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The sensitivity of cells to progranulin deficiency raises important questions about how cells coordinate intracellular trafficking of progranulin to ensure its efficient delivery to lysosomes. In this study, we discover that progranulin interactions with prosaposin, another lysosomal protein, first occur within the lumen of the endoplasmic reticulum (ER) and are required for the efficient ER exit of progranulin. Mechanistically, we identify an interaction between prosaposin and Surf4, a receptor that promotes loading of lumenal cargos into COPII-coated vesicles, and establish that Surf4 is critical for the efficient export of progranulin and prosaposin from the ER. Collectively, this work demonstrates that a network of interactions occurring early in the secretory pathway promote the ER exit and subsequent lysosomal delivery of newly translated progranulin and prosaposin.<\/jats:p>","DOI":"10.1083\/jcb.202104044","type":"journal-article","created":{"date-parts":[[2021,11,16]],"date-time":"2021-11-16T02:22:21Z","timestamp":1637029341000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":22,"title":["Efficient progranulin exit from the ER requires its interaction with prosaposin, a Surf4 cargo"],"prefix":"10.1083","volume":"221","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7068-5947","authenticated-orcid":true,"given":"Swathi","family":"Devireddy","sequence":"first","affiliation":[{"name":"Departments of Cell Biology and Neuroscience, Program in Cellular Neuroscience, Neurodegeneration and Repair, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3092-7718","authenticated-orcid":true,"given":"Shawn M.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Departments of Cell Biology and Neuroscience, Program in Cellular Neuroscience, Neurodegeneration and Repair, Wu Tsai Institute, Yale University School of Medicine, New Haven, CT"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2021,12,17]]},"reference":[{"key":"2023072801293389900_bib1","doi-asserted-by":"publisher","first-page":"653","DOI":"10.1016\/j.ccell.2015.10.002","article-title":"Targeting the AAA ATPase p97 as an Approach to Treat Cancer through Disruption of Protein Homeostasis","volume":"28","author":"Anderson","year":"2015","journal-title":"Cancer Cell."},{"key":"2023072801293389900_bib2","doi-asserted-by":"publisher","first-page":"330","DOI":"10.1038\/14020","article-title":"The lectin ERGIC-53 is a cargo transport receptor for glycoproteins","volume":"1","author":"Appenzeller","year":"1999","journal-title":"Nat. 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