Activation of the innate immune receptor NLRP1B leads to the formation of an inflammasome, which induces autoproteolytic processing of pro-caspase-1, and ultimately to the release of inflammatory cytokines and to the execution of pyroptosis. One of the signals to which NLRP1B responds is metabolic stress that occurs in cells deprived of glucose or treated with metabolic inhibitors. NLRP1B might therefore sense microbial infection, as intracellular pathogens such as Listeria monocytogenes and Shigella flexneri cause metabolic stress as a result of nutrient scavenging and host cell damage. Here we addressed whether these pathogens activate the NLRP1B inflammasome. We found that Listeria infection activated the NLRP1B inflammasome in a reconstituted fibroblast model. Activation of NLRP1B by Listeria was diminished in an NLRP1B mutant shown previously to be defective at detecting energy stress and was dependent on the expression of listeriolysin O (LLO), a protein required for vacuolar escape. Infections of either Listeria or Shigella activated NLRP1B in the RAW264.7 murine macrophage line, which expresses endogenous NLRP1B. We conclude that NLRP1B senses cellular infection by distinct invasive pathogens.KEYWORDS Listeria monocytogenes, NLRP1B, Shigella, caspase-1, inflammasome N LRP1B is a pattern recognition receptor that forms a multiprotein complex termed an inflammasome after it detects an activating signal (1). The NLRP1B inflammasome complex consists of multiple copies of NLRP1B and pro-caspase-1. The assembly of the complex leads to autoproteolysis of pro-caspase-1 and, consequently, to processing of inflammatory cytokines interleukin-1 (IL-1) and IL-18 and to a type of cell death called pyroptosis (2, 3). NLRP1B has four domains (2) (Fig. 1A). The N-terminal NACHT domain (a domain present in NAIP, CIITA, HET-E, and TP-1) is a nucleotide-binding domain that selfassociates. The leucine-rich repeat (LRR) domain is involved in autoinhibition (4, 5), and the function to find domain (FIIND) undergoes autoproteolytic processing, which facilitates inflammasome assembly (6-8). The C-terminal caspase-activating and recruitment domain (CARD) binds the CARD of pro-caspase-1 (4).Anthrax lethal toxin is the only known direct activator of murine NLRP1B (1). The proteolytic component of the toxin cleaves NLRP1B near its N terminus; this cleavage is sufficient to relieve autoinhibition and allow oligomerization (9-11). Depletion of intracellular ATP is another activator of NLRP1B but one that probably triggers inflammasome assembly indirectly (12). The N-terminal region of NLRP1B is not cleaved after depletion of ATP, and the FIIND of NLRP1B facilitated the detection of this signal instead (5). Thus, activation of NLRP1B occurs through at least two distinct mechanisms.The intracellular parasite Toxoplasma gondii is also detected by NLRP1B (13,14), although the direct signal has not been determined. It is possible that Toxoplasma infection causes a reduction in cytosolic ATP. Notably, the parasite cannot synthesiz...
Pattern recognition receptors monitor for signs of infection or cellular dysfunction and respond to these events by initiating an immune response. NLRP1B is a receptor that upon activation recruits multiple copies of procaspase-1, which promotes cytokine processing and a proinflammatory form of cell death termed pyroptosis. NLRP1B detects anthrax lethal toxin when the toxin cleaves an amino-terminal fragment from the protein. In addition, NLRP1B is activated when cells are deprived of glucose or treated with metabolic inhibitors, but the mechanism by which the resulting reduction in cytosolic ATP is sensed by NLRP1B is unknown. Here, we addressed whether these two activating signals of NLRP1B converge on a common sensing system. We show that an NLRP1B mutant lacking the amino-terminal region exhibits some spontaneous activity and fails to be further activated by lethal toxin. This mutant was still activated in cells depleted of ATP, however, indicating that the amino-terminal region is not the sole sensing domain of NLRP1B. Mutagenesis of the leucine-rich repeat domain of NLRP1B provided evidence that this domain is involved in autoinhibition of the receptor, but none of the mutants tested was specifically defective at sensing activating signals. Comparison of two alleles of NLRP1B that differed in their response to metabolic inhibitors, but not to lethal toxin, led to the finding that a repeated sequence in the function to find domain (FIIND) that arose from exon duplication facilitated detection of ATP depletion. These results suggest that distinct regions of NLRP1B detect activating signals.
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