiology in Infection and Immunity
- Vol. 77 (10) , 4327-4336
- https://doi.org/10.1128/iai.00730-09
Abstract
Anthrax lethal toxin (LT) activates the NLRP1b (NALP1b) inflammasome and caspase-1 in macrophages from certain inbred mouse strains, but the mechanism by which this occurs is poorly understood. We report here that similar to several NLRP3 (NALP3, cryopyrin)-activating stimuli, LT activation of the NLRP1b inflammasome involves lysosomal membrane permeabilization (LMP) and subsequent cytoplasmic cathepsin B activity. CA-074Me, a potent cathepsin B inhibitor, protects LT-sensitive macrophages from cell death and prevents the activation of caspase-1. RNA interference knockdown of cathepsin B expression, however, cannot prevent LT-mediated cell death, suggesting that CA-074Me may also act on other cellular proteases released during LMP. CA-074Me appears to function downstream of LT translocation to the cytosol (as assessed by mitogen-activated protein kinase kinase cleavage), K + effluxes, and proteasome activity. The initial increase in cytoplasmic activity of cathepsin B occurs at the same time or shortly before caspase-1 activation but precedes a larger-scale lysosomal destabilization correlated closely with cytolysis. We present results suggesting that LMP may be involved in the activation of the NLRP1b inflammasome.Keywords
This publication has 63 references indexed in Scilit:
- Anthrax Lethal Toxin Triggers the Formation of a Membrane-Associated Inflammasome Complex in Murine MacrophagesInfection and Immunity, 2009
- The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesisNature Immunology, 2009
- Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasomeProceedings of the National Academy of Sciences, 2009
- Heat shock inhibits caspase-1 activity while also preventing its inflammasome-mediated activation by anthrax lethal toxinCellular Microbiology, 2008
- The NALP3 inflammasome is involved in the innate immune response to amyloid-βNature Immunology, 2008
- Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilizationNature Immunology, 2008
- Anthrax lethal toxin and Salmonella elicit the common cell death pathway of caspase-1-dependent pyroptosis via distinct mechanismsProceedings of the National Academy of Sciences, 2008
- Microbial Pathogen-Induced Necrotic Cell Death Mediated by the Inflammasome Components CIAS1/Cryopyrin/NLRP3 and ASCCell Host & Microbe, 2007
- Anthrax lethal toxin-induced inflammasome formation and caspase-1 activation are late events dependent on ion fluxes and the proteasomeCellular Microbiology, 2007
- Lysosomal labilizationIUBMB Life, 2006