title: Anthrax lethal factor cleavage of Nlrp1 is required for activation of the inflammasome.
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.
authors.affiliation: Laboratory of Parasitic Diseases, National Institutes of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Levinsohn
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Newman
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Hellmich
authors.forename: Rasem
authors.initials: R
authors.lastname: Fattah
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Getz
authors.forename: Shihui
authors.initials: S
authors.lastname: Liu
authors.forename: Inka
authors.initials: I
authors.lastname: Sastalla
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000494:pharmacology*; D016466:CHO Cells; D002478:Cells, Cultured; D006224:Cricetinae; D003412:Cricetulus; D058847:Inflammasomes / Q000096:biosynthesis / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D058847:Inflammasomes; D009419:Nerve Tissue Proteins; C526260:Nlrp1a protein, rat; C030325:anthrax toxin