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

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.

Pubmed ID: 18239685

Authors

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

Journal

The EMBO journal

Publication Data

February 20, 2008

Associated Grants

  • Agency: NCI NIH HHS, Id: N01-CO-12400
  • Agency: Intramural NIH HHS, Id:

Mesh Terms

  • Animals
  • Cysteine Endopeptidases
  • Female
  • GTPase-Activating Proteins
  • Heart Diseases
  • Heart Valves
  • Hypersensitivity
  • Inflammation
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NF-kappa B
  • Neoplasm Proteins
  • TNF Receptor-Associated Factor 6
  • Tumor Necrosis Factor-alpha