Activation of Inflammasomes Requires Intracellular Redistribution of the Apoptotic Speck-Like Protein Containing a Caspase Recruitment Domain

J Immunol. 2009 Mar 1;182(5):3173-82. doi: 10.4049/jimmunol.0802367.

Abstract

Activation of caspase 1 is essential for the maturation and release of IL-1beta and IL-18 and occurs in multiprotein complexes, referred to as inflammasomes. The apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is the essential adaptor protein for recruiting pro-caspase 1 into inflammasomes, and consistently gene ablation of ASC abolishes caspase 1 activation and secretion of IL-1beta and IL-18. However, distribution of endogenous ASC has not yet been examined in detail. In the present study, we demonstrated that ASC localized primarily to the nucleus in resting human monocytes/macrophages. Upon pathogen infection, ASC rapidly redistributed to the cytosol, followed by assembly of perinuclear aggregates, containing several inflammasome components, including caspase 1 and Nod-like receptors. Prevention of ASC cytosolic redistribution completely abolished pathogen-induced inflammasome activity, which affirmed that cytosolic localization of ASC is essential for inflammasome function. Thus, our study characterized a novel mechanism of inflammasome regulation in host defense.

Publication types

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

MeSH terms

  • Apoptosis / immunology*
  • CARD Signaling Adaptor Proteins
  • Carrier Proteins / metabolism*
  • Caspase 1 / chemistry
  • Caspase 1 / metabolism*
  • Cell Line
  • Cell Line, Tumor
  • Cell Nucleus / enzymology
  • Cell Nucleus / metabolism
  • Cytoskeletal Proteins / metabolism*
  • Cytosol / enzymology
  • Cytosol / immunology
  • Cytosol / metabolism
  • HL-60 Cells
  • Humans
  • Inflammation Mediators / metabolism*
  • Inflammation Mediators / physiology
  • Intracellular Fluid / metabolism*
  • Macrophages / enzymology
  • Macrophages / immunology
  • Macrophages / metabolism
  • Monocytes / enzymology
  • Monocytes / immunology
  • Monocytes / metabolism
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Protein Structure, Tertiary
  • Resting Phase, Cell Cycle / immunology
  • U937 Cells

Substances

  • CARD Signaling Adaptor Proteins
  • Carrier Proteins
  • Cytoskeletal Proteins
  • Inflammation Mediators
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human
  • PYCARD protein, human
  • Caspase 1