title: Distinct regions of NLRP1B are required to respond to anthrax lethal toxin and metabolic inhibition.
abstract: Pattern recognition receptors monitor for signs of infection or cellular dysfunction and respond to these events by initiating an immune response. NLRP1B is a receptor that upon activation recruits multiple copies of procaspase-1, which promotes cytokine processing and a proinflammatory form of cell death termed pyroptosis. NLRP1B detects anthrax lethal toxin when the toxin cleaves an amino-terminal fragment from the protein. In addition, NLRP1B is activated when cells are deprived of glucose or treated with metabolic inhibitors, but the mechanism by which the resulting reduction in cytosolic ATP is sensed by NLRP1B is unknown. Here, we addressed whether these two activating signals of NLRP1B converge on a common sensing system. We show that an NLRP1B mutant lacking the amino-terminal region exhibits some spontaneous activity and fails to be further activated by lethal toxin. This mutant was still activated in cells depleted of ATP, however, indicating that the amino-terminal region is not the sole sensing domain of NLRP1B. Mutagenesis of the leucine-rich repeat domain of NLRP1B provided evidence that this domain is involved in autoinhibition of the receptor, but none of the mutants tested was specifically defective at sensing activating signals. Comparison of two alleles of NLRP1B that differed in their response to metabolic inhibitors, but not to lethal toxin, led to the finding that a repeated sequence in the function to find domain (FIIND) that arose from exon duplication facilitated detection of ATP depletion. These results suggest that distinct regions of NLRP1B detect activating signals.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Jana
authors.initials: J
authors.lastname: Neiman-Zenevich
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
authors.forename: Kuo-Chieh
authors.initials: KC
authors.lastname: Liao
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada jeremy.mogridge@utoronto.ca.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Mogridge
mesh_terms: D000255:Adenosine Triphosphate / Q000276:immunology; D000881:Anthrax / Q000276:immunology* / Q000382:microbiology; D000942:Antigens, Bacterial / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000276:immunology*; D001408:Bacillus anthracis / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology*; D002460:Cell Line; D006801:Humans; D058847:Inflammasomes / Q000276:immunology; D007930:Leucine / Q000276:immunology / Q000378:metabolism; D051192:Receptors, Pattern Recognition / Q000276:immunology
chemical_list: D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; D058847:Inflammasomes; D051192:Receptors, Pattern Recognition; C030325:anthrax toxin; D000255:Adenosine Triphosphate; D007930:Leucine