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EMBO J. 2008 Feb 20;27(4):629-41. doi: 10.1038/emboj.2008.5. Epub 2008 Jan 31.

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

Author information

1
Laboratory of Molecular Microbiology, Molecular Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0460, USA.

Abstract

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.

PMID:
18239685
PMCID:
PMC2262037
DOI:
10.1038/emboj.2008.5
[Indexed for MEDLINE]
Free PMC Article

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