Abstract
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.
Highlights
Recognition of pathogens is an essential first step in the initiation of protective host immune responses
We show that anthrax lethal factor cleaves NLRP1B and this cleavage event is both necessary and sufficient for the activation of this sensor
Mutation of the cleavage site in rat NLRP1 rendered NLRP1 resistant to cleavage by lethal factor (LF) and prevented NLRP1 activation in response to LF. These results suggest that cleavage of rat NLRP1 by LF is essential for NLRP1 activation, but it is difficult to rule out the possibility that mutation of the cleavage site disrupted the fold of NLRP1, or rendered NLRP1 non-functional for other reasons
Summary
Recognition of pathogens is an essential first step in the initiation of protective host immune responses. Recognition of pathogens has been shown to be mediated by several families of germ-line encoded receptors that include the Toll-like receptors (TLRs), Nucleotide-binding domain and Leucine-rich Repeat containing proteins (NLRs), and RIG-I-like receptors (RLRs) [1]. Most TLRs, NLRs, and RLRs for which activation mechanisms have been defined appear to function as ‘‘pattern recognition receptors’’ [2] that directly bind to molecular structures called pathogen-associated molecular patterns (PAMPs) that are broadly conserved among many microbes. In addition to detection of PAMPs, it has been previously proposed that the innate immune system might respond to ‘Patterns of Pathogenesis’, the virulence-associated activities that pathogens utilize to invade or manipulate their hosts [3]. Disruption of the actin cytoskeletal signaling by bacterial toxins was found to lead to a protective innate immune response [6,7] Overall, there is still considerable uncertainty as to whether or how ‘patterns of pathogenesis’ are sensed by the innate immune system
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