The pathway of unconventional protein secretion involves CUPS and a modified trans-Golgi network

Curwin, Amy; Kurokawa, Kazuo; Bigliani, Gonzalo; Brouwers, Nathalie; Nakano, Akihiko; Malhotra, Vivek

The pathway of unconventional protein secretion involves CUPS and a modified trans-Golgi network

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dc.contributor.author Curwin, Amy
dc.contributor.author Kurokawa, Kazuo
dc.contributor.author Bigliani, Gonzalo
dc.contributor.author Brouwers, Nathalie
dc.contributor.author Nakano, Akihiko
dc.contributor.author Malhotra, Vivek
dc.date.accessioned 2025-05-16T05:41:49Z
dc.date.available 2025-05-16T05:41:49Z
dc.date.issued 2025
dc.description.abstract Compartment for unconventional protein secretion (CUPS), a compartment for secretion of signal sequence-lacking proteins, forms through COPI-independent extraction of membranes from early Golgi cisternae, lacks Golgi-specific glycosyltransferases, and requires phosphatidylinositol 4-phosphate (PI4P) for biogenesis, as well as phosphatidylinositol 3-phosphate for stability. Our findings demonstrate that Drs2, a PI4P effector from the trans-Golgi network (TGN), is essential for CUPS formation, specifically through its interaction with Rcy1, and Rcy1 is crucial for the unconventional secretion. Using 4D super-resolution confocal live imaging microscopy, we observed that CUPS interact with a modified TGN that contains Drs2 in addition to proteins Tlg2 and Snc2, which are necessary for membrane fusion. Notably, while CUPS remain stable, the modified TGN undergoes remodeling during the later stages of unconventional secretion. In summary, we suggest that CUPS and the modified TGN, without the function of COPII and COPI, participate in collecting and sorting unconventionally secreted proteins, reflecting the role of Golgi membranes in receiving cargo from the ER during conventional secretion.
dc.description.sponsorship This work was funded by grants from the Spanish Ministry of Economy and Competitiveness (BFU2013-44188-P and BFU2016_75372-P to V. Malhotra) and by Grants-in-Aid for Scientific Research from Japan Society for the Promotion of Science (JP17H06420 and JP18H05275 to A. Nakano and K. Kurokawa). We acknowledge support of the Spanish Ministry of Economy, Industry and Competitiveness to the European Molecular Biology Laboratory partnership, the Programmes “Centro de Excelencia Severo Ochoa 2013-2017” (SEV-2012-0208 & SEV-2013-0347), and the Centres de Recerca de Catalunya Programme/Generalitat de Catalunya. This work reflects only the authors’ views, and the EU Community is not liable for any use that may be made of the information contained therein. Open Access funding provided by the Universitat Pompeu Fabra.
dc.format.mimetype application/pdf
dc.identifier.citation Curwin AJ, Kurokawa K, Bigliani G, Brouwers N, Nakano A, Malhotra V. The pathway of unconventional protein secretion involves CUPS and a modified trans-Golgi network. J Cell Biol. 2025 May 5;224(5):e202312120. DOI: 10.1083/jcb.202312120
dc.identifier.doi http://dx.doi.org/10.1083/jcb.202312120
dc.identifier.issn 0021-9525
dc.identifier.uri http://hdl.handle.net/10230/70417
dc.language.iso eng
dc.publisher Rockefeller University Press
dc.relation.ispartof J Cell Biol. 2025 May 5;224(5):e202312120
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2013-44188-P
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2016_75372-P
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0
dc.subject.keyword Biochemistry
dc.subject.keyword Trafficking
dc.title The pathway of unconventional protein secretion involves CUPS and a modified trans-Golgi network
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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