Control of Golgi- V-ATPase through Sac1-dependent co-regulation of PI(4)P and cholesterol
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Abstract
Sac1 is a conserved phosphoinositide phosphatase, whose loss-of-function compromises cell and organism viability. Here, we employ acute auxin-inducible Sac1 degradation to identify its immediate downstream effectors in human cells. Most of Sac1 is degraded in ~1 h, paralleled by increased PI(4)P and decreased cholesterol in the trans- Golgi network (TGN) during the following hour, and superseded by Golgi fragmentation, impaired glycosylation, and selective degradation of TGN proteins by ~4 h. The TGN disintegration results from its acute deacidification caused by disassembly of the Golgi V-ATPase. Mechanistically, Sac1 mediated TGN membrane composition maintains an assembly-promoting conformation of the V 0 a2 subunit. Key phenotypes of acute Sac1 degradation are recapitulated in human differentiated trophoblasts, causing processing defects of chorionic gonadotropin, in line with loss-of-function intolerance of the human SACM1L gene. Collectively, our findings reveal that the assembly of the Golgi V-ATPase is controlled by the TGN membrane via Sac1 fuelled lipid exchange.
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The ER cholesterol sensor SCAP promotes CARTS biogenesis at ER–Golgi membrane contact sites
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Fluorescence Lifetime Imaging of pH along the Secretory Pathway
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Phosphoinositide switches in cell physiology - From molecular mechanisms to disease
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Lipid exchange at ER–trans-Golgi contact sites governs polarized cargo sorting
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Distinct roles for luminal acidification in apical protein sorting and trafficking in zebrafish
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Functional studies of the mammalian Sac1 phosphoinositide phosphatase
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Flagged first, then by citations
1 of the 109 references couldn’t be matched to a known paper.
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The multifaceted significance of phosphoinositides in endocytic trafficking
Xie, C., & Shi, A. (2026) · FEBS Letters · doi:10.1002/1873-3468.70268 · Cited by 1 · see citing works
Cheng, C., Cheng, H., Yao, B., Hu, J., Zheng, F., Zhao, Z., Chen, Q., Zeng, W., Zhang, P., Dong, H. F., et al. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.147668
TOM1 family proteins: from cargo sorting to immune dysregulation and cancer
Collins, M. V., Lång, H. K. M., Finkielstein, C. V., Ryhänen, S. J., Ikonen, E., & Capelluto, D. G. S. (2026) · Cell Communication and Signaling · doi:10.1186/s12964-026-02961-6
Self-citationYang, H., Matsuhisa, K., Wei, M., Nishi, W., Koh, D. H. Z., Sim, A. Y., Bonne, I., & Saheki, Y. (2026) · Nature Communications · doi:10.1038/s41467-026-77423-1
Golgi CATCHR complexes function as organizing hubs for vesicle tethering and fusionPreprint
Aragon‐Ramirez, W. S., Khakurel, A., Pokrovskaya, I. D., Sumya, F. T., & Lupashin, V. V. (2026) · eLife · doi:10.7554/elife.112810.1
Golgi CATCHR complexes function as organizing hubs for vesicle tethering and fusionPreprint
Aragon‐Ramirez, W. S., Khakurel, A., Pokrovskaya, I. D., Sumya, F. T., & Lupashin, V. V. (2026) · eLife · doi:10.7554/elife.112810
- Authors
- Zhou, X., van der Stoel, M. M., Kaptan, S., Li, H., Li, S., Hölttä, M., Vihinen, H., Jokitalo, E., Thiele, C., Pietiläinen, O., Morioka, S., Sasaki, J., Sasaki, T., Vattulainen, I., & Ikonen, E.
- Affiliations
- University of Helsinki (FI)
- University of Bonn (DE)
- Tokyo Medical and Dental University (JP)
- Corresponding author
- Ikonen, Elina
- ORCID
- Venue
- Nature Communications
- Published
- 2025-08-21
- Volume
- 16
- Issue
- 1
- Pages
- 7808-7808
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC12371084
- OpenAlex
- W4413376468
- Cited by
- 6
- References
- 109
- Citations by year
- 2026: 5 · 2025: 1
- FWCI
- 2.98
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Työväentutkimus Vuosikirja (submittedVersion)
- Funders
- Academy of Finland (332096, 364185)
- Jane ja Aatos Erkon Säätiö
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › ATP Synthase and ATPases Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
- Keywords
- Sac1, phosphoinositide phosphatase, trans-Golgi network, cholesterol, Golgi fragmentation, membrane acidification, lipid exchange, trophoblast, auxin-inducible degradation
- MeSH terms
- Cholesterol, Glycosylation, Golgi Apparatus, HeLa Cells, Humans, Indoleacetic Acids, Membrane Proteins, Phosphoric Monoester Hydrolases, Trophoblasts, Phosphatidylinositol Phosphates, trans-Golgi Network, Vacuolar Proton-Translocating ATPases, HEK293 Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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