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

Nuclear factor kappa B (NF-κB) is a key mediator of inflammation. Unchecked NF-κB signalling can engender autoimmune pathologies and cancers. Here, we show that Tax1-binding protein 1 (TAX1BP1) is a negative regulator of TNF-α- and IL-1β-induced NF-κB activation and that binding to mono- and polyubiquitin by a ubiquitin-binding Zn finger domain in TAX1BP1 is needed for TRAF6 association and NF-κB 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-α and IL-1β. TAX1BP1−/− cells are more highly activated for NF-κB than control cells when stimulated with TNF-α or IL-1β. Mechanistically, TAX1BP1 acts in NF-κB signalling as an essential adaptor between A20 and its targets.