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.
Iha
Hidekatsu
H
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
JM
Verstrepen
Lynn
L
Zapart
Grzegorz
G
Ikeda
Fumiyo
F
Smith
C Dahlem
CD
Starost
Matthew F
MF
Yedavalli
Venkat
V
Heyninck
Karen
K
Dikic
Ivan
I
Beyaert
Rudi
R
Jeang
Kuan-Teh
KT
D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D005260:Female; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006331:Heart Diseases / Q000378:metabolism*; D006351:Heart Valves; D006967:Hypersensitivity / Q000276:immunology; D007249:Inflammation / Q000378:metabolism*; D053583:Interleukin-1beta / Q000276:immunology / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000494:pharmacology
D020690:GTPase-Activating Proteins; D053583:Interleukin-1beta; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; C490620:Ralbp1 protein, mouse; C523855:TAX1BP1 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse