Journal
CELL HOST & MICROBE
Volume 8, Issue 6, Pages 471-483Publisher
CELL PRESS
DOI: 10.1016/j.chom.2010.11.007
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Funding
- National Institutes of Health National Institute of Allergy and Infectious Diseases [P01 AI063302, R01 AI075039]
- Burroughs Wellcome Fund
- Cancer Research Institute
- Stanford Institute for Immunity
- Swiss National Science Foundation
- Human Frontiers in Science Program
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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-1 beta 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-1 beta/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-1 beta/18 inefficiently. Our results suggest the formation of spatially and functionally distinct inflammasomes complexes in response to bacterial pathogens.
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