Abstract
The protein kinase C (PKC)-MAPK signaling cascade is activated and is essential for viability when cells are starved for the phospholipid precursor inositol. In this study, we report that inhibiting inositol-containing sphingolipid metabolism, either by inositol starvation or treatment with agents that block sphingolipid synthesis, triggers PKC signaling independent of sphingoid base accumulation. Under these same growth conditions, a fluorescent biosensor that detects the necessary PKC signaling intermediate, phosphatidylinositol (PI)-4-phosphate (PI4P), is enriched on the plasma membrane. The appearance of the PI4P biosensor on the plasma membrane correlates with PKC activation and requires the PI 4-kinase Stt4p. Like other mutations in the PKC-MAPK pathway, mutants defective in Stt4p and the PI4P 5-kinase Mss4p, which generates phosphatidylinositol 4,5-bisphosphate, exhibit inositol auxotrophy, yet fully derepress INO1, encoding inositol-3-phosphate synthase. These observations suggest that inositol-containing sphingolipid metabolism controls PKC signaling by regulating access of the signaling lipids PI4P and phosphatidylinositol 4,5-bisphosphate to effector proteins on the plasma membrane.
Highlights
The protein kinase C (PKC) pathway, known in yeast as the cell wall integrity pathway, is a highly conserved signal transduction pathway that is activated in Saccharomyces cerevisiae during periods of polarized cell growth [1, 2] as well as by numerous environmental stresses, including elevated temperature [3], entry into stationary growth phase [4], and treatment with agents that interfere with cell wall biogenesis [5, 6]
We demonstrate that inositol-containing sphingolipid metabolism generates a signal that regulates PKC activity during inositol starvation
Activation of PKC signaling during inositol starvation requires the activity of Stt4p and Mss4p, which produce phosphatidylinositol 4-phosphate (PI4P) and PI[4,5]P2 on the plasma membrane
Summary
We reported that lipid metabolism is substantially altered in yeast cells grown in the absence of inositol, including a significant reduction in PI [25]. These metabolic changes are accompanied by activation of numerous signaling pathways, including PKC signaling (26 –28). In agreement with previous reports [31, 32], we show that inositol starvation results in major changes in sphingolipid metabolism, even in wild type cells Together, these results suggest that inositol-containing sphingolipid metabolism regulates PKC activity by regulating access of protein effectors to signaling lipids on the plasma membrane
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