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

doi:10.1038/emboj.2008.5

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

Research output: Contribution to journal › Article › peer-review

127 Citations (Scopus)

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 language	English
Pages (from-to)	629-641
Number of pages	13
Journal	EMBO Journal
Volume	27
Issue number	4
DOIs	https://doi.org/10.1038/emboj.2008.5
Publication status	Published - Feb 20 2008
Externally published	Yes

All Science Journal Classification (ASJC) codes

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

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10.1038/emboj.2008.5

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title = "Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-κB activation",

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.",

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

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T1 - Inflammatory cardiac valvulitis in TAX1BP1-deficient mice through selective NF-κB activation

AU - Iha, Hidekatsu

AU - Peloponese, Jean Marie

AU - Verstrepen, Lynn

AU - Zapart, Grzegorz

AU - Ikeda, Fumiyo

AU - Smith, C. Dahlem

AU - Starost, Matthew F.

AU - Yedavalli, Venkat

AU - Heyninck, Karen

AU - Dikic, Ivan

AU - Beyaert, Rudi

AU - Jeang, Kuan Teh

PY - 2008/2/20

Y1 - 2008/2/20

N2 - 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.

AB - 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.

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

Abstract

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