title: The NLR adaptor ASC/PYCARD regulates DUSP10, mitogen-activated protein kinase (MAPK), and chemokine induction independent of the inflammasome.
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.
authors.affiliation: Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
authors.forename: Debra J
authors.initials: DJ
authors.lastname: Taxman
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Holley-Guthrie
authors.forename: Max Tze-Han
authors.initials: MT
authors.lastname: Huang
authors.forename: Chris B
authors.initials: CB
authors.lastname: Moore
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Bergstralh
authors.forename: Irving C
authors.initials: IC
authors.lastname: Allen
authors.forename: Yu
authors.initials: Y
authors.lastname: Lei
authors.forename: Denis
authors.initials: D
authors.lastname: Gris
authors.forename: Jenny Pan-Yun
authors.initials: JP
authors.lastname: Ting
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D002460:Cell Line; D018925:Chemokines / Q000096:biosynthesis* / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D054637:Dual-Specificity Phosphatases / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000502:physiology; D055785:Gene Knockdown Techniques; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases / Q000235:genetics / Q000378:metabolism*; D054639:Mitogen-Activated Protein Kinase Phosphatases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D053468:CARD Signaling Adaptor Proteins; D018925:Chemokines; D003598:Cytoskeletal Proteins; D058847:Inflammasomes; C402202:PYCARD protein, human; C498534:Pycard protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases; C120407:DUSP10 protein, human; C505617:Dusp10 protein, mouse; D054639:Mitogen-Activated Protein Kinase Phosphatases; D054637:Dual-Specificity Phosphatases