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

Cell Host Microbe. 2010 Dec 16;8(6):471-83. doi: 10.1016/j.chom.2010.11.007.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / physiology
  • Bacterial Infections / metabolism
  • Bacterial Infections / pathology
  • CARD Signaling Adaptor Proteins / physiology
  • Calcium-Binding Proteins / physiology
  • Caspase 1 / genetics
  • Caspase 1 / physiology*
  • Cell Death
  • Cell Line
  • Cytokines / physiology*
  • Cytoskeletal Proteins / physiology
  • DNA-Binding Proteins
  • Francisella / physiology
  • Inflammasomes / physiology
  • Legionella pneumophila / physiology
  • Macrophages / metabolism
  • Macrophages / microbiology*
  • Macrophages / pathology
  • Mice
  • Mice, Inbred C57BL
  • Nuclear Proteins / metabolism
  • Protein Structure, Tertiary
  • Pseudomonas aeruginosa / physiology
  • Salmonella typhimurium / physiology

Substances

  • Aim2 protein, mouse
  • Apoptosis Regulatory Proteins
  • CARD Signaling Adaptor Proteins
  • Calcium-Binding Proteins
  • Cytokines
  • Cytoskeletal Proteins
  • DNA-Binding Proteins
  • Inflammasomes
  • Ipaf protein, mouse
  • Nuclear Proteins
  • Pycard protein, mouse
  • Caspase 1