title: Anthrax lethal factor cleaves mouse nlrp1b in both toxin-sensitive and toxin-resistant macrophages.
abstract: Anthrax lethal factor (LF) is the protease component of anthrax lethal toxin (LT). LT induces pyroptosis in macrophages of certain inbred mouse and rat strains, while macrophages from other inbred strains are resistant to the toxin. In rats, the sensitivity of macrophages to toxin-induced cell death is determined by the presence of an LF cleavage sequence in the inflammasome sensor Nlrp1. LF cleaves rat Nlrp1 of toxin-sensitive macrophages, activating caspase-1 and inducing cell death. Toxin-resistant macrophages, however, express Nlrp1 proteins which do not harbor the LF cleavage site. We report here that mouse Nlrp1b proteins are also cleaved by LF. In contrast to the situation in rats, sensitivity and resistance of Balb/cJ and NOD/LtJ macrophages does not correlate to the susceptibility of their Nlrp1b proteins to cleavage by LF, as both proteins are cleaved. Two LF cleavage sites, at residues 38 and 44, were identified in mouse Nlrp1b. Our results suggest that the resistance of NOD/LtJ macrophages to LT, and the inability of the Nlrp1b protein expressed in these cells to be activated by the toxin are likely due to polymorphisms other than those at the LF cleavage sites.
authors.affiliation: Microbial Pathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Kristina A
authors.initials: KA
authors.lastname: Hellmich
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Levinsohn
authors.forename: Rasem
authors.initials: R
authors.lastname: Fattah
authors.forename: Zachary L
authors.initials: ZL
authors.lastname: Newman
authors.forename: Nolan
authors.initials: N
authors.lastname: Maier
authors.forename: Inka
authors.initials: I
authors.lastname: Sastalla
authors.forename: Shihui
authors.initials: S
authors.lastname: Liu
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Leppla
authors.forename: Mahtab
authors.initials: M
authors.lastname: Moayeri
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism* / Q000633:toxicity; D051017:Apoptosis Regulatory Proteins / Q000737:chemistry / Q000378:metabolism*; D001427:Bacterial Toxins / Q000378:metabolism* / Q000633:toxicity; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; C509168:Nalp1b protein, mouse; D011993:Recombinant Fusion Proteins; C030325:anthrax toxin; D020170:Caspase 1