Abstract
NOD-like receptor (NLR) proteins (Nlrps) are cytosolic sensors responsible for detection of pathogen and danger-associated molecular patterns through unknown mechanisms. Their activation in response to a wide range of intracellular danger signals leads to formation of the inflammasome, caspase-1 activation, rapid programmed cell death (pyroptosis) and maturation of IL-1β and IL-18. Anthrax lethal toxin (LT) induces the caspase-1-dependent pyroptosis of mouse and rat macrophages isolated from certain inbred rodent strains through activation of the NOD-like receptor (NLR) Nlrp1 inflammasome. Here we show that LT cleaves rat Nlrp1 and this cleavage is required for toxin-induced inflammasome activation, IL-1 β release, and macrophage pyroptosis. These results identify both a previously unrecognized mechanism of activation of an NLR and a new, physiologically relevant protein substrate of LT.
Highlights
Anthrax lethal toxin (LT) is a key virulence determinant of Bacillus anthracis
In this study we report that lethal factor (LF) cleaves Nlrp1 and that susceptibility of Nlrp1 to this cleavage dictates sensitivity of macrophages to the pyroptosis induced by this toxin
Anthrax lethal toxin (LT) is a protease which can induce rapid death of macrophages accompanied by activation and release of pro-inflammatory cytokines
Summary
Anthrax lethal toxin (LT) is a key virulence determinant of Bacillus anthracis. This bipartite toxin consists of the receptorbinding protein protective antigen (PA) and the metalloprotease lethal factor (LF) [1]. LT injection into experimental animals induces a vascular collapse similar to that occurring during anthrax infections. LT induces rapid lysis of macrophages from certain inbred rodent strains, but macrophage lysis in vivo is not essential for toxin-induced death of mice. LF’s only known substrates are the mitogen-activated protein kinase kinases (MEKs 1, 2, 3, 4, 6 and 7). No link between their cleavage and macrophage lysis or animal death has been found [1]
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