TY - JOUR
T1 - The inflammasome adaptor ASC regulates the function of adaptive immune cells by controlling Dock2-mediated Rac activation and actin polymerization
AU - Ippagunta, Sirish K.
AU - Malireddi, R. K.Subbarao
AU - Shaw, Patrick J.
AU - Neale, Geoffrey A.
AU - Walle, Lieselotte Vande
AU - Green, Douglas R.
AU - Fukui, Yoshinori
AU - Lamkanfi, Mohamed
AU - Kanneganti, Thirumala Devi
N1 - Funding Information:
We thank R. Flavell (Yale University School of Medicine), G. Nunez (University of Michigan) and S. Akira (Osaka University) for mutant mice; P. Vandenabeele (Ghent University) for anti-caspase-1; and H. Chi (St. Jude Children’s Research Hospital) for retroviral plasmids and mutant mice. Supported by the US National Institutes of Health (R01AR056296 and R21AI088177 to T.-D.K.), the American Lebanese Syrian Associated Charities (T.-D.K.), the European Union Framework Program 7 (Marie-Curie grant 256432 to M.L.) and the Fund for Scientific Research-Flanders (M.L. and L.V.W.).
PY - 2011/10
Y1 - 2011/10
N2 - 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 nucleotideĝ€"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.
AB - 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 nucleotideĝ€"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.
UR - http://www.scopus.com/inward/record.url?scp=80052968438&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=80052968438&partnerID=8YFLogxK
U2 - 10.1038/ni.2095
DO - 10.1038/ni.2095
M3 - Article
C2 - 21892172
AN - SCOPUS:80052968438
SN - 1529-2908
VL - 12
SP - 1010
EP - 1016
JO - Nature Immunology
JF - Nature Immunology
IS - 10
ER -