Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response

Zheng Sun, Zheping Huang, Donna Zhang

Research output: Contribution to journalArticle

181 Citations (Scopus)

Abstract

The bZIP transcription factor Nrf2 has emerged as a pivotal regulator of intracellular redox homeostasis by controlling the expression of many endogenous antioxidants and phase II detoxification enzymes. Upon oxidative stress, Nrf2 is induced at protein levels through redox-sensitive modifications on cysteine residues of Keap1, a component of the E3 ubiquitin ligase that targets Nrf2 for ubiquitin-dependent degradation. The mitogen activated protein kinases (MAPKs) have previously been proposed to regulate Nrf2 in response to oxidative stress. However, the exact role of MAPKs and the underlying molecular mechanism remain poorly defined. Here we report the first evidence that Nrf2 is phosphorylated in vivo by MAPKs. We have identified multiple serine/threonine residues as major targets of MAPK-mediated phosphorylation. Combined alanine substitution on those residues leads to a moderate decrease in the transcriptional activity of Nrf2, most likely due to a slight reduction in its nuclear accumulation. More importantly, Nrf2 protein stability, primarily controlled by Keap1, is not altered by Nrf2 phosphorylation in vivo. These data indicate that direct phosphorylation of Nrf2 by MAPKs has limited contribution in modulating Nrf2 activity. We suggest that MAPKs regulate the Nrf2 signaling pathway mainly through indirect mechanisms.

Original languageEnglish (US)
Article numbere6588
JournalPLoS One
Volume4
Issue number8
DOIs
StatePublished - Aug 11 2009

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Phosphorylation
Mitogen-Activated Protein Kinases
mitogen-activated protein kinase
phosphorylation
Phosphotransferases
Antioxidants
antioxidants
Oxidative stress
Oxidation-Reduction
Oxidative Stress
Phase II Metabolic Detoxication
oxidative stress
Basic-Leucine Zipper Transcription Factors
Detoxification
ubiquitin-protein ligase
Ubiquitin-Protein Ligases
Protein Stability
Threonine
ubiquitin
Ubiquitin

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response. / Sun, Zheng; Huang, Zheping; Zhang, Donna.

In: PLoS One, Vol. 4, No. 8, e6588, 11.08.2009.

Research output: Contribution to journalArticle

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