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- Title
Heat shock inhibits caspase-1 activity while also preventing its inflammasome-mediated activation by anthrax lethal toxin.
- Authors
Levin, Tera C; Wickliffe, Katherine E; Leppla, Stephen H; Moayeri, Mahtab
- Abstract
Anthrax lethal toxin (LT) rapidly kills macrophages from certain mouse strains in a mechanism dependent on the breakdown of unknown protein(s) by the proteasome, formation of the Nalp1b (NLRP1b) inflammasome and subsequent activation of caspase-1. We report that heat-shocking LT-sensitive macrophages rapidly protects them against cytolysis by inhibiting caspase-1 activation without upstream effects on LT endocytosis or cleavage of the toxin's known cytosolic substrates (mitogen-activated protein kinases). Heat shock protection against LT occurred through a mechanism independent of de novo protein synthesis, HSP90 activity, p38 activation or proteasome inhibition and was downstream of mitogen-activated protein kinase cleavage and degradation of an unknown substrate by the proteasome. The heat shock inhibition of LT-mediated caspase-1 activation was not specific to the Nalp1b (NLRP1b) inflammasome, as heat shock also inhibited Nalp3 (NLRP3) inflammasome-mediated caspase-1 activation in macrophages. We found that heat shock induced pro-caspase-1 association with a large cellular complex that could prevent its activation. Additionally, while heat-shocking recombinant caspase-1 did not affect its activity in vitro, lysates from heat-shocked cells completely inhibited recombinant active caspase-1 activity. Our results suggest that heat shock inhibition of active caspase-1 can occur independently of an inflammasome platform, through a titratable factor present within intact, functioning heat-shocked cells.
- Publication
Cellular microbiology, 2008, Vol 10, Issue 12, p2434
- ISSN
1462-5822
- Publication type
Journal Article
- DOI
10.1111/j.1462-5822.2008.01220.x