PLoS Pathogens (Jan 2012)

Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome.

  • Jonathan L Levinsohn,
  • Zachary L Newman,
  • Kristina A Hellmich,
  • Rasem Fattah,
  • Matthew A Getz,
  • Shihui Liu,
  • Inka Sastalla,
  • Stephen H Leppla,
  • Mahtab Moayeri

DOI
https://doi.org/10.1371/journal.ppat.1002638
Journal volume & issue
Vol. 8, no. 3
p. e1002638

Abstract

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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.