Anthrax Lethal Factor Cleavage of Nlrp1 Is Required for Activation of the Inflammasome |
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| Authors: | Jonathan L Levinsohn Zachary L Newman Kristina A Hellmich Rasem Fattah Matthew A Getz Shihui Liu Inka Sastalla Stephen H Leppla Mahtab Moayeri |
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| Institution: | Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.;The Salk Institute for Biological Studies, United States of America |
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| 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. |
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