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

  • Autophagy in Pathobiology (W-X Ding and H-M Shen, Section Editors)
  • Published:
Current Pathobiology Reports

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.

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Acknowledgements

The authors are funded by the following grants from the National Institutes of Health: ES023758 (EC & DDZ), CA154377 (DDZ), ES015010 (DDZ), DK109555 (DDZ), and ES006694 (a center grant).

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, 1703 East Mabel Street, Tucson, AZ, 85721, USA

    Matthew Dodson & Donna D. Zhang

  2. Arizona Cancer Center, University of Arizona, Tucson, AZ, 85724, USA

    Donna D. Zhang

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Correspondence to Donna D. Zhang.

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Dodson, M., Zhang, D.D. Non-Canonical Activation of NRF2: New Insights and Its Relevance to Disease. Curr Pathobiol Rep 5, 171–176 (2017). https://doi.org/10.1007/s40139-017-0131-0

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