Non-Canonical Activation of NRF2: New Insights and Its Relevance to Disease

Matthew Dodson, Donna Zhang

Research output: Contribution to journalReview article

7 Scopus citations

Abstract

Purpose of Review: The goal of this review is to summarize the current knowledge in the field regarding the non-canonical activation of the NRF2 pathway. Specifically, we address what role p62 plays in mediating this pathway, which pathologies have been linked to the p62-dependent activation of NRF2, as well as what therapeutic strategies could be used to treat diseases associated with the non-canonical pathway. Recent Findings: It has recently been shown that autophagic dysfunction leads to the aggregation or autophagosomal accumulation of p62, which sequesters KEAP1, resulting in prolonged activation of NRF2. The ability of p62 to outcompete NRF2 for KEAP1 binding depends on its abundance, or post-translational modifications to its key domains. Furthermore, the relevance of the p62-dependent activation of NRF2 in disease has been demonstrated in human hepatocellular carcinomas, as well as neurodegenerative diseases. Summary: These findings indicate that targeting p62, or the enzymes that modify it, could prove to be an advantageous strategy for treating diseases associated with autophagy dysregulation and prolonged activation of NRF2. Other therapeutic possibilities include restoring proper autophagic function, or directly inhibiting NRF2 or its targets, to restore redox and metabolic homeostasis. Future studies will help further clarify the mechanisms, regulation, and relevance of the non-canonical pathway in driving disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)171-176
Number of pages6
JournalCurrent Pathobiology Reports
Volume5
Issue number2
DOIs
StatePublished - Jun 1 2017

Keywords

  • Autophagy
  • KEAP1
  • Non-canonical pathway
  • NRF2
  • p62
  • Therapeutics

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology
  • Pathology and Forensic Medicine
  • Cancer Research

Fingerprint Dive into the research topics of 'Non-Canonical Activation of NRF2: New Insights and Its Relevance to Disease'. Together they form a unique fingerprint.

  • Cite this