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bioRxiv · 10.1101/2025.11.20.689427

Csf1, a tunnel-like lipid-transfer protein, mediates lipid remodeling and underpins eukaryotic membrane resilience to high hydrostatic pressure and cold

Abe, F.·Mioka, T.·Suzuki, Y.·Ogasawara, A.·Mochizuki, D.·Imura, S.·Kato, Y.·Mochizuki, T.
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Abstract

Biological membranes continuously remodel their lipid composition to preserve functionality under environmental stress, yet the molecular basis of this process in eukaryotes remains incompletely understood. Here, we identify the tunnel-like lipid transfer protein Csf1 as a central factor mediating adaptive lipid remodeling that enables Saccharomyces cerevisiae to tolerate high hydrostatic pressure and low temperature. Quantitative lipidomic and membrane biophysical analyses revealed that loss of Csf1 markedly reduces the unsaturation of phosphatidylserine (PS) and phosphatidylethanolamine (PE), leading to rigidification of the endoplasmic reticulum (ER) membrane. Whereas OLE1 overexpression partially mitigated this defect at low temperature, no compensatory response occurred under pressure. Overexpression of the PS/phosphatidylinositol 4-phosphate exchanger Osh6/7 restored PS and PE unsaturation and rescued growth of the Csf1-deficient mutant, indicating a cooperative role in sustaining PS flux at ER-plasma membrane (PM) contact sites. Pressure-induced degradation of the amino-acid permease Bap2 further linked lipid imbalance to membrane-protein instability. By supplying unsaturated PS and PE, Csf1 preserves ER and PM flexibility, defining a conserved mechanism of eukaryotic membrane adaptation to extreme physical stress.

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Abe, F., Mioka, T., Suzuki, Y., Ogasawara, A., Mochizuki, D., Imura, S., Kato, Y., Mochizuki, T.. 2025-11-20. Csf1, a tunnel-like lipid-transfer protein, mediates lipid remodeling and underpins eukaryotic membrane resilience to high hydrostatic pressure and cold. https://doi.org/10.1101/2025.11.20.689427

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