Differential requirement for Caspase-1 autoproteolysis in pathogen-induced cell death and cytokine processing

By Petr Brož, Jakob von Moltke, Jonathan W. Jones, R. Vance, D. Monack. Cell Host and Microbe, 2010

611 citations recorded by the source corpus.

Summary Activation of the cysteine protease Caspase-1 is a key event in the innate immune response to infections. Synthesized as a pro-protein, Caspase-1 undergoes autoproteolysis within multi-protein complexes called inflammasomes. Activated Caspase-1 is required for proteolytic processing and release of the cytokines interleukin-1β and interleukin-18, and 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.

Subfields: Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/8d94f8b3fa3c2e42274b37549383e78029081eea

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In Immunology

1. T. Kanneganti
2. M. Lamkanfi
3. G. Núñez
4. V. Dixit
5. L. Franchi
6. Katherine A. Fitzgerald
7. S. Man
8. Yaqiu Wang

In Molecular Biology

1. T. Kanneganti
2. M. Lamkanfi
3. G. Núñez
4. S. Man
5. V. Dixit
6. Yaqiu Wang
7. Katherine A. Fitzgerald
8. L. Franchi

Citations in the corpus

• Pattern Recognition Receptors and the Host Cell Death Molecular Machinery (2018, background): “Activation of one of these cytosolic sensors in response to PAMPs, DAMPs or cytosolic disturbances such as ionic imbalance leads to the recruitment and activation of caspase-1 either directly or through the ASC adaptor molecule [(140); Figure 3].”
• Inflammasomes in neuroinflammatory and neurodegenerative diseases (2019, background): “In agreement, NLRP3 knockout mice were resistant to the loss of nigral dopaminergic neurons induced by treatment with the neurotoxin 1-methyl-4-phenyl1,2,3,6-tetrahydropyridine (MPTP), which was associated with a reduction in caspase-1 activation and IL-1b and IL-18 secretion (Yan et al, 2015).”
• Programmed cell death in the plant immune system (2011, background): “Interestingly, cytokine maturation is genetically separable from pyroptotic cell death: a recent report has shown that ASC-independent inflammasomes can activate caspase-1 without autoproteolysis , promoting cell death without processing IL-1b/IL-18.”
• Caspases in cell death, inflammation and disease (2019, background): “This is a surprising observation given that ASC expression and TLR priming have been previously shown to be dispensable for pyroptosis induction by the NLRP1b and NLRC4 inflammasomes (Broz et al., 2010; Guey et al., 2014; Van Opdenbosch et al., 2014).”
• Mechanisms and functions of inflammasomes. (2014, background): “Caspases 1 and 11 in Immunity and Host Defense Inflammasomes modulate host defense responses through the production of eicosanoids (von Moltke et al., 2012) and other mechanisms (Lamkanfi, 2011), but the induction of pyroptosis and secretion of proinflammatory IL-1b and IL-18 are considered the prom”
• From pyroptosis, apoptosis and necroptosis to PANoptosis: A mechanistic compendium of programmed cell death pathways (2021, background): “Alternatively, CARD-containing sensors such as NLRP1b and NLRC4 can directly interact with CASP1, causing pyroptosis without inducing CASP1 autoprocessing [63,64], although the physiological relevance of ASC-independent interactions remains unclear.”
• STING is a direct innate immune sensor of cyclic-di-GMP (2011, methodology): “Barton, and immortalized macrophages were generated as described previousl”
• Sensing and Reacting to Microbes via the Inflammasomes (2012, background): “, whereas ASC is required for lethal toxin–induced production of IL-1β but is dispensable for pyroptosi”
• Inflammasomes and their roles in health and disease. (2012, background): “In this regard, Nlrc4 was recently suggested to assemble two distinct inflammasome complexes, one that contains and one that lacks ASC (Broz et al. 2010).”
• Inflammasomes in health and disease (2012, background): “In addition, it has been suggested that differential processing of caspase-1 might contribute to this finding because catalytically active caspase-1 that has been rendered unable to perform autocleavage is impaired in its ability to cleave cytokines, but it is still able to initiate pyroptosis on NL”
• Regulation of inflammasome activation (2015, background): “This interaction may explain why NLRC4 is able to induce pyroptosis independently of ASC (13, 150).”