Article
- The EMBO Journal (2008) 27, 629 - 641
- doi:10.1038/emboj.2008.5
Published online: 31 January 2008
Subject Category:
Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-
B activation
Hidekatsu Iha1,6,7, Jean-Marie Peloponese1,7, Lynn Verstrepen2, Grzegorz Zapart3, Fumiyo Ikeda3, C Dahlem Smith4, Matthew F Starost5, Venkat Yedavalli1, Karen Heyninck2, Ivan Dikic3, Rudi Beyaert2 and Kuan-Teh Jeang1
- Laboratory of Molecular Microbiology, Molecular Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
- Department for Molecular Biomedical Research, Unit of Molecular Signal Transduction in Inflammation, Ghent University—VIB, Ghent (Zwijnaarde), Belgium
- Institute for Biochemistry II, Goethe University Medical School, Frankfurt, Germany
- Pathology/Histotechnology Laboratory, SAIC-Frederick Inc., NCI-FCR, Frederick, MD, USA
- Division of Veterinary Resources, National Institutes of Health, Bethesda, MD, USA
- Department of Infectious Diseases, Faculty of Medicine, Oita University Idaiga-oka, Hasama Yufu, Japan
Correspondence to:
Kuan-Teh Jeang, Laboratory of Molecular Microbiology, Molecular Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 4, Room 306, 9000 Rockville Pike, Bethesda, MD 20892-0460, USA. Tel.: +1 301 496 6680; Fax: +1 301 480 3686; E-mail: kjeang@niaid.nih.gov
7These authors contributed equally to this work
Received 18 September 2007; Accepted 4 January 2008
Abstract
Nuclear factor kappa B (NF-
B) is a key mediator of inflammation. Unchecked NF-B signalling can engender autoimmune pathologies and cancers. Here, we show that Tax1-binding protein 1 (TAX1BP1) is a negative regulator of TNF-
- and IL-1
-induced NF-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-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- and IL-1. TAX1BP1-/- cells are more highly activated for NF-B than control cells when stimulated with TNF- or IL-1. Mechanistically, TAX1BP1 acts in NF-B signalling as an essential adaptor between A20 and its targets.
Keywords:
- A20,
- NF-B,
- Tax,
- TAX1BP1,
- TRAF6
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