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* Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611;
Program in Cancer Cell Biology, Health Sciences Center, West Virginia University, Morgantown, WV 26506;
Department of Pharmaceutical Sciences, School of Pharmacy, Health Sciences Center, West Virginia University, Morgantown, WV 26506
Activation of caspase 1 is essential for the maturation and release of IL-1β 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-1β 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This project was supported by National Institutes of Health Grants 1R21AI067680, 1R03AI067806, and 1R21AI082406 from the National Institute of Allergy and Infectious Diseases, Grant 1R01GM071723 from the National Institute of General Medical Sciences, the American Heart Association (Grant 0950125G), The Concern Foundation, and the John P. Gallagher Research Professorship.
2 Address correspondence and reprint requests to Dr. Christian Stehlik, Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, 240 East Huron, McGaw Pavilion, Chicago, IL 60611. E-mail address: c-stehlik{at}northwestern.edu
3 Abbreviations used in this paper: DAMP, damage-associated molecular pattern; NLR, Nod-like receptor; PYD, pyrin domain; CARD, caspase recruitment domain; PAMP, pathogen-associated molecular pattern; ASC, apoptotic speck-like protein containing a CARD; NLS, nuclear localization sequence; siRNA, small interfering RNA; HKLP, heat-killed Legionella pneumophila; HKSA, heat-killed Staphylococcus aureus; DAPI, 4',6-diamidino-2-phenylindole; shRNA, short hairpin RNA.
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