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The NLR Adaptor ASC/PYCARD Regulates DUSP10, Mitogen-activated Protein Kinase (MAPK), and Chemokine Induction Independent of the Inflammasome*

By Debra J. Taxman, Elizabeth A. Holley-Guthrie, Max Tze-Han Huang, Chris B. Moore, Daniel T. Bergstralh, Irving C. Allen, Yu Lei, Denis Gris and Jenny Pan-Yun Ting


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

Topics: Signal Transduction
Publisher: American Society for Biochemistry and Molecular Biology
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Provided by: PubMed Central
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