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PMID:21892172

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Citation

Ippagunta, SK, Malireddi, RK, Shaw, PJ, Neale, GA, Walle, LV, Green, DR, Fukui, Y, Lamkanfi, M and Kanneganti, TD (2011) The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization. Nat. Immunol. 12:1010-6

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.

Links

PubMed PMC3178750 Online version:10.1038/ni.2095

Keywords

Actins/chemistry; Actins/metabolism; Adaptive Immunity; Animals; Antigen Presentation; Cell Movement; Chemotaxis, Leukocyte; Cytoskeletal Proteins/physiology; Dendritic Cells/immunology; GTPase-Activating Proteins/genetics; GTPase-Activating Proteins/physiology; Inflammasomes/physiology; Lymphocytes/immunology; Mice; Mice, Inbred C57BL; Polymerization; RNA Stability; rac GTP-Binding Proteins/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:DOCK2

involved_in

GO:0002277: myeloid dendritic cell activation involved in immune response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DOCK2

involved_in

GO:0050766: positive regulation of phagocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:DOCK2

involved_in

GO:0044351: macropinocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0002277: myeloid dendritic cell activation involved in immune response

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0002588: positive regulation of antigen processing and presentation of peptide antigen via MHC class II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0030838: positive regulation of actin filament polymerization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0031647: regulation of protein stability

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0043087: regulation of GTPase activity

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0032729: positive regulation of interferon-gamma production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0032755: positive regulation of interleukin-6 production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0042104: positive regulation of activated T cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0044351: macropinocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0050766: positive regulation of phagocytosis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:2000406: positive regulation of T cell migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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