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PMID: 18239685 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

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

The EMBO journal ·Vol. 27 ·No. 4 ·2008-02-20 ·Pages 629-41

Iha H, Peloponese JM, Verstrepen L, Zapart G, Ikeda F, Smith CD, Starost MF, Yedavalli V, Heyninck K, Dikic I, Beyaert R, Jeang KT

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.

MeSH Terms
Animals Cysteine Endopeptidases/metabolism Female GTPase-Activating Proteins/metabolism Heart Diseases/metabolism Heart Valves Hypersensitivity/immunology Inflammation/metabolism Interleukin-1beta/immunology,pharmacology Intracellular Signaling Peptides and Proteins/deficiency,genetics,metabolism Mice Mice, Inbred C57BL Mice, Knockout NF-kappa B/metabolism Neoplasm Proteins/deficiency,genetics,metabolism TNF Receptor-Associated Factor 6/metabolism Tumor Necrosis Factor alpha-Induced Protein 3 Tumor Necrosis Factor-alpha/immunology,pharmacology
Chemicals
GTPase-Activating Proteins Interleukin-1beta Intracellular Signaling Peptides and Proteins NF-kappa B Neoplasm Proteins Ralbp1 protein, mouse TAX1BP1 protein, mouse TNF Receptor-Associated Factor 6 Tumor Necrosis Factor-alpha Tumor Necrosis Factor alpha-Induced Protein 3 Cysteine Endopeptidases Tnfaip3 protein, mouse
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Iha Hidekatsu
Laboratory of Molecular Microbiology, Molecular Virology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892-0460, USA.
Peloponese Jean-Marie
Verstrepen Lynn
Zapart Grzegorz
Ikeda Fumiyo
Smith C Dahlem
Starost Matthew F
Yedavalli Venkat
Heyninck Karen
Dikic Ivan
Beyaert Rudi
Jeang Kuan-Teh
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Article Info
Journal
The EMBO journal
Abbr.
EMBO J
ISSN
1460-2075
DOI
10.1038/emboj.2008.5
Published
2008-02-20
Epub
2008-00-31
Pages
629-41
Language
English
Region
England
NLM ID
8208664
PMCID
PMC2262037
Subset
IM
Grants
NCI NIH HHS · N01CO12400 · United States
NCI NIH HHS · N01-CO-12400 · United States
Intramural NIH HHS · United States
External Links
PubMed source DOI: 10.1038/emboj.2008.5 PMC Full Text View journal details
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