Peer-reviewedCC BYNature Communications
Molecular regulation and physiological role of GOLPH3-mediated Golgi retention
11 affiliations
- 1Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- 2Laboratory of Lipid Cell Biology, Institute of Bioengineering and Global Health Institute, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- 3Global Health Institute, School of Life Sciences, EPFL, Lausanne, Switzerland
- 4Institute of Genetics and Biophysics, National Research Council, Naples, Italy
- 5Department of Pharmacology and Toxicology, Veterinary Research Institute, Brno, Czech Republic
- 6Copenhagen Center for Glycocalyx Research, Departments of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
- 7Laboratory of Regenerative Hematopoiesis, Department of Biomedical Sciences, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland
- 8Laboratory of Brain Development and Biological Data Science, Brain Mind Institute, Faculty of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
- 9Hematology Service, Departments of Oncology and Laboratory Medicine, Lausanne University Hospital (CHUV), Lausanne, Switzerland
- 10Global Health Institute, School of Life Sciences, EPFL, Lausanne, Switzerland. [email protected]
- 11Laboratory for Biomolecular Modeling, Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland. [email protected]
Abstract
The Golgi complex serves as the central hub of the biosynthetic pathway, where anterograde and retrograde trafficking converge. How cargo and Golgi-resident proteins traverse this organelle has long been debated. Recent studies have identified a molecular machinery that sorts resident proteins into retrograde-directed COPI vesicles during cisternal maturation. Golgi phosphoprotein 3 (GOLPH3) is a key component of this system; however, its physiological relevance and regulatory mechanisms remain poorly defined. Here, we show that GOLPH3 depletion in mice alters both protein and lipid glycosylation, causes partially penetrant embryonic lethality, and severely impairs growth and bone mineralization. At the molecular level, we find that GOLPH3 is regulated by functionally antagonistic S-acylation events that control the topology of its membrane association. To mediate retrograde trafficking of Golgi-resident glycosyltransferases, GOLPH3 must bind their cytosolic tails. This occurs via a negatively charged surface region, which is correctly oriented only in one of the S-acylated GOLPH3 conformations. Together, these findings reveal a lipid-mediated regulatory mechanism for intra-Golgi trafficking and establish the critical role of GOLPH3 in vertebrate development.
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BibTeX
@article{theodoropoulou2026molecular,
title = {{Molecular regulation and physiological role of GOLPH3-mediated Golgi retention}},
author = {Anastasia Theodoropoulou and Anita Nasrallah and Luciano A. Abriata and Laurence Abrami and Juliane Da Graça and Irmak Kaysudu and Francesco Talotta and María J. Marcaida and Muhammad U. Anwar and Ondrej Kováč and Sergey Y. Vakhrushev and Alejandro Alonso Calleja and Sylvia Ho and Antonino Asaro and Francisco Sarmento Mesquita and Leila Haj Abdullah Alieh and Charlotte Julie Caroline Gehin and Lucie Josepha Bracq and Nika Gorsek and Sarah Vacle and Arthur Samurkas and Alessio Prunotto and Luca Fusar Bassini and Miroslav Machala and Olaia Naveiras and Katrine T.-B. G. Schjoldager and F. Gisou van der Goot and Matteo Dal Peraro and Giovanni D’Angelo},
journal = {Nature Communications},
year = {2026},
month = jun,
doi = {10.1038/s41467-026-74133-6},
url = {https://doi.org/10.1038/s41467-026-74133-6},
note = {CC BY},
}
RIS
TY - JOUR
TI - Molecular regulation and physiological role of GOLPH3-mediated Golgi retention
AU - Anastasia Theodoropoulou
AU - Anita Nasrallah
AU - Luciano A. Abriata
AU - Laurence Abrami
AU - Juliane Da Graça
AU - Irmak Kaysudu
AU - Francesco Talotta
AU - María J. Marcaida
AU - Muhammad U. Anwar
AU - Ondrej Kováč
AU - Sergey Y. Vakhrushev
AU - Alejandro Alonso Calleja
AU - Sylvia Ho
AU - Antonino Asaro
AU - Francisco Sarmento Mesquita
AU - Leila Haj Abdullah Alieh
AU - Charlotte Julie Caroline Gehin
AU - Lucie Josepha Bracq
AU - Nika Gorsek
AU - Sarah Vacle
AU - Arthur Samurkas
AU - Alessio Prunotto
AU - Luca Fusar Bassini
AU - Miroslav Machala
AU - Olaia Naveiras
AU - Katrine T.-B. G. Schjoldager
AU - F. Gisou van der Goot
AU - Matteo Dal Peraro
AU - Giovanni D’Angelo
PY - 2026
DA - 2026/06/11
JO - Nature Communications
DO - 10.1038/s41467-026-74133-6
UR - https://doi.org/10.1038/s41467-026-74133-6
AB - The Golgi complex serves as the central hub of the biosynthetic pathway, where anterograde and retrograde trafficking converge. How cargo and Golgi-resident proteins traverse this organelle has long been debated. Recent studies have identified a molecular machinery that sorts resident proteins into retrograde-directed COPI vesicles during cisternal maturation. Golgi phosphoprotein 3 (GOLPH3) is a key component of this system; however, its physiological relevance and regulatory mechanisms remain poorly defined. Here, we show that GOLPH3 depletion in mice alters both protein and lipid glycosylation, causes partially penetrant embryonic lethality, and severely impairs growth and bone mineralization. At the molecular level, we find that GOLPH3 is regulated by functionally antagonistic S-acylation events that control the topology of its membrane association. To mediate retrograde trafficking of Golgi-resident glycosyltransferases, GOLPH3 must bind their cytosolic tails. This occurs via a negatively charged surface region, which is correctly oriented only in one of the S-acylated GOLPH3 conformations. Together, these findings reveal a lipid-mediated regulatory mechanism for intra-Golgi trafficking and establish the critical role of GOLPH3 in vertebrate development.
SN - 2041-1723
ER -