Differential Requirement for Caspase-1 Autoproteolysis in Pathogen-Induced Cell Death and Cytokine Processing

Department of Microbiology and Immunology, Stanford School of Medicine, Stanford University, Stanford, CA 94305, USA.
Cell host & microbe (Impact Factor: 12.33). 12/2010; 8(6):471-83. DOI: 10.1016/j.chom.2010.11.007
Source: PubMed


Activation of the cysteine protease Caspase-1 is a key event in the innate immune response to infections. Synthesized as a proprotein, Caspase-1 undergoes autoproteolysis within multiprotein complexes called inflammasomes. Activated Caspase-1 is required for proteolytic processing and for release of the cytokines interleukin-1β and interleukin-18, and it can also cause rapid macrophage cell death. We show that macrophage cell death and cytokine maturation in response to infection with diverse bacterial pathogens can be separated genetically and that two distinct inflammasome complexes mediate these events. Inflammasomes containing the signaling adaptor Asc form a single large "focus" in which Caspase-1 undergoes autoproteolysis and processes IL-1β/IL-18. In contrast, Asc-independent inflammasomes activate Caspase-1 without autoproteolysis and do not form any large structures in the cytosol. Caspase-1 mutants unable to undergo autoproteolysis promoted rapid cell death, but processed IL-1β/18 inefficiently. Our results suggest the formation of spatially and functionally distinct inflammasomes complexes in response to bacterial pathogens.

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    • "In contrast, self-processing between the large and the small subunits appeared dispensable for the initiation of pyroptosis, as wild-type and uncleavable mutants of caspase-1 were equally able to trigger pyroptosis in murine macrophages [14]. Pyroptosis execution does however absolutely require the catalytic activity of caspase-1 [5] [14]. "
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    • "NLRC4 can activate the caspase-1 inflammasome upon cytosolic detection of bacterial flagellin, but also components of the type III secretion system (T3SSs) in associations with NAIP proteins (96) (Table 1). In addition to cytokine production, activation of caspase-1 through a NLRC4 dependent pathway has been associated with subsequent death of cells, termed pyroptosis, which can take place independent of ASC (97, 98). Therefore, although there are structural similarities with other NLR proteins, activation of NLRC4 may have an opposite function in determining the activity of caspase-1, adding more specificity to the function of the innate immune system in response to bacteria. "
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    • "In one previous study, infection by S. typhimurium resulted in NLRC4- and caspase-1-dependent secretion of IL-1α (81). Interestingly, in contrast with most of the NLRP3 agonists, the secretion of IL-1α in response to S. typhimurium was completely independent of ASC, indicating a differential requirement for this adaptor molecule in cytokine secretion in response to NLRC4 agonists, as IL-1β is entirely dependent on ASC (2). However, Barry et al. showed that IL-1α initiates the inflammatory response driven by L. pneumophila independent of caspase-1 and NLRC4 (83). "
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