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Neuronal Development and Degeneration

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Front. Genet. | doi: 10.3389/fgene.2018.00658

Regulation of Nrf2 by X Box-binding Protein 1 in Retinal Pigment Epithelium

 Chen Chen1, 2, 3*, Yimin Zhong3, 4,  Joshua J. Wang3, 5, Qiang Yu4, Kendra Plafker6, Scott Plafker6 and  Sarah X. Zhang3, 5*
  • 1Second People’s Hospital of Yunnan Province, China
  • 2Key Laboratory of Yunnan Province for the Prevention and Treatment of Ophthalmic diseases, Yunnan Eye Institute, China
  • 3College of Medicine, University of Oklahoma, United States
  • 4State Key Laboratory of Ophthalmology, Sun Yat-Sen University, China
  • 5The State University of New York (SUNY), United States
  • 6Aging and Metabolism Research Program, Oklahoma Medical Research Foundation, United States

Normal function of the retinal pigment epithelium (RPE) is essential for maintaining the structural integrity of retinal photoreceptors and the visual process. Sustained oxidative damage of the RPE due to aging and other risk factors contributes to the development of age-related macular degeneration (AMD). The transcription factor NF-E2-related factor2 (Nrf2) is a central regulator of cellular antioxidant and detoxification responses. Enhancing Nrf2 function protects RPE cells from oxidation-related apoptosis and cell death. Previously, we demonstrated that Nrf2 activation can be induced by endoplasmic reticulum (ER) stress; however, the mechanisms are not fully understood. In the present study, we examined the role of X box-binding protein 1 (XBP1), an ER stress-inducible transcription factor, in regulation of Nrf2 in the RPE. We found that RPE-specific XBP1 conditional knockout (cKO) mice exhibit a significant reduction in Nrf2 mRNA and protein levels, along with decreased expression of major Nrf2 target genes, in the RPE/choroid complex. Using primary RPE cells isolated from XBP1 cKO mice and human ARPE-19 cell line, we confirmed that loss of XBP1 gene or pharmacological inhibition of XBP1 splicing drastically reduces Nrf2 levels in the RPE. Conversely, overexpression of spliced XBP1 results in a modest but significant increase in cytosolic and nuclear Nrf2 protein levels without affecting the transcription of Nrf2 gene. Moreover, induction of ER stress by tunicamycin and thapsigargin markedly increases Nrf2 expression, which is abolished in cells pretreated with XBP1 splicing inhibitors 4µ8C and quinotrierixin. Mechanistic studies indicate that quinotrierixin reduces Nrf2 expression likely through inhibition of protein translation. Finally, we demonstrate that overexpression of Nrf2 protected RPE cells against oxidative injury but appeared to be insufficient to rescue from XBP1 deficiency-induced cell death. Taken together, our results indicate that XBP1 modulates Nrf2 activity in RPE cells and that XBP1 deficiency contributes to oxidative injury of the RPE.

Keywords: Retinal pigment epithelium (RPE), NF-E2-Related Factor 2 (Nrf2), X-box binding protein 1 (XBP1), Endoplasmic reticulum stress (ER stress), Oxidative Stress, Apoptosis

Received: 15 Aug 2018; Accepted: 03 Dec 2018.

Edited by:

Nan-Jie Xu, Shanghai Jiao Tong University, China

Reviewed by:

Nirmalya Chatterjee, Harvard Medical School, United States
Shusheng Wang, Tulane University, United States  

Copyright: © 2018 Chen, Zhong, Wang, Yu, Plafker, Plafker and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
MD, PhD. Chen Chen, Second People’s Hospital of Yunnan Province, Kunming, China,
Prof. Sarah X. Zhang, The State University of New York (SUNY), Albany, United States,