Control of Golgi- V-ATPase through Sac1-dependent co-regulation of PI(4)P and cholesterol

Xin Zhou, Miesje M. van der Stoel, Shreyas Kaptan, Haoran Li, Shiqian Li, Maarit Hölttä, Helena Vihinen, Eija Jokitalo, Christoph Thiele, Olli Pietiläinen, Shin Morioka, Junko Sasaki, Takehiko Sasaki, Ilpo Vattulainen and Elina Ikonen ()
Additional contact information
Xin Zhou: University of Helsinki
Miesje M. van der Stoel: University of Helsinki
Shreyas Kaptan: University of Helsinki
Haoran Li: University of Helsinki
Shiqian Li: University of Helsinki
Maarit Hölttä: University of Helsinki
Helena Vihinen: University of Helsinki
Eija Jokitalo: University of Helsinki
Christoph Thiele: University of Bonn
Olli Pietiläinen: University of Helsinki
Shin Morioka: Tokyo Medical and Dental University
Junko Sasaki: Tokyo Medical and Dental University
Takehiko Sasaki: Tokyo Medical and Dental University
Ilpo Vattulainen: University of Helsinki
Elina Ikonen: University of Helsinki

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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by increased PI(4)P and decreased cholesterol in the trans-Golgi network (TGN) during the following hour, and superseded by Golgi fragmentation, impaired glycosylation, and selective degradation of TGN proteins by ~4 h. The TGN disintegration results from its acute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 V0a2 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.

Date: 2025
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-63125-7 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63125-7

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-63125-7

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().