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Once synthesized and processed at the Golgi, some of these proteins are packaged for delivery to the plasma membrane. While this transport and sorting rely on complex molecular machinery, the precise mechanisms remain unclear. In this study, we affinity-isolated and analyzed post-Golgi carriers by mass spectrometry. Candidate machinery was subsequently assessed in a pooled CRISPR-KO screen. This led to the identification of a rich set of new genes functionally important for Golgi-to-plasma membrane delivery including PTPN23, a component of the endosomal sorting complex required for transport (ESCRT) complex. Depletion of PTPN23, as well as the ESCRT subunits CHMP1 and VPS4, disrupts tubule fission from the trans-Golgi, impairing cargo delivery to the surface. Furthermore, the loss of PTPN23 also prevents the constitutive secretion of soluble cargoes, and of endogenous hormones and antibodies in specialized cells. We propose that PTPN23 is essential for secretion from the trans-Golgi.<\/jats:p>","DOI":"10.1083\/jcb.202506111","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T13:30:15Z","timestamp":1773840615000},"update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["A PTPN23-dependent ESCRT pathway is essential for constitutive secretion in mammalian cells"],"prefix":"10.1083","volume":"225","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6996-4006","authenticated-orcid":true,"given":"Dani\u00e8le","family":"Stalder","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Cambridge Institute for Medical Research, University of Cambridge 1 , Cambridge,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0164-4169","authenticated-orcid":true,"given":"Concei\u00e7\u00e3o","family":"Pereira","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Cambridge Institute for Medical Research, University of Cambridge 1 , Cambridge,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6474-3661","authenticated-orcid":true,"given":"Dick J.H.","family":"van den Boomen","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge 2 , Cambridge,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4407-4277","authenticated-orcid":true,"given":"Petia","family":"Adarska","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046ak2485","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Chemistry and Biochemistry, Freie Universit\u00e4t Berlin 3 , Berlin,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2568-6689","authenticated-orcid":true,"given":"Dilip","family":"Menon","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Metabolic Research Laboratory, Institute of Metabolic Science, University of Cambridge 4 , Cambridge,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8241-2903","authenticated-orcid":true,"given":"Daniel J.","family":"Fazakerley","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Metabolic Research Laboratory, Institute of Metabolic Science, University of Cambridge 4 , Cambridge,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5360-1550","authenticated-orcid":true,"given":"Francesca","family":"Bottanelli","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/046ak2485","id-type":"ROR","asserted-by":"publisher"}],"name":"Institute of Chemistry and Biochemistry, Freie Universit\u00e4t Berlin 3 , Berlin,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9383-1054","authenticated-orcid":true,"given":"Paul J.","family":"Lehner","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Cambridge Institute of Therapeutic Immunology and Infectious Disease, University of Cambridge 2 , Cambridge,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0602-210X","authenticated-orcid":true,"given":"David C.","family":"Gershlick","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/013meh722","id-type":"ROR","asserted-by":"publisher"}],"name":"Cambridge Institute for Medical Research, University of Cambridge 1 , Cambridge,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,3,18]]},"reference":[{"key":"2026031809295253400_bib1","doi-asserted-by":"publisher","first-page":"807","DOI":"10.1126\/science.aan6298","article-title":"Lysosomal metabolomics reveals V-ATPase- and mTOR-dependent regulation of amino acid efflux from lysosomes","volume":"358","author":"Abu-Remaileh","year":"2017","journal-title":"Science"},{"key":"2026031809295253400_bib2","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.cub.2013.02.033","article-title":"Recruitment of UBPY and ESCRT exchange drive HD-PTP-dependent sorting of EGFR to the MVB","volume":"23","author":"Ali","year":"2013","journal-title":"Curr. 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