Regulation of Nrf2 by X Box-Binding Protein 1 in Retinal Pigment Epithelium
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...
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| Format: | Article |
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Frontiers Media S.A.
2018-12-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fgene.2018.00658/full |
| _version_ | 1818162704999776256 |
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| author | Chen Chen Chen Chen Chen Chen Yimin Zhong Yimin Zhong Joshua J. Wang Joshua J. Wang Qiang Yu Kendra Plafker Scott Plafker Sarah X. Zhang Sarah X. Zhang |
| author_facet | Chen Chen Chen Chen Chen Chen Yimin Zhong Yimin Zhong Joshua J. Wang Joshua J. Wang Qiang Yu Kendra Plafker Scott Plafker Sarah X. Zhang Sarah X. Zhang |
| author_sort | Chen Chen |
| collection | DOAJ |
| description | 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 factor 2 (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. |
| first_indexed | 2024-12-11T16:37:54Z |
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| id | doaj.art-6055f4dc1b1b4c40bde50df3c2e61723 |
| institution | Directory Open Access Journal |
| issn | 1664-8021 |
| language | English |
| last_indexed | 2024-12-11T16:37:54Z |
| publishDate | 2018-12-01 |
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| series | Frontiers in Genetics |
| spelling | doaj.art-6055f4dc1b1b4c40bde50df3c2e617232022-12-22T00:58:24ZengFrontiers Media S.A.Frontiers in Genetics1664-80212018-12-01910.3389/fgene.2018.00658419530Regulation of Nrf2 by X Box-Binding Protein 1 in Retinal Pigment EpitheliumChen Chen0Chen Chen1Chen Chen2Yimin Zhong3Yimin Zhong4Joshua J. Wang5Joshua J. Wang6Qiang Yu7Kendra Plafker8Scott Plafker9Sarah X. Zhang10Sarah X. Zhang11Department of Ophthalmology, The Second People’s Hospital of Yunnan Province, Kunming, ChinaKey Laboratory of Yunnan Province for the Prevention and Treatment of Ophthalmic Diseases, Yunnan Eye Institute, Kunming, ChinaDepartment of Medicine, The University of Oklahoma, Oklahoma City, OK, United StatesDepartment of Medicine, The University of Oklahoma, Oklahoma City, OK, United StatesState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, ChinaDepartment of Medicine, The University of Oklahoma, Oklahoma City, OK, United StatesDepartment of Ophthalmology, University at Buffalo, The State University of New York, Buffalo, NY, United StatesState Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, ChinaAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United StatesAging and Metabolism Research Program, Oklahoma Medical Research Foundation, Oklahoma City, OK, United StatesDepartment of Medicine, The University of Oklahoma, Oklahoma City, OK, United StatesDepartment of Ophthalmology, University at Buffalo, The State University of New York, Buffalo, NY, United StatesNormal 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 factor 2 (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.https://www.frontiersin.org/article/10.3389/fgene.2018.00658/fullretinal pigment epitheliumNF-E2-related factor 2X-box binding protein 1endoplasmic reticulum stressoxidative stresscell death |
| spellingShingle | Chen Chen Chen Chen Chen Chen Yimin Zhong Yimin Zhong Joshua J. Wang Joshua J. Wang Qiang Yu Kendra Plafker Scott Plafker Sarah X. Zhang Sarah X. Zhang Regulation of Nrf2 by X Box-Binding Protein 1 in Retinal Pigment Epithelium Frontiers in Genetics retinal pigment epithelium NF-E2-related factor 2 X-box binding protein 1 endoplasmic reticulum stress oxidative stress cell death |
| title | Regulation of Nrf2 by X Box-Binding Protein 1 in Retinal Pigment Epithelium |
| title_full | Regulation of Nrf2 by X Box-Binding Protein 1 in Retinal Pigment Epithelium |
| title_fullStr | Regulation of Nrf2 by X Box-Binding Protein 1 in Retinal Pigment Epithelium |
| title_full_unstemmed | Regulation of Nrf2 by X Box-Binding Protein 1 in Retinal Pigment Epithelium |
| title_short | Regulation of Nrf2 by X Box-Binding Protein 1 in Retinal Pigment Epithelium |
| title_sort | regulation of nrf2 by x box binding protein 1 in retinal pigment epithelium |
| topic | retinal pigment epithelium NF-E2-related factor 2 X-box binding protein 1 endoplasmic reticulum stress oxidative stress cell death |
| url | https://www.frontiersin.org/article/10.3389/fgene.2018.00658/full |
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