1. The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization
- Author
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Douglas R. Green, R. K. Subbarao Malireddi, Mohamed Lamkanfi, Lieselotte Vande Walle, Geoffrey Neale, Thirumala-Devi Kanneganti, Sirish K. Ippagunta, Yoshinori Fukui, and Patrick J. Shaw
- Subjects
Inflammasomes ,RNA Stability ,animal diseases ,caspase-1 ,Adaptive Immunity ,Cytoplasmic receptor ,Polymerization ,Mice ,0302 clinical medicine ,Cell Movement ,Guanine Nucleotide Exchange Factors ,Immunology and Allergy ,Lymphocytes ,Antigen Presentation ,0303 health sciences ,biology ,Dock2 ,GTPase-Activating Proteins ,DOCK2 ,hemic and immune systems ,Inflammasome ,Acquired immune system ,rac GTP-Binding Proteins ,Cell biology ,Rac GTP-Binding Proteins ,Chemotaxis, Leukocyte ,medicine.drug ,Immunology ,Antigen presentation ,chemical and pharmacologic phenomena ,ASC ,antigen uptake ,Article ,NLR ,03 medical and health sciences ,Immune system ,inflammasome ,TLR ,medicine ,Animals ,030304 developmental biology ,Innate immune system ,Dendritic Cells ,Molecular biology ,Actins ,eye diseases ,CARD Signaling Adaptor Proteins ,Mice, Inbred C57BL ,Cytoskeletal Proteins ,biology.protein ,Apoptosis Regulatory Proteins ,030215 immunology - 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.
- Published
- 2011
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