anthrax lethal toxin induced lysosomal membrane permeabilization and cytosolic cathepsin release is nlrp1bnalp1b-dependent炭疽致命毒素引起溶酶体膜透化作用和胞质组织蛋白酶释放nlrp1bnalp1b-dependent.pdfVIP

Anthrax Lethal Toxin Induced Lysosomal Membrane Permeabilization and Cytosolic Cathepsin Release Is Nlrp1b/Nalp1b-Dependent 1 2 3 4 4 Kathleen M. Averette , Matthew R. Pratt , Yanan Yang , Sara Bassilian , Julian P. Whitelegge , Joseph A. 3 2 1 Loo , Tom W. Muir , Kenneth A. Bradley * 1 Department of Microbiology, Immunology Molecular Genetics, University of California Los Angeles, Los Angeles, California, United States of America, 2 Laboratory of Synthetic Protein Chemistry, The Rockefeller University, New York, New York, United States of America, 3 Department of Chemistry and Biochemistry, University of California Los Angeles, Los Angeles, California, United States of America, 4 The Pasarow Mass Spectrometry Laboratory, The NPI-Semel Institute, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America 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 bloc