Direct proteolytic cleavage of NLRP1B is necessary and sufficient for inflammasome activation by anthrax lethal factor

• Published in: PLoS pathogens Vol. 9; no. 6; p. e1003452
• Main Authors: Chavarría-Smith, Joseph, Vance, Russell E
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.06.2013; Public Library of Science (PLoS)
• Subjects: Animals; Anthrax; Antigens, Bacterial - genetics; Antigens, Bacterial - immunology; Antigens, Bacterial - metabolism; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - immunology; Apoptosis Regulatory Proteins - metabolism; Bacillus anthracis - genetics; Bacillus anthracis - immunology; Bacillus anthracis - metabolism; Bacterial Toxins - genetics; Bacterial Toxins - immunology; Bacterial Toxins - metabolism; Biology; Cell Line, Transformed; Cytokines; Health aspects; Host-parasite relationships; Humans; Immune response; Immune system; Inflammasomes - genetics; Inflammasomes - immunology; Inflammasomes - metabolism; Kinases; Medical research; Mice; Physiological aspects; Proteins; Proteolysis; Rats; Rats, Inbred F344; United States
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1003452

Inflammasomes are multimeric protein complexes that respond to infection by recruitment and activation of the Caspase-1 (CASP1) protease. Activated CASP1 initiates immune defense by processing inflammatory cytokines and by causing a rapid and lytic cell death called pyroptosis. Inflammasome formation is orchestrated by members of the nucleotide-binding domain and leucine-rich repeat (NLR) or AIM2-like receptor (ALR) protein families. Certain NLRs and ALRs have been shown to function as direct receptors for specific microbial ligands, such as flagellin or DNA, but the molecular mechanism responsible for activation of most NLRs is still poorly understood. Here we determine the mechanism of activation of the NLRP1B inflammasome in mice. NLRP1B, and its ortholog in rats, is activated by the lethal factor (LF) protease that is a key virulence factor secreted by Bacillus anthracis, the causative agent of anthrax. LF was recently shown to cleave mouse and rat NLRP1 directly. However, it is unclear if cleavage is sufficient for NLRP1 activation. Indeed, other LF-induced cellular events have been suggested to play a role in NLRP1B activation. Surprisingly, we show that direct cleavage of NLRP1B is sufficient to induce inflammasome activation in the absence of LF. Our results therefore rule out the need for other LF-dependent cellular effects in activation of NLRP1B. We therefore propose that NLRP1 functions primarily as a sensor of protease activity and thus could conceivably detect a broader spectrum of pathogens than just B. anthracis. By adding proteolytic cleavage to the previously established ligand-receptor mechanism of NLR activation, our results illustrate the remarkable flexibility with which the NLR architecture can be deployed for the purpose of pathogen-detection and host defense.