Lipid engineering reveals regulatory roles for membrane fluidity in yeast flocculation and oxygen-limited growth

• A titratable promoter can be used to systematically manipulate lipid unsaturation and membrane fluidity in budding yeast.
• ER unsaturated lipid sensors strongly activate FLO1 transcription, causing yeast to flocculate as lipid unsaturation decreases.
• Lipid-induced FLO1 activation provides a mechanism for flocculation long-observed during microaerobic fermentation.
• A large set of membrane fluidity-regulated genes is activated similarly to FLO1 during fermentation.

Cells modulate lipid metabolism in order to maintain membrane homeostasis. Here we use a metabolic engineering approach to manipulate the stoichiometry of fatty acid unsaturation, a regulator of cell membrane fluidity, in Saccharomyces cerevisiae. Unexpectedly, reduced lipid unsaturation triggered cell-cell adhesion (flocculation), a phenomenon characteristic of industrial yeast but uncommon in laboratory strains. We find that ER lipid saturation sensors induce expression of FLO1 – encoding a cell wall polysaccharide binding protein – independently of its canonical regulator. In wild-type cells, Flo1p-dependent flocculation occurs under oxygen-limited growth, which reduces unsaturated lipid synthesis and thus serves as the environmental trigger for flocculation. Transcriptional analysis shows that FLO1 is one of the most highly induced genes in response to changes in lipid unsaturation, and that the set of membrane fluidity-sensitive genes is globally activated as part of the cell's long-term response to hypoxia during fermentation. Our results show how the lipid homeostasis machinery of budding yeast is adapted to carry out a broad response to an environmental stimulus important in biotechnology.

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