Mandal P, Hazra B, Sett A, Patra N, Ghosh T, Sil AK, Sarkar S

Ethanol stress in Saccharomyces cerevisiae induces a rapid morphological transition in the vacuole from a multilobed (2-3 lobes) structure to a unilobed form. This change reflects a shift in the dynamic equilibrium between vacuolar fusion and fission, towards fusion. The process is mediated by inhibition of the fission machinery, as ...

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cells pre-conditioned with ethanol retain enlarged vacuoles even upon subsequent exposure to vacuole fission-inducing agents, indicating a block in vacuole fragmentation. This inhibition is progressive, as prolonged ethanol exposure results in an increasingly pronounced fission block. The underlying mechanism involves the downregulation of Fab1, a lipid kinase responsible for synthesizing phosphatidylinositol-3,5-bisphosphate (PtdIns(3,5)P?), a key phospholipid regulator facilitating vacuole fission. Ethanol-induced modulation of PtdIns(3,5)P? pools is indicated by the redistribution of this lipid's sensor away from the vacuole membrane. This redistribution is prevented in the presence of the hyperactive mutant Fab1*, which produces elevated PtdIns(3,5)P?. The concomitant delayed vacuole enlargement under ethanol stress in cells expressing Fab1* supports ethanol-induced suppression of PtdIns(3,5)P? levels. Reduced levels of PtdIns(3,5)P? promote dissociation of this lipid's effector, Atg18, from the vacuole membrane. There is also uncoupling of Atg18 from the Fab1 complex via disrupted interaction with the Vac14 scaffold. Further, ethanol exposure induces differential phosphorylation of Atg18, thereby altering its affinity for PtdIns(3,5)P?. Consequently, ethanol rapidly remodels vacuole morphology by simultaneously reducing PtdIns(3,5)P? abundance and weakening effector-lipid interactions. This concerted mechanism ensures a rapid inhibition of vacuole fission in the presence of ethanol.

Date: Jun. 11, 2026

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