Ist2 promotes lipid transfer by Osh6 via its membrane tethering and lipid scramblase activities
Lipid transfer proteins unevenly distribute lipids within the cell, which is crucial for its functioning. In yeast, Osh6 transfers phosphatidylserine (PS) from the endoplasmic reticulum (ER) to the plasma membrane (PM) by exchange with phosphatidylinositol 4-phosphate. We investigated why its activity depends on Ist2, an ER-resident lipid scramblase that connects the ER to the PM via an intrinsically disordered region (IDR). We found that Osh6, in a lipid-loaded state, binds the Ist2 IDR with micromolar affinity and functions at ER-PM contact sites only if its binding site within the IDR is sufficiently distant from the ER membrane. We determined, in reconstituted contact sites, that the association of Osh6 with the Ist2 IDR enables rapid, directed PS transfer. We identified the Ist2-binding site in Osh6 by molecular modeling and functional analyses. Last, we established that Ist2's scramblase activity sustains Osh6-mediated PS transfer between membranes. Identifying these functional partnerships highlights why lipid transport processes are organized in membrane contact sites.
Authors
- Guillaume Lenoir (ORCID: https://orcid.org/0000-0002-8759-5179)
- Cédric Montigny (ORCID: https://orcid.org/0000-0003-0905-9861)
- Maud Magdeleine (ORCID: https://orcid.org/0000-0001-9006-4486)
- Camille Syska (ORCID: https://orcid.org/0000-0001-8632-1339)
- Heitor Gobbi Sebinelli (ORCID: https://orcid.org/0000-0002-4961-560X)
- Noha Al-Qatabi (ORCID: https://orcid.org/0000-0002-5826-1815)
- Guillaume Drin (ORCID: https://orcid.org/0000-0002-3484-4581)
- Alenka Čopič (ORCID: https://orcid.org/0000-0003-0166-7731)
- Juan Martín D’Ambrosio (ORCID: https://orcid.org/0000-0003-2834-1838)
- Alicia Fabbre (ORCID: https://orcid.org/0009-0008-7023-2794)
- Anna Cardinal (ORCID: https://orcid.org/0009-0001-6717-6516)
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Commissariat à l'Énergie Atomique et aux Énergies Alternatives (FR)
- Université Paris-Saclay (FR)
- Institut de Biologie Intégrative de la Cellule (FR)
- CEA Paris-Saclay (FR)
- Institut de Pharmacologie Moléculaire et Cellulaire (FR)
Publication Details
- Journal
- Science Advances
- Published
- 2025-11-14
- DOI
- https://doi.org/10.1126/sciadv.adz2217
- Citations
- 2
- Primary Topic
- Lipid Membrane Structure and Behavior
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- Agence Nationale de la Recherche