title: Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity.
abstract: The inflammasome adaptor ASC contributes to innate immunity through the activation of caspase-1. Here we found that signaling pathways dependent on the kinases Syk and Jnk were required for the activation of caspase-1 via the ASC-dependent inflammasomes NLRP3 and AIM2. Inhibition of Syk or Jnk abolished the formation of ASC specks without affecting the interaction of ASC with NLRP3. ASC was phosphorylated during inflammasome activation in a Syk- and Jnk-dependent manner, which suggested that Syk and Jnk are upstream of ASC phosphorylation. Moreover, phosphorylation of Tyr144 in mouse ASC was critical for speck formation and caspase-1 activation. Our results suggest that phosphorylation of ASC controls inflammasome activity through the formation of ASC specks.
authors.affiliation: 1] Department of Microbiology, Kyoto University Graduate School of Medicine, Kyoto, Japan. [2].
authors.forename: Hideki
authors.initials: H
authors.lastname: Hara
authors.forename: Kohsuke
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Ikuo
authors.initials: I
authors.lastname: Kawamura
authors.forename: Rendong
authors.initials: R
authors.lastname: Fang
authors.forename: Eduardo
authors.initials: E
authors.lastname: Hernandez-Cuellar
authors.forename: Yanna
authors.initials: Y
authors.lastname: Shen
authors.forename: Junichiro
authors.initials: J
authors.lastname: Mizuguchi
authors.forename: Edina
authors.initials: E
authors.lastname: Schweighoffer
authors.forename: Victor
authors.identifier: 0000000324390798
authors.initials: V
authors.lastname: Tybulewicz
authors.forename: Masao
authors.initials: M
authors.lastname: Mitsuyama
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020170:Caspase 1 / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004268:DNA-Binding Proteins; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020382:Interleukin-18 / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009550:Nigericin / Q000494:pharmacology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000276:immunology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D034622:RNA Interference; D000072377:Syk Kinase; D014443:Tyrosine / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: C540422:Aim2 protein, mouse; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D058847:Inflammasomes; D020382:Interleukin-18; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D009687:Nuclear Proteins; C498534:Pycard protein, mouse; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases; D020170:Caspase 1; D009550:Nigericin