{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T19:02:31Z","timestamp":1789671751353,"version":"4.0.1"},"reference-count":27,"publisher":"National Academy of Sciences","issue":"38","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000069","name":"HHS | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["5R01AR057352"],"award-info":[{"award-number":["5R01AR057352"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,9,22]]},"abstract":"<jats:p>Lysosomal enzymes are synthesized in the Endoplasmic Reticulum (ER) and transported to lysosomes to execute their functions. Deficiencies in lysosomal enzymes or components of the lysosomal transport machinery result in lysosomal storage disorders. While mannose-6-phosphate mediated lysosomal enzymes sorting in the Golgi has been extensively characterized, the mechanisms governing their export from the ER remain elusive. Here, we show that de novo lipogenesis, a metabolic pathway responsible for fatty acid synthesis, regulates lysosomal enzyme transport. Inhibition of de novo lipogenesis leads to the retention of lysosomal enzymes within the ER. Mechanistically, fatty acid derived from de novo lipogenesis is used for Arf1 myristoylation. Myristoylated Arf1 promotes retrograde vesicle trafficking from the Golgi to the ER, thereby maintaining the homeostatic bidirectional flux required for efficient ER export of lysosomal enzymes. Our findings uncover a critical functional link between lipid metabolism and lysosomal enzyme trafficking.<\/jats:p>","DOI":"10.1073\/pnas.2616684123","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T18:07:04Z","timestamp":1789668424000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Lipids regulate export of lysosomal enzymes from the endoplasmic reticulum"],"prefix":"10.1073","volume":"123","author":[{"given":"Baolong","family":"Xia","sequence":"first","affiliation":[{"name":"Department of Genetics, Blavatnik Institute, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myeonghoon","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Genetics, Blavatnik Institute, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isaac","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Genetics, Blavatnik Institute, Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7542-472X","authenticated-orcid":false,"given":"Norbert","family":"Perrimon","sequence":"additional","affiliation":[{"name":"Department of Genetics, Blavatnik Institute, Harvard Medical School","place":["Boston"]},{"name":"HHMI","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2022.101702"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1205677"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1242\/bio.013334"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M410626200"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.20.11041"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1534-5807(01)00119-8"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M900346200"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2331794100"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200708092"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.abn5648"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-022-33025-1"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2004.09.018"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-44393-7"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5919"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1002\/bies.202200214"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.3.1573"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(18)53145-8"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/0076-6879(95)50087-1"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111282"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0060292"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature06928"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1080\/0968768031000122548"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature04377"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.12.025"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF03402003"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2017.00005"},{"key":"e_1_3_4_27_2","doi-asserted-by":"crossref","unstructured":"B. Xia Raw data for \u201cLipids regulate export of lysosomal enzymes from the endoplasmic reticulum.\u201d Figshare. https:\/\/doi.org\/10.6084\/m9.figshare.33412273. Deposited 1 September 2026.","DOI":"10.64898\/2026.04.16.719038"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2616684123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T18:07:36Z","timestamp":1789668456000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2616684123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,17]]},"references-count":27,"journal-issue":{"issue":"38","published-print":{"date-parts":[[2026,9,22]]}},"alternative-id":["10.1073\/pnas.2616684123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2616684123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,17]]},"assertion":[{"value":"2026-05-11","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-08-14","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-09-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2616684123"}}