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Although retromer can form a stable complex with \u03b3-secretase, the functional consequences of this interaction are not known. Here, we report that retromer-mediated retrograde protein trafficking in cultured human epithelial cells is impaired by the \u03b3-secretase inhibitor XXI or by knockout of PS1 (also known as PSEN1), the catalytic subunit of \u03b3-secretase. These treatments inhibited endosome-to-TGN trafficking of retromer-dependent retrograde cellular cargoes, divalent metal transporter 1 isoform II, cation-independent mannose-6-phosphate receptor and shiga toxin, whereas trafficking of retromer-independent cargoes, cholera toxin and a mutant CIMPR unable to bind retromer was not affected. Moreover, we found that \u03b3-secretase associates with retromer cargoes even in the absence of retromer. XXI treatment and PS1 knockout did not inhibit the ability of retromer or \u03b3-secretase to associate with cargo and did not affect the expression of retromer subunits or Rab7-GTP, which regulates retromer\u2013cargo interaction. These results imply that the \u03b3-secretase\u2013retromer interaction facilitates retromer-mediated retrograde trafficking of cellular transmembrane proteins.<\/jats:p>","DOI":"10.1242\/jcs.263538","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T03:43:52Z","timestamp":1737949432000},"source":"Crossref","is-referenced-by-count":0,"title":["\u03b3-secretase facilitates retromer-mediated retrograde transport"],"prefix":"10.1242","volume":"138","author":[{"given":"Yuka","family":"Takeo","sequence":"first","affiliation":[{"name":"Yale School of Medicine 1 Department of Genetics , , New Haven , CT 06510,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mac","family":"Crite","sequence":"additional","affiliation":[{"name":"Yale School of Medicine 1 Department of Genetics , , New Haven , CT 06510,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kashif","family":"Mehmood","sequence":"additional","affiliation":[{"name":"Yale School of Medicine 1 Department of Genetics , , New Haven , CT 06510,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2060-5977","authenticated-orcid":false,"given":"Daniel","family":"DiMaio","sequence":"additional","affiliation":[{"name":"Yale School of Medicine 1 Department of Genetics , , New Haven , CT 06510,","place":["USA"]},{"name":"Yale University 2 Department of Molecular Biophysics and Biochemistry , , New Haven , CT 06510,","place":["USA"]},{"name":"Yale School of Medicine 3 Department of Therapeutic Radiology , , New Haven , CT 06510,","place":["USA"]},{"name":"Yale Cancer Center, Yale School of Medicine 4 , New Haven , CT 06510,","place":["USA"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"2025022408273346200_JCS263538C1","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.advenzreg.2009.10.002","article-title":"The retromer complex","volume":"50","author":"Attar","year":"2010","journal-title":"Adv. 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