title: The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization.
abstract: The adaptor ASC contributes to innate immunity through the assembly of inflammasome complexes that activate the cysteine protease caspase-1. Here we demonstrate that ASC has an inflammasome-independent, cell-intrinsic role in cells of the adaptive immune response. ASC-deficient mice showed defective antigen presentation by dendritic cells (DCs) and lymphocyte migration due to impaired actin polymerization mediated by the small GTPase Rac. Genome-wide analysis showed that ASC, but not the cytoplasmic receptor NLRP3 or caspase-1, controlled the mRNA stability and expression of Dock2, a guanine nucleotide-exchange factor that mediates Rac-dependent signaling in cells of the immune response. Dock2-deficient DCs showed defective antigen uptake similar to that of ASC-deficient cells. Ectopic expression of Dock2 in ASC-deficient cells restored Rac-mediated actin polymerization, antigen uptake and chemotaxis. Thus, ASC shapes adaptive immunity independently of inflammasomes by modulating Dock2-dependent Rac activation and actin polymerization in DCs and lymphocytes.
authors: Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors: Sirish K
authors: SK
authors: Ippagunta
authors: R K Subbarao
authors: RK
authors: Malireddi
authors: Patrick J
authors: PJ
authors: Shaw
authors: Geoffrey A
authors: GA
authors: Neale
authors: Lieselotte
authors: L
authors: Vande Walle
authors: Douglas R
authors: DR
authors: Green
authors: Yoshinori
authors: Y
authors: Fukui
authors: Mohamed
authors: M
authors: Lamkanfi
authors: Thirumala-Devi
authors: TD
authors: Kanneganti
mesh_terms: D000199:Actins / Q000737:chemistry* / Q000378:metabolism; D056704:Adaptive Immunity; D000818:Animals; D017951:Antigen Presentation; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002465:Cell Movement; D002634:Chemotaxis, Leukocyte; D003598:Cytoskeletal Proteins / Q000502:physiology*; D003713:Dendritic Cells / Q000276:immunology; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000502:physiology*; D020662:Guanine Nucleotide Exchange Factors; D058847:Inflammasomes / Q000502:physiology*; D008214:Lymphocytes / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D058105:Polymerization; D020871:RNA Stability; D020744:rac GTP-Binding Proteins / Q000378:metabolism*
chemical_list: D000199:Actins; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; C471356:DOCK2 protein, mouse; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D058847:Inflammasomes; C498534:Pycard protein, mouse; D020744:rac GTP-Binding Proteins