Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model
Abstract The endoplasmic reticulum (ER) is a subcellular organelle essential for cellular homeostasis. Perturbation of ER functions due to various conditions can induce apoptosis. Chronic ER stress has been implicated in a wide range of diseases, including autosomal dominant retinitis pigmentosa (AD...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-07-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-023-01044-7 |
| _version_ | 1797752862876368896 |
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| author | Jung-Eun Park Jiyoun Lee Soonhyuck Ok Seunghee Byun Eun-Ju Chang Sung-Eun Yoon Young-Joon Kim Min-Ji Kang |
| author_facet | Jung-Eun Park Jiyoun Lee Soonhyuck Ok Seunghee Byun Eun-Ju Chang Sung-Eun Yoon Young-Joon Kim Min-Ji Kang |
| author_sort | Jung-Eun Park |
| collection | DOAJ |
| description | Abstract The endoplasmic reticulum (ER) is a subcellular organelle essential for cellular homeostasis. Perturbation of ER functions due to various conditions can induce apoptosis. Chronic ER stress has been implicated in a wide range of diseases, including autosomal dominant retinitis pigmentosa (ADRP), which is characterized by age-dependent retinal degeneration caused by mutant rhodopsin alleles. However, the signaling pathways that mediate apoptosis in response to ER stress remain poorly understood. In this study, we performed an unbiased in vivo RNAi screen with a Drosophila ADRP model and found that Wg/Wnt1 mediated apoptosis. Subsequent transcriptome analysis revealed that ER stress-associated serine protease (Erasp), which has been predicted to show serine-type endopeptidase activity, was a downstream target of Wg/Wnt1 during ER stress. Furthermore, knocking down Erasp via RNAi suppressed apoptosis induced by mutant rhodopsin-1 (Rh-1P37H) toxicity, alleviating retinal degeneration in the Drosophila ADRP model. In contrast, overexpression of Erasp resulted in enhanced caspase activity in Drosophila S2 cells treated with apoptotic inducers and the stabilization of the initiator caspase Dronc (Death regulator Nedd2-like caspase) by stimulating DIAP1 (Drosophila inhibitor of apoptosis protein 1) degradation. These findings helped identify a novel cell death signaling pathway involved in retinal degeneration in an autosomal dominant retinitis pigmentosa model. |
| first_indexed | 2024-03-12T17:09:37Z |
| format | Article |
| id | doaj.art-c91f11690d89476ea6ad3600f2cd78c0 |
| institution | Directory Open Access Journal |
| issn | 2092-6413 |
| language | English |
| last_indexed | 2024-03-12T17:09:37Z |
| publishDate | 2023-07-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj.art-c91f11690d89476ea6ad3600f2cd78c02023-08-06T11:08:02ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132023-07-015571544155510.1038/s12276-023-01044-7Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa modelJung-Eun Park0Jiyoun Lee1Soonhyuck Ok2Seunghee Byun3Eun-Ju Chang4Sung-Eun Yoon5Young-Joon Kim6Min-Ji Kang7Department of Pharmacology, Asan Medical Center, University of Ulsan College of MedicineSchool of Biopharmaceutical and Medical Sciences, Sungshin UniversityDepartment of Pharmacology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Pharmacology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of MedicineKorea Drosophila Resource Center, Gwangju Institute of Science and Technology (GIST)School of Life Sciences, Gwangju Institute of Science and Technology (GIST)Department of Pharmacology, Asan Medical Center, University of Ulsan College of MedicineAbstract The endoplasmic reticulum (ER) is a subcellular organelle essential for cellular homeostasis. Perturbation of ER functions due to various conditions can induce apoptosis. Chronic ER stress has been implicated in a wide range of diseases, including autosomal dominant retinitis pigmentosa (ADRP), which is characterized by age-dependent retinal degeneration caused by mutant rhodopsin alleles. However, the signaling pathways that mediate apoptosis in response to ER stress remain poorly understood. In this study, we performed an unbiased in vivo RNAi screen with a Drosophila ADRP model and found that Wg/Wnt1 mediated apoptosis. Subsequent transcriptome analysis revealed that ER stress-associated serine protease (Erasp), which has been predicted to show serine-type endopeptidase activity, was a downstream target of Wg/Wnt1 during ER stress. Furthermore, knocking down Erasp via RNAi suppressed apoptosis induced by mutant rhodopsin-1 (Rh-1P37H) toxicity, alleviating retinal degeneration in the Drosophila ADRP model. In contrast, overexpression of Erasp resulted in enhanced caspase activity in Drosophila S2 cells treated with apoptotic inducers and the stabilization of the initiator caspase Dronc (Death regulator Nedd2-like caspase) by stimulating DIAP1 (Drosophila inhibitor of apoptosis protein 1) degradation. These findings helped identify a novel cell death signaling pathway involved in retinal degeneration in an autosomal dominant retinitis pigmentosa model.https://doi.org/10.1038/s12276-023-01044-7 |
| spellingShingle | Jung-Eun Park Jiyoun Lee Soonhyuck Ok Seunghee Byun Eun-Ju Chang Sung-Eun Yoon Young-Joon Kim Min-Ji Kang Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model Experimental and Molecular Medicine |
| title | Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model |
| title_full | Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model |
| title_fullStr | Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model |
| title_full_unstemmed | Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model |
| title_short | Wg/Wnt1 and Erasp link ER stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model |
| title_sort | wg wnt1 and erasp link er stress to proapoptotic signaling in an autosomal dominant retinitis pigmentosa model |
| url | https://doi.org/10.1038/s12276-023-01044-7 |
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