Sfh3 is a sterol-modulated PI/PI4P transfer protein that confers azole resistance in yeast by specifically mediating lanosterol/PI exchange
- 1Université Côte d'Azur, CNRS, INSERM, Institut de Pharmacologie Moléculaire et Cellulaire, 660 route des lucioles, 06560 Valbonne, France
Abstract
Lipid transfer proteins precisely distribute lipids within eukaryotic cells, supporting functions such as vesicular trafficking and cellular signaling. Here, we analyzed whether Sfh3 (Sec14 homolog 3) functions as a sterol/phosphatidylinositol (PI) exchanger to clarify its role in neutral lipid mobilization from lipid droplets and in azole resistance in yeast. Using real-time assays, we found that its ergosterol transfer capacity is not activated by PI and is inhibited by ergosterol biosynthesis intermediates, such as lanosterol. Next, we found that Sfh3 exhibits both PI and PI4P transfer activities, which sterols can modulate. Through kinetic, structure-function, and thermal stability analyses, we identified remarkable Sfh3 mutants and ranked Sfh3's relative affinity for its lipid ligands. This allowed us to show that Sfh3 performs selective lanosterol/PI exchange, provided it recognizes PI, in the presence of ergosterol, and that this activity is necessary for yeast resistance to miconazole. Collectively, our data show that Sfh3 is a sterol-regulated PI/PI4P transfer protein, potentially linking sterol metabolism and PI4P signaling during lipid droplet utilization. In azole-treated yeast, elevated lanosterol levels may shift Sfh3 into an exclusive PI/lanosterol exchange mode, promoting cellular detoxification and conferring drug resistance. By revealing unanticipated Sfh-mediated lipid transfer mechanisms, our study provides new insights into the Sec14 family.
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BibTeX
@misc{hamai2026sfh3,
title = {{Sfh3 is a sterol-modulated PI/PI4P transfer protein that confers azole resistance in yeast by specifically mediating lanosterol/PI exchange}},
author = {A. Hamaï and P. Perne and A. Tripathi and C. Syska and A. Cardinal and V. Delfosse and A. Copic and N. A. Murugan and D. Debayle and G. Drin},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.26.761302},
url = {https://www.biorxiv.org/content/10.64898/2026.10.26.761302v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Sfh3 is a sterol-modulated PI/PI4P transfer protein that confers azole resistance in yeast by specifically mediating lanosterol/PI exchange
AU - A. Hamaï
AU - P. Perne
AU - A. Tripathi
AU - C. Syska
AU - A. Cardinal
AU - V. Delfosse
AU - A. Copic
AU - N. A. Murugan
AU - D. Debayle
AU - G. Drin
PY - 2026
DA - 2026/10/26
PB - bioRxiv
DO - 10.64898/2026.10.26.761302
UR - https://www.biorxiv.org/content/10.64898/2026.10.26.761302v1
AB - Lipid transfer proteins precisely distribute lipids within eukaryotic cells, supporting functions such as vesicular trafficking and cellular signaling. Here, we analyzed whether Sfh3 (Sec14 homolog 3) functions as a sterol/phosphatidylinositol (PI) exchanger to clarify its role in neutral lipid mobilization from lipid droplets and in azole resistance in yeast. Using real-time assays, we found that its ergosterol transfer capacity is not activated by PI and is inhibited by ergosterol biosynthesis intermediates, such as lanosterol. Next, we found that Sfh3 exhibits both PI and PI4P transfer activities, which sterols can modulate. Through kinetic, structure-function, and thermal stability analyses, we identified remarkable Sfh3 mutants and ranked Sfh3's relative affinity for its lipid ligands. This allowed us to show that Sfh3 performs selective lanosterol/PI exchange, provided it recognizes PI, in the presence of ergosterol, and that this activity is necessary for yeast resistance to miconazole. Collectively, our data show that Sfh3 is a sterol-regulated PI/PI4P transfer protein, potentially linking sterol metabolism and PI4P signaling during lipid droplet utilization. In azole-treated yeast, elevated lanosterol levels may shift Sfh3 into an exclusive PI/lanosterol exchange mode, promoting cellular detoxification and conferring drug resistance. By revealing unanticipated Sfh-mediated lipid transfer mechanisms, our study provides new insights into the Sec14 family.
ER -