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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| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2025-03-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253125000149 |
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| Summary: | 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. |
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| ISSN: | 2162-2531 |