title: Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-kappaB activation.
abstract: Nuclear factor kappa B (NF-kappaB) is a key mediator of inflammation. Unchecked NF-kappaB signalling can engender autoimmune pathologies and cancers. Here, we show that Tax1-binding protein 1 (TAX1BP1) is a negative regulator of TNF-alpha- and IL-1beta-induced NF-kappaB activation and that binding to mono- and polyubiquitin by a ubiquitin-binding Zn finger domain in TAX1BP1 is needed for TRAF6 association and NF-kappaB inhibition. Mice genetically knocked out for TAX1BP1 are born normal, but develop age-dependent inflammatory cardiac valvulitis, die prematurely, and are hypersensitive to low doses of TNF-alpha and IL-1beta. TAX1BP1-/- cells are more highly activated for NF-kappaB than control cells when stimulated with TNF-alpha or IL-1beta. Mechanistically, TAX1BP1 acts in NF-kappaB signalling as an essential adaptor between A20 and its targets.
authors.affiliation: Laboratory of Molecular Microbiology, Molecular Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0460, USA.
authors.forename: Hidekatsu
authors.initials: H
authors.lastname: Iha
authors.forename: Jean-Marie
authors.initials: JM
authors.lastname: Peloponese
authors.forename: Lynn
authors.initials: L
authors.lastname: Verstrepen
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Zapart
authors.forename: Fumiyo
authors.initials: F
authors.lastname: Ikeda
authors.forename: C Dahlem
authors.initials: CD
authors.lastname: Smith
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.forename: Venkat
authors.initials: V
authors.lastname: Yedavalli
authors.forename: Karen
authors.initials: K
authors.lastname: Heyninck
authors.forename: Ivan
authors.initials: I
authors.lastname: Dikic
authors.forename: Rudi
authors.initials: R
authors.lastname: Beyaert
authors.forename: Kuan-Teh
authors.initials: KT
authors.lastname: Jeang
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006331:Heart Diseases / Q000378:metabolism*; D006351:Heart Valves; D006967:Hypersensitivity / Q000276:immunology; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
chemical_list: D020690:GTPase-Activating Proteins; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; C490620:Ralbp1 protein, mouse; C523855:TAX1BP1 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse