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

Hidekatsu Iha, Jean Marie Peloponese, Lynn Verstrepen, Grzegorz Zapart, Fumiyo Ikeda, C. Dahlem Smith, Matthew F. Starost, Venkat Yedavalli, Karen Heyninck, Ivan Dikic, Rudi Beyaert, Kuan Teh Jeang

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Abstract

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.

Original languageEnglish
Pages (from-to)629-641
Number of pages13
JournalEMBO Journal
Volume27
Issue number4
DOIs
Publication statusPublished - Feb 20 2008

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)
  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Immunology and Microbiology(all)

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    Iha, H., Peloponese, J. M., Verstrepen, L., Zapart, G., Ikeda, F., Smith, C. D., Starost, M. F., Yedavalli, V., Heyninck, K., Dikic, I., Beyaert, R., & Jeang, K. T. (2008). Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-κB activation. EMBO Journal, 27(4), 629-641. https://doi.org/10.1038/emboj.2008.5