RPA1 binding to NRF2 switches ARE-dependent transcriptional activation to ARE-NRE-dependent repression

Pengfei Liu, Montserrat Rojo De La Vega, Saad Sammani, Joseph B. Mascarenhas, Michael Kerins, Matthew Dodson, Xiaoguang Sun, Ting Wang, Aikseng Ooi, Joe G.N. Garcia, Donna D. Zhang

Research output: Contribution to journalArticlepeer-review

10 Scopus citations

Abstract

NRF2 regulates cellular redox homeostasis, metabolic balance, and proteostasis by forming a dimer with small musculoaponeurotic fibrosarcoma proteins (sMAFs) and binding to antioxidant response elements (AREs) to activate target gene transcription. In contrast, NRF2-ARE-dependent transcriptional repression is unreported. Here, we describe NRF2-mediated gene repression via a specific seven-nucleotide sequence flanking the ARE, which we term the NRF2-replication protein A1 (RPA1) element (NRE). Mechanistically, RPA1 competes with sMAF for NRF2 binding, followed by interaction of NRF2-RPA1 with the ARE-NRE and eduction of promoter activity. Genome-wide in silico and RNA-seq analyses revealed this NRF2-RPA1-ARE-NRE complex mediates negative regulation of many genes with diverse functions, indicating that this mechanism is a fundamental cellular process. Notably, repression of MYLK, which encodes the nonmuscle myosin light chain kinase, by the NRF2-RPA1-ARE-NRE complex disrupts vascular integrity in preclinical inflammatory lung injury models, illustrating the translational significance of NRF2-mediated transcriptional repression. Our findings reveal a gene-suppressive function of NRF2 and a subset of negatively regulated NRF2 target genes, underscoring the broad impact of NRF2 in physiological and pathological settings.

Original languageEnglish (US)
Pages (from-to)E10352-E10361
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number44
DOIs
StatePublished - Oct 30 2018

Keywords

  • Acute lung injury
  • MYLK/MLCK
  • NRF2
  • RPA1
  • Transcriptional regulation

ASJC Scopus subject areas

  • General

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