Abstract
All organisms have stress response systems to protect themselves from various environmental stresses, and regulation of membrane lipids is thought to play an important role in acquirement of stress tolerance. Complex sphingolipids in the yeast Saccharomyces cerevisiae are classified into three types based on differences in the structure of the polar head group, and the compositions and quantities of complex sphingolipids in biomembranes are tightly regulated. In this study, we found that the accumulation of inositol phosphorylceramides (IPCs) due to a defect of mannosylinositol phosphorylceramide biosynthesis (sur1∆ csh1∆), i.e., disruption of the balance of the composition of complex sphingolipids, causes hypersensitivity to low pH conditions (pH 4.0–2.5). Furthermore, screening of suppressor mutations that confer low pH resistance to sur1∆ csh1∆ cells revealed that a change in ergosterol homeostasis at plasma membranes can rescue the hypersensitivity, suggesting the functional relationship between complex sphingolipids and ergosterol under low pH conditions. Under low pH conditions, wild-type yeast cells exhibited decreases in IPC levels, and forced enhancement of the biosynthesis of IPCs causes low pH hypersensitivity. Thus, it was suggested that the accumulation of IPCs is detrimental to yeast under low pH conditions, and downregulation of IPC levels is one of the adaptation mechanisms for low pH conditions.
Highlights
All organisms have stress response systems to protect themselves from various environmental stresses, and regulation of membrane lipids is thought to play an important role in acquirement of stress tolerance
A delay of growth of wild-type cells was observed after 1-day culture on YPD plates buffered to pH 2.5 (Supplementary Fig. S1), the growth patterns on YPD plates buffered to pH 5.5 and pH 2.5 were nearly indistinguishable after 2 days culture (Fig. 1C). sur1∆, csg2∆, and sur1∆ csh1∆ cells exhibited a strong growth defect on YPD plates buffered to pH 3.5, 3.0, and 2.5 with glycine–HCl, the most robust growth defect being observed in sur1∆ csh1∆ cells (Fig. 1C)
The low pH hypersensitivity of mannosylinositol phosphorylceramide (MIPC) biosynthesis-deficient cells was confirmed when pH 2.5 YPD plates were prepared by the addition of phospholic acid-sodium dihydrogen phosphate or HCl, indicating that the hypersensitivity does not depend on the means of adjusting the pH of the medium (Fig. 1C)
Summary
All organisms have stress response systems to protect themselves from various environmental stresses, and regulation of membrane lipids is thought to play an important role in acquirement of stress tolerance. We found that the accumulation of inositol phosphorylceramides (IPCs) due to a defect of mannosylinositol phosphorylceramide biosynthesis (sur1∆ csh1∆), i.e., disruption of the balance of the composition of complex sphingolipids, causes hypersensitivity to low pH conditions (pH 4.0–2.5). In S. cerevisiae, according to differences in the polar head group structure, complex sphingolipids are classified into three types, inositol phosphorylceramide (IPC), mannosylinositol phosphorylceramide (MIPC), and mannosyldiinositol phosphorylceramide (M(IP)2C)[3] (Fig. 1A,B). The growth defects caused by these stressful conditions are suppressed by inhibition of biosynthesis of hydroxylated IPCs, suggesting that these phenotypes are not due to loss of MIPCs themselves but to the accumulation of hydroxylated IPCs13,15. MIPCs are involved in maintenance of the asymmetry of glycerophospholipids at plasma membranes through regulation of glycerophospholipid flippases-regulating kinase, Fpk[119]
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