Involvement of TRAF4 in oxidative activation of c-Jun N-terminal kinase

You Cheng Xu, Ru Feng Wu, Ying Gu, Yih Sheng Yang, Meng Chun Yang, Fiemu E. Nwariaku, Lance S. Terada

Research output: Contribution to journalArticle

68 Scopus citations

Abstract

We previously found that the angiogenic factors TNFα and HIV-1 Tat activate an NAD(P)H oxidase in endothelial cells, which operates upstream of c-Jun N-terminal kinase (JNK), a MAPK involved in the determination of cell fate. To further understand oxidant-related signaling pathways, we screened lung and endothelial cell libraries for interaction partners of p47phox and recovered the orphan adapter TNF receptor-associated factor 4 (TRAF4). Domain analysis suggested a tail-to-tail interaction between the C terminus of p47phox and the conserved TRAF domain of TRAF4. In addition, TRAF4, like p47phox, was recovered largely in the cytoskeleton/ membrane fraction. Coexpression of p47phox and TRAF4 increased oxidant production and JNK activation, whereas each alone had minimal effect. In addition, a fusion between p47phox and the TRAF4 C terminus constitutively activated JNK, and this activation was decreased by the antioxidant N-acetyl cysteine. In contrast, overexpression of the p47phox binding domain of TRAF4 blocked endothelial cell JNK activation by TNFα and HIV-1 Tat, suggesting an uncoupling of p47phox from upstream signaling events. A secondary screen of endothelial cell proteins for TRAF4-interacting partners yielded a number of proteins known to control cell fate. We conclude that endothelial cell agonists such as TNFα and HIV-1 Tat initiate signals that enter basic signaling cassettes at the level of TRAF4 and an NAD(P)H oxidase. We speculate that endothelial cells may target endogenous oxidant production to specific sites critical to cytokine signaling as a mechanism for increasing signal specificity and decreasing toxicity of these reactive species.

Original languageEnglish (US)
Pages (from-to)28051-28057
Number of pages7
JournalJournal of Biological Chemistry
Volume277
Issue number31
DOIs
StatePublished - Aug 2 2002

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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