Activation of inflammasomes requires intracellular redistribution of the apoptotic speck-like protein containing a caspase recruitment domain.
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.
Bryan
Nicole B
NB
Division of Rheumatology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
Dorfleutner
Andrea
A
Rojanasakul
Yon
Y
Stehlik
Christian
C
D017209:Apoptosis / Q000276:immunology*; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000378:metabolism*; D020170:Caspase 1 / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000201:enzymology / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D003600:Cytosol / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018922:HL-60 Cells; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism* / Q000502:physiology; D007424:Intracellular Fluid / Q000378:metabolism*; D008264:Macrophages / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017434:Protein Structure, Tertiary; D016192:Resting Phase, Cell Cycle / Q000276:immunology; D020298:U937 Cells
D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D018836:Inflammation Mediators; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C402202:PYCARD protein, human; D020170:Caspase 1