Reactive Oxygen Species Are Downstream Products of TRAF-mediated Signal Transduction

Navdeep S. Chandel, Paul T. Schumacker, Robert H. Arch*

*Corresponding author for this work

Research output: Contribution to journalArticle

157 Scopus citations

Abstract

Members of the TNFR (tumor necrosis factor receptor) superfamily are involved in regulating activation and differentiation of cells as well as cell survival and programmed cell death/apoptosis. Multimerization of TNFRs can lead to recruitment of TRAFs (TNFR-associated factors) by the receptors resulting in activation of kinases and transcription factors, such as c-Jun N-terminal kinase and nuclear factor κB (NF-κB). Signal transduction triggered by TNF-α also induces an increase in intracellular reactive oxygen species (ROS). ROS have been suggested to play a role in NF-κB activation, which is thought to promote cell survival. However, oxidation of proteins and lipids by ROS can also result in apoptosis. The processes generating intracellular ROS and the mechanism(s) regulating the cellular redox status have not been fully elucidated. We investigated whether TRAFs play a role in controlling intracellular ROS levels. Our results indicate that recruitment of TRAFs to the plasma membrane of human embryonic kidney (HEK) 293 cells is crucial for activation of signaling pathways, which regulate ROS production in mitochondria. TRAF-mediated changes in ROS levels enhanced NF-κB activation but were not dependent on NF-κB-inducing kinase. Consistent with its anti-apoptotic function, Bcl-xL interfered with TRAF-mediated ROS generation but not NF-κB activation. Taken together, our results suggest a novel role of TRAFs in signal transduction pathways triggered by TNFR-related proteins, which balance cell survival and apoptosis by regulating the electron transport in mitochondria.

Original languageEnglish (US)
Pages (from-to)42728-42736
Number of pages9
JournalJournal of Biological Chemistry
Volume276
Issue number46
DOIs
StatePublished - Nov 16 2001

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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