Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-κB activation

Nuclear factor kappa B (NF-kappa B) is a key mediator of inflammation. Unchecked NF-kappa B 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-1 beta-induced NF-kappa B activation and that binding to mono- and polyubiquitin by a ubiquitin-binding Zn finger domain in TAX1BP1 is needed for TRAF6 association and NF-kappa B 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-1 beta. TAX1BP1(-/-) cells are more highly activated for NF-kappa B than control cells when stimulated with TNF-alpha or IL-1 beta. Mechanistically, TAX1BP1 acts in NF-kappa B signalling as an essential adaptor between A20 and its targets.