PLoS Pathogens · 2012 · 319 citations · 18 references
Nlrp1 Is RequiredApoptosisImmunologyImmune RegulationPathologyCell DeathInnate Immune SystemInnate ImmunityImmune SystemCell Death MechanismsInflammationRat MacrophagesNod-like ReceptorInflammasomeAutoinflammatory DiseaseCell SignalingPyroptosisChronic InflammationImmune FunctionCell BiologyPhagocyteCytokineAnti-inflammatorySignal TransductionAnthrax Lethal ToxinMedicineNecroptosis
NLR proteins detect intracellular danger signals and trigger inflammasome assembly, caspase‑1 activation, pyroptosis, and IL‑1β/IL‑18 maturation, with anthrax lethal toxin inducing these responses via the Nlrp1 inflammasome in susceptible rodent macrophages. We demonstrate that anthrax lethal toxin cleaves rat Nlrp1, and this cleavage is essential for inflammasome activation, IL‑1β release, and macrophage pyroptosis, revealing a novel activation mechanism and a new physiological substrate of the toxin.
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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