Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-kappaB activation.
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.
Mesh Terms:
Animals, Cysteine Endopeptidases, Female, GTPase-Activating Proteins, Heart Diseases, Heart Valves, Hypersensitivity, Inflammation, Interleukin-1beta, Intracellular Signaling Peptides and Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Neoplasm Proteins, TNF Receptor-Associated Factor 6, Tumor Necrosis Factor-alpha
Animals, Cysteine Endopeptidases, Female, GTPase-Activating Proteins, Heart Diseases, Heart Valves, Hypersensitivity, Inflammation, Interleukin-1beta, Intracellular Signaling Peptides and Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B, Neoplasm Proteins, TNF Receptor-Associated Factor 6, Tumor Necrosis Factor-alpha
EMBO J.
Date: Feb. 20, 2008
PubMed ID: 18239685
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