TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axis
Epithelial-mesenchymal transition (EMT) is associated with retinal pigment epithelium (RPE) dysfunction in degenerative retinal diseases. However, the role of partial EMT (pEMT), a hybrid state exhibiting both epithelial and mesenchymal markers, remains poorly understood in this context. Our previou...
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253125000149 |
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| author | Jing Li Yosuke Nagasaka Hongtao Shen Xinyu Zhou Jianjie Ma Dilza Trevisan-Silva Nicholas E. Sherman Jayakrishna Ambati Bradley D. Gelfand Lian-Wang Guo |
| author_facet | Jing Li Yosuke Nagasaka Hongtao Shen Xinyu Zhou Jianjie Ma Dilza Trevisan-Silva Nicholas E. Sherman Jayakrishna Ambati Bradley D. Gelfand Lian-Wang Guo |
| author_sort | Jing Li |
| collection | DOAJ |
| description | Epithelial-mesenchymal transition (EMT) is associated with retinal pigment epithelium (RPE) dysfunction in degenerative retinal diseases. However, the role of partial EMT (pEMT), a hybrid state exhibiting both epithelial and mesenchymal markers, remains poorly understood in this context. Our previous research demonstrated that TMEM97 ablation in mice worsens photoreceptor loss in an oxidant-induced RPE damage model. Here, we link TMEM97 to pEMT in RPE cells and explore the underlying molecular mechanisms. We found that re-expressing TMEM97 in the RPE of TMEM97-knockout mice, via subretinal lentiviral delivery, mitigated oxidant (NaIO3)-induced photoreceptor loss. Interestingly, TMEM97 knockout in ARPE19 cells in vitro led to upregulation of cadherin/adhesion-binding pathways, even without oxidant exposure. Integrated proteomic, transcriptomic, segmentation, and immunoblot analyses revealed that TMEM97 ablation induces pEMT, marked by the concurrent expression of epithelial E-cadherin and mesenchymal N-cadherin, a process reversed upon TMEM97 re-expression. Furthermore, TMEM97 negatively regulated CTNND2 protein (catenin δ-2), but not the known EMT driver β-catenin, and CTNND2 was found to promote ADAM10, which sustains both E- and N-cadherin protein levels. These findings identify TMEM97 as a novel regulator of RPE-cell pEMT through the CTNND2-ADAM10 axis, highlighting potential new targets for therapeutic intervention in RPE-related pathophysiology. |
| format | Article |
| id | doaj-art-9cd6ba77f5204a55991ba9d990ee59ed |
| institution | Kabale University |
| issn | 2162-2531 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj-art-9cd6ba77f5204a55991ba9d990ee59ed2025-02-08T05:00:10ZengElsevierMolecular Therapy: Nucleic Acids2162-25312025-03-01361102460TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axisJing Li0Yosuke Nagasaka1Hongtao Shen2Xinyu Zhou3Jianjie Ma4Dilza Trevisan-Silva5Nicholas E. Sherman6Jayakrishna Ambati7Bradley D. Gelfand8Lian-Wang Guo9Division of Surgical Sciences, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22903, USADepartment of Ophthalmology, University of Virginia, Charlottesville, VA 22903, USADivision of Surgical Sciences, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22903, USADivision of Surgical Sciences, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22903, USADivision of Surgical Sciences, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22903, USASchool of Medicine Core Facilities, University of Virginia, Charlottesville, VA 22903, USASchool of Medicine Core Facilities, University of Virginia, Charlottesville, VA 22903, USADepartment of Ophthalmology, University of Virginia, Charlottesville, VA 22903, USADepartment of Ophthalmology, University of Virginia, Charlottesville, VA 22903, USA; Corresponding author: Bradley D. Gelfand, Department of Ophthalmology, University of Virginia, Charlottesville, VA 22903, USA.Division of Surgical Sciences, Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA 22903, USA; Department of Ophthalmology, University of Virginia, Charlottesville, VA 22903, USA; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22903, USA; Corresponding author: Lian-Wang Guo, Department of Surgery, School of Medicine, University of Virginia, 409 Lane Road, Charlottesville, VA 22903, USA.Epithelial-mesenchymal transition (EMT) is associated with retinal pigment epithelium (RPE) dysfunction in degenerative retinal diseases. However, the role of partial EMT (pEMT), a hybrid state exhibiting both epithelial and mesenchymal markers, remains poorly understood in this context. Our previous research demonstrated that TMEM97 ablation in mice worsens photoreceptor loss in an oxidant-induced RPE damage model. Here, we link TMEM97 to pEMT in RPE cells and explore the underlying molecular mechanisms. We found that re-expressing TMEM97 in the RPE of TMEM97-knockout mice, via subretinal lentiviral delivery, mitigated oxidant (NaIO3)-induced photoreceptor loss. Interestingly, TMEM97 knockout in ARPE19 cells in vitro led to upregulation of cadherin/adhesion-binding pathways, even without oxidant exposure. Integrated proteomic, transcriptomic, segmentation, and immunoblot analyses revealed that TMEM97 ablation induces pEMT, marked by the concurrent expression of epithelial E-cadherin and mesenchymal N-cadherin, a process reversed upon TMEM97 re-expression. Furthermore, TMEM97 negatively regulated CTNND2 protein (catenin δ-2), but not the known EMT driver β-catenin, and CTNND2 was found to promote ADAM10, which sustains both E- and N-cadherin protein levels. These findings identify TMEM97 as a novel regulator of RPE-cell pEMT through the CTNND2-ADAM10 axis, highlighting potential new targets for therapeutic intervention in RPE-related pathophysiology.http://www.sciencedirect.com/science/article/pii/S2162253125000149MT: Oligonucleotides: Therapies and Applicationspartial EMTE-cadherinN-cadherinZO-1catenin |
| spellingShingle | Jing Li Yosuke Nagasaka Hongtao Shen Xinyu Zhou Jianjie Ma Dilza Trevisan-Silva Nicholas E. Sherman Jayakrishna Ambati Bradley D. Gelfand Lian-Wang Guo TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axis Molecular Therapy: Nucleic Acids MT: Oligonucleotides: Therapies and Applications partial EMT E-cadherin N-cadherin ZO-1 catenin |
| title | TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axis |
| title_full | TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axis |
| title_fullStr | TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axis |
| title_full_unstemmed | TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axis |
| title_short | TMEM97 governs partial epithelial-mesenchymal transition of retinal pigment epithelial cells via the CTNND2-ADAM10 axis |
| title_sort | tmem97 governs partial epithelial mesenchymal transition of retinal pigment epithelial cells via the ctnnd2 adam10 axis |
| topic | MT: Oligonucleotides: Therapies and Applications partial EMT E-cadherin N-cadherin ZO-1 catenin |
| url | http://www.sciencedirect.com/science/article/pii/S2162253125000149 |
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