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PMID: 19234215 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain.

Journal of immunology (Baltimore, Md. : 1950) ·Vol. 182 ·No. 5 ·2009-03-01 ·Pages 3173-82

Bryan NB, Dorfleutner A, Rojanasakul Y, Stehlik C

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.

MeSH Terms
Apoptosis/immunology CARD Signaling Adaptor Proteins Carrier Proteins/metabolism Caspase 1/chemistry,metabolism Cell Line Cell Line, Tumor Cell Nucleus/enzymology,metabolism Cytoskeletal Proteins/metabolism Cytosol/enzymology,immunology,metabolism HL-60 Cells Humans Inflammation Mediators/metabolism,physiology Intracellular Fluid/metabolism Macrophages/enzymology,immunology,metabolism Monocytes/enzymology,immunology,metabolism NLR Family, Pyrin Domain-Containing 3 Protein Protein Structure, Tertiary Resting Phase, Cell Cycle/immunology U937 Cells
Chemicals
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
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Bryan Nicole B
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Dorfleutner Andrea
Rojanasakul Yon
Stehlik Christian
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Article Info
Journal
Journal of immunology (Baltimore, Md. : 1950)
Abbr.
J Immunol
ISSN
1550-6606
DOI
10.4049/jimmunol.0802367
Published
2009-03-01
Pages
3173-82
Language
English
Region
United States
NLM ID
2985117R
PMCID
PMC2652671
Subset
IM
Grants
NIAID NIH HHS · R21 AI067680-02 · United States
NIGMS NIH HHS · 1R01GM071723 · United States
NIAID NIH HHS · R21 AI067680 · United States
NIAID NIH HHS · R03 AI067806 · United States
NIGMS NIH HHS · R01 GM071723-03 · United States
NIAID NIH HHS · 1R21AI082406 · United States
NIGMS NIH HHS · R01 GM071723 · United States
NIAID NIH HHS · 1R21AI067680, · United States
NIAID NIH HHS · R21 AI082406 · United States
NIAID NIH HHS · R03 AI067806-02 · United States
NIAID NIH HHS · R21 AI082406-01 · United States
NIAID NIH HHS · 1R03AI067806, · United States
External Links
PubMed source DOI: 10.4049/jimmunol.0802367 PMC Full Text View journal details
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