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Here, we describe an unconventional protein secretion pathway for galectin-3 that is mediated by phase separation and condensation. Using four lysosomal damage models, we observed a rapid, pronounced release of galectin-3 in large, non-exosomal particles. This secretion is driven by glycoprotein-induced galectin-3 phase separation and is independent of pyroptosis and secretory autophagy. During phase separation, the S-face of galectin-3 carbohydrate recognition domain binds glycoproteins that triggers galectin-3 N-terminal tail release and condensation. These condensates then recruit ALG-2 via the exposed N-terminal tail. ALG-2 directs the condensates to the endoplasmic reticulum\u2013late endosome interface. After translocation into late endosomes, galectin-3 condensates are secreted into the extracellular milieu by SNARE-dependent vesicular transport. This mechanism of exporting phase-separated protein condensates may serve as a clean-up response to membrane damage.<\/jats:p>","DOI":"10.1038\/s41467-026-76321-w","type":"journal-article","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T21:32:38Z","timestamp":1786051958000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Glycoprotein-induced phase separation drives unconventional secretion of galectin-3"],"prefix":"10.1038","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4558-0606","authenticated-orcid":false,"given":"Zihan","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-0704-9366","authenticated-orcid":false,"given":"Zhen","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongming","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andong","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yibing","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-1334-0503","authenticated-orcid":false,"given":"Zhaoyi","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Geng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejiao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Menghui","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunyao","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8873-4946","authenticated-orcid":false,"given":"Yuying","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairong","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin H.","family":"Mayo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avraham","family":"Raz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4709-6922","authenticated-orcid":false,"given":"Guihua","family":"Tai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1917-2000","authenticated-orcid":false,"given":"Yifa","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,6]]},"reference":[{"key":"76321_CR1","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1146\/annurev-cellbio-100616-060439","volume":"33","author":"TA Rapoport","year":"2017","unstructured":"Rapoport, T. 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