title: The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor kappaB activation pathways.
abstract: Apoptosis-associated speck-like protein containing a Caspase recruitment domain (ASC) belongs to a large family of proteins that contain a Pyrin, AIM, ASC, and death domain-like (PAAD) domain (also known as PYRIN, DAPIN, Pyk). Recent data have suggested that ASC functions as an adaptor protein linking various PAAD-family proteins to pathways involved in nuclear factor (NF)-kappaB and pro-Caspase-1 activation. We present evidence here that the role of ASC in modulating NF-kappaB activation pathways is much broader than previously suspected, as it can either inhibit or activate NF-kappaB, depending on cellular context. While coexpression of ASC with certain PAAD-family proteins such as Pyrin and Cryopyrin increases NF-kappaB activity, ASC has an inhibitory influence on NF-kappaB activation by various proinflammatory stimuli, including tumor necrosis factor (TNF)alpha, interleukin 1beta, and lipopolysaccharide (LPS). Elevations in ASC protein levels or of the PAAD domain of ASC suppressed activation of IkappaB kinases in cells exposed to pro-inflammatory stimuli. Conversely, reducing endogenous levels of ASC using siRNA enhanced TNF- and LPS-induced degradation of the IKK substrate, IkappaBalpha. Our findings suggest that ASC modulates diverse NF-kappaB induction pathways by acting upon the IKK complex, implying a broad role for this and similar proteins containing PAAD domains in regulation of inflammatory responses.
authors.affiliation: The Burnham Institute, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Stehlik
authors.forename: Loredana
authors.initials: L
authors.lastname: Fiorentino
authors.forename: Andrea
authors.initials: A
authors.lastname: Dorfleutner
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Bruey
authors.forename: Eugenia M
authors.initials: EM
authors.lastname: Ariza
authors.forename: Junji
authors.initials: J
authors.lastname: Sagara
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D001665:Binding Sites; D053468:CARD Signaling Adaptor Proteins; D002460:Cell Line; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D017930:Genes, Reporter; D006801:Humans; D051550:I-kappa B Kinase; D046911:Macromolecular Substances; D016328:NF-kappa B / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D053468:CARD Signaling Adaptor Proteins; D003598:Cytoskeletal Proteins; D046911:Macromolecular Substances; D016328:NF-kappa B; C402202:PYCARD protein, human; D011506:Proteins; D011993:Recombinant Fusion Proteins; D047990:TNF Receptor-Associated Factor 1; D014409:Tumor Necrosis Factor-alpha; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human