Essential role for TAX1BP1 in the termination of TNF-alpha-, IL-1- and LPS-mediated NF-kappaB and JNK signaling.
The NF-kappaB transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-kappaB activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-alpha- and LPS-mediated NF-kappaB signaling by inactivating key signaling molecules. However, little is known about how A20 is regulated and if other molecules play a role in the termination of NF-kappaB signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-kappaB and JNK activation in response to TNF-alpha, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF-alpha-, IL-1- and LPS-mediated IKK and JNK activation is elevated and persistent owing to enhanced ubiquitination of RIP1 and TRAF6. Furthermore, in the absence of TAX1BP1, A20 is impaired in RIP1 binding, deubiquitination of TRAF6 and inhibition of NF-kappaB activation. Thus, TAX1BP1 is pivotal for the termination of NF-kappaB and JNK signaling by functioning as an essential regulator of A20.
Shembade
Noula
N
Department of Microbiology and Immunology, Sylvester Comprehensive Cancer Center, Miller School of Medicine, The University of Miami, Miami, FL 33136, USA.
Harhaj
Nicole S
NS
Liebl
Daniel J
DJ
Harhaj
Edward W
EW
D000818:Animals; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation; D007375:Interleukin-1 / Q000378:metabolism* / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000502:physiology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism* / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D048029:TNF Receptor-Associated Factor 6 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism* / Q000494:pharmacology; D025801:Ubiquitin / Q000378:metabolism
D007375:Interleukin-1; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D016328:NF-kappa B; D009363:Neoplasm Proteins; C523855:TAX1BP1 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D014409:Tumor Necrosis Factor-alpha; D025801:Ubiquitin; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506251:Ripk1 protein, mouse; D048031:JNK Mitogen-Activated Protein Kinases
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