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 t...

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Veröffentlicht in:The EMBO journal 2008-02, Vol.27 (4), p.629-641
Hauptverfasser: Iha, Hidekatsu, Peloponese, Jean-Marie, Verstrepen, Lynn, Zapart, Grzegorz, Ikeda, Fumiyo, Smith, C Dahlem, Starost, Matthew F, Yedavalli, Venkat, Heyninck, Karen, Dikic, Ivan, Beyaert, Rudi, Jeang, Kuan-Teh
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Sprache:eng
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Zusammenfassung: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.
ISSN:1460-2075
DOI:10.1038/emboj.2008.5