title: Anthrax lethal toxin induced lysosomal membrane permeabilization and cytosolic cathepsin release is Nlrp1b/Nalp1b-dependent.
abstract: NOD-like receptors (NLRs) are a group of cytoplasmic molecules that recognize microbial invasion or 'danger signals'. Activation of NLRs can induce rapid caspase-1 dependent cell death termed pyroptosis, or a caspase-1 independent cell death termed pyronecrosis. Bacillus anthracis lethal toxin (LT), is recognized by a subset of alleles of the NLR protein Nlrp1b, resulting in pyroptotic cell death of macrophages and dendritic cells. Here we show that LT induces lysosomal membrane permeabilization (LMP). The presentation of LMP requires expression of an LT-responsive allele of Nlrp1b, and is blocked by proteasome inhibitors and heat shock, both of which prevent LT-mediated pyroptosis. Further the lysosomal protease cathepsin B is released into the cell cytosol and cathepsin inhibitors block LT-mediated cell death. These data reveal a role for lysosomal membrane permeabilization in the cellular response to bacterial pathogens and demonstrate a shared requirement for cytosolic relocalization of cathepsins in pyroptosis and pyronecrosis.
authors.affiliation: Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, Los Angeles, California, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Averette
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Pratt
authors.forename: Yanan
authors.initials: Y
authors.lastname: Yang
authors.forename: Sara
authors.initials: S
authors.lastname: Bassilian
authors.forename: Julian P
authors.initials: JP
authors.lastname: Whitelegge
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Loo
authors.forename: Tom W
authors.initials: TW
authors.lastname: Muir
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Bradley
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000483:Alleles; D000818:Animals; D000942:Antigens, Bacterial / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D001408:Bacillus anthracis / Q000378:metabolism; D001427:Bacterial Toxins / Q000378:metabolism*; D002401:Cathepsin B / Q000378:metabolism*; D002460:Cell Line; D003600:Cytosol / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D000070576:NLR Proteins; D009336:Necrosis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D001427:Bacterial Toxins; D000070576:NLR Proteins; C427903:NLRP1 protein, human; C030325:anthrax toxin; D002401:Cathepsin B; D046988:Proteasome Endopeptidase Complex