p97 negatively regulates NRF2 by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex

Shasha Tao, Pengfei Liu, Gang Luo, Montserrat Rojo de la Vega, Heping Chen, Tongde Wu, Joseph Tillotson, Eli Chapman, Donna D. Zhang

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Activation of the stress-responsive transcription factor NRF2 is the major line of defense to combat oxidative or electrophilic insults. Under basal conditions, NRF2 is continuously ubiquitylated by the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex and is targeted to the proteasome for degradation (the canonical mechanism). However, the path from the CUL3 complex to ultimate proteasomal degradation was previously unknown. p97 is a ubiquitin-targeted ATP-dependent segregase that extracts ubiquitylated client proteins from membranes, protein complexes, or chromatin and has an essential role in autophagy and the ubiquitin proteasome system (UPS). In this study, we show that p97 negatively regulates NRF2 through the canonical pathway by extracting ubiquitylated NRF2 from the KEAP1-CUL3 E3 complex, with the aid of the heterodimeric cofactor UFD1/NPL4 and the UBA-UBXcontaining protein UBXN7, for efficient proteasomal degradation. Given the role of NRF2 in chemoresistance and the surging interest in p97 inhibitors to treat cancers, our results indicate that dual p97/NRF2 inhibitors may offer a more potent and long-term avenue of p97-targeted treatment.

Original languageEnglish (US)
Article numbere00660-16
JournalMolecular and cellular biology
Volume37
Issue number8
DOIs
StatePublished - Apr 1 2017

Keywords

  • Autophagy
  • Cancer chemoresistance
  • KEAP1
  • NRF2
  • Oxidative stress
  • P97
  • Proteasome
  • Protein quality control
  • Ubiquitylation

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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