Essential role for TAX1BP1 in the termination of TNF-α-, IL-1- and LPS-mediated NF-κB and JNK signaling

Noula Shembade, Nicole S. Harhaj, Daniel J. Liebl, Edward Harhaj

Research output: Contribution to journalArticle

127 Citations (Scopus)

Abstract

The NF-κB transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-κB activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-α- and LPS-mediated NF-κB 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-κB signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-κB and JNK activation in response to TNF-α, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF-α-, 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-κB activation. Thus, TAX1BP1 is pivotal for the termination of NF-κB and JNK signaling by functioning as an essential regulator of A20.

Original languageEnglish (US)
Pages (from-to)3910-3922
Number of pages13
JournalEMBO Journal
Volume26
Issue number17
DOIs
StatePublished - Sep 5 2007

Fingerprint

Interleukin-1
Lipopolysaccharides
Carrier Proteins
Chemical activation
TNF Receptor-Associated Factor 6
Molecules
Ubiquitination
Fibroblasts
Ubiquitin
Transcription Factors
Cytokines
Enzymes
Neoplasms

All Science Journal Classification (ASJC) codes

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

Cite this

Shembade, Noula ; Harhaj, Nicole S. ; Liebl, Daniel J. ; Harhaj, Edward. / Essential role for TAX1BP1 in the termination of TNF-α-, IL-1- and LPS-mediated NF-κB and JNK signaling. In: EMBO Journal. 2007 ; Vol. 26, No. 17. pp. 3910-3922.
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Essential role for TAX1BP1 in the termination of TNF-α-, IL-1- and LPS-mediated NF-κB and JNK signaling. / Shembade, Noula; Harhaj, Nicole S.; Liebl, Daniel J.; Harhaj, Edward.

In: EMBO Journal, Vol. 26, No. 17, 05.09.2007, p. 3910-3922.

Research output: Contribution to journalArticle

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AB - The NF-κB transcription factor is normally transiently activated by proinflammatory cytokines and bacterial lipopolysaccharide (LPS); however, persistent NF-κB activation is commonly observed in inflammatory disease and malignancy. The ubiquitin editing enzyme A20 serves an essential role in the termination of TNF-α- and LPS-mediated NF-κB 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-κB signaling. Here we demonstrate that Tax1-binding protein 1 (TAX1BP1) is essential for the termination of NF-κB and JNK activation in response to TNF-α, IL-1 and LPS stimulation. In TAX1BP1-deficient mouse fibroblasts, TNF-α-, 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-κB activation. Thus, TAX1BP1 is pivotal for the termination of NF-κB and JNK signaling by functioning as an essential regulator of A20.

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