Anthrax Lethal Toxin Induced Lysosomal Membrane Permeabilization and Cytosolic Cathepsin Release Is Nlrp1b/Nalp1b-Dependent

Department of Microbiology, Immunology & Molecular Genetics, University of California Los Angeles, Los Angeles, California, USA.
PLoS ONE (Impact Factor: 3.23). 11/2009; 4(11):e7913. DOI: 10.1371/journal.pone.0007913
Source: PubMed


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.

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    • "Many of the activating substrates for the other three inflammasomes are also known. The NLRP1 inflammasome is recruited by Bacillus anthracis lethal toxin and muramyl dipeptide of bacteria (Averette et al., 2009). The AIM2 inflammasome is stimulated by double stranded DNA in the cytosol and is responsible for the development of inflammatory response to viruses, bacterial DNA, and in some cases one's own DNA (Choubey, 2012). "
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    • "There is evidence supporting a function in bacterial recognition for several NLRs. These include NOD1/2 (recognizing peptidoglycan fragments) (Martinon et al., 2009), NLRP1 (sensing anthrax lethal toxin) (Averette et al., 2009), NLRP3 (activated by exposure to many pathogens, bacterial RNA, toxins, and crystal structures) (Davis et al., 2011; Duewell et al., 2010; Halle et al., 2008; Hornung et al., 2008; Kanneganti et al., 2006; Sander et al., 2011), NLRC4 (sensing of Salmonella, intracellular flagellin and bacterial type III secretion rod proteins) (Franchi et al., 2006; Miao et al., 2010), and Naip5 (promoting resistance to Legionella) (Kofoed and Vance, 2011; Molofsky et al., 2006; Ren et al., 2006). Recent results also suggested a role for NLRP6 in maintenance of bacterial homeostasis in the colon and for NLRP7 in the recognition of lipoproteins (Khare et al., 2012). "
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