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

Activation of caspase I is essential for the maturation and release of IL-1 beta 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 I into inflammasomes, and consistently gene ablation of ASC abolishes caspase 1 activation and secretion of IL-1 beta 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 I and Nod-like receptors. Prevention of ASC cytosolic redistribution completely abolished pathogen-induced inflammasome activity, which affirmed that cytosolic localization or ASC is essential for inflammasome function. Thus, our study characterized a novel mechanism of inflammasome regulation in host defense. The Journal of Immunology, 2009, 182: 3173-3182.