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PMID:21487011

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Citation

Taxman, DJ, Holley-Guthrie, EA, Huang, MT, Moore, CB, Bergstralh, DT, Allen, IC, Lei, Y, Gris, D and Ting, JP (2011) The NLR adaptor ASC/PYCARD regulates DUSP10, mitogen-activated protein kinase (MAPK), and chemokine induction independent of the inflammasome. J. Biol. Chem. 286:19605-16

Abstract

ASC/PYCARD is a common adaptor for a diverse set of inflammasomes that activate caspase-1, most prominently the NLR-based inflammasome. Mounting evidence indicates that ASC and these NLRs also elicit non-overlapping functions, but the molecular basis for this difference is unclear. To address this, we performed microarray and network analysis of ASC shRNA knockdown cells. In pathogen-infected cells, an ASC-dependent interactome is centered on the mitogen-activated protein kinase (MAPK) ERK and on multiple chemokines. ASC did not affect the expression of MAPK but affected its phosphorylation by pathogens and Toll-like receptor agonists via suppression of the dual-specificity phosphatase, DUSP10/MKP5. Chemokine induction, DUSP function, and MAPK phosphorylation were independent of caspase-1 and IL-1β. MAPK activation by pathogen was abrogated in Asc(-/-) but not Nlrp3(-/-), Nlrc4(-/-), or Casp1(-/-) macrophages. These results demonstrate a function for ASC that is distinct from the inflammasome in modulating MAPK activity and chemokine expression and further identify DUSP10 as a novel ASC target.

Links

PubMed PMC3103340 Online version:10.1074/jbc.M111.221077

Keywords

Animals; Cell Line; Chemokines/biosynthesis; Chemokines/genetics; Cytoskeletal Proteins/genetics; Cytoskeletal Proteins/metabolism; Dual-Specificity Phosphatases/genetics; Dual-Specificity Phosphatases/metabolism; Enzyme Activation/physiology; Gene Knockdown Techniques; Humans; Inflammasomes/genetics; Inflammasomes/metabolism; Macrophages/cytology; Macrophages/metabolism; Mice; Mice, Knockout; Mitogen-Activated Protein Kinase Kinases/genetics; Mitogen-Activated Protein Kinase Kinases/metabolism; Mitogen-Activated Protein Kinase Phosphatases/genetics; Mitogen-Activated Protein Kinase Phosphatases/metabolism

Significance

Annotations

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

MOUSE:ASC

involved_in

GO:0032722: positive regulation of chemokine production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ASC

involved_in

GO:0032760: positive regulation of tumor necrosis factor production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ASC

involved_in

GO:0032722: positive regulation of chemokine production

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ASC

involved_in

GO:0050829: defense response to Gram-negative bacterium

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ASC

involved_in

GO:0046330: positive regulation of JNK cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:ASC

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0070374: positive regulation of ERK1 and ERK2 cascade

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:ASC

involved_in

GO:0090197: positive regulation of chemokine secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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