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We have shown that human retinal pigment epithelial (RPE) homeostasis is under the control of Prom1\u2010dependent autophagy, demonstrating that Prom1 plays different roles in the photoreceptors and RPE. It is unclear if retinal and macular degeneration caused by the loss of Prom1 function is a cell\u2010autonomous feature of the RPE or a generalized disease of photoreceptor degeneration. In this study, we investigated whether Prom1 is required for mouse RPE (mRPE) autophagy and phagocytosis, which are cellular processes essential for photoreceptor survival. We found that Prom1\u2010KO decreases autophagy flux, activates mTORC1, and concomitantly decreases transcription factor EB (TFEB) and Cathepsin\u2010D activities in mRPE cells. In addition, Prom1\u2010KO reduces the clearance of bovine photoreceptor outer segments in mRPE cells due to increased mTORC1 and reduced TFEB activities. Dysfunction of Prom1\u2010dependent autophagy correlates with both a decrease in ZO\u20101 and E\u2010cadherin and a concomitant increase in Vimentin, SNAI1, and ZEB1 levels, consistent with induction of epithelial\u2010mesenchymal transition (EMT) in Prom1\u2010KO mRPE cells. Our results demonstrate that Prom1\u2010mTORC1\u2010TFEB signaling is a central driver of cell\u2010autonomous mRPE homeostasis. We show that Prom1\u2010KO in mRPE leads to RPE defects similar to that seen in atrophic age\u2010related macular degeneration and opens new avenues of investigation targeting Prom1 in retinal degenerative diseases.<\/jats:p>","DOI":"10.1002\/jcp.31094","type":"journal-article","created":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T10:44:40Z","timestamp":1692787480000},"page":"2373-2389","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Loss of Prom1 impairs autophagy and promotes epithelial\u2010mesenchymal transition in mouse retinal pigment epithelial cells"],"prefix":"10.1002","volume":"238","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4443-9691","authenticated-orcid":false,"given":"Sujoy","family":"Bhattacharya","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences Vanderbilt University Medical Center Nashville Tennessee 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