The emergence of yeast lipidomics

Gaspar, María L.; Aregullin, Manuel; Jesch, Stephen A.; Nunez, Lilia R.; Villa-Garcia, Manuel; Henry, Susan A.

doi:10.1016/j.bbalip.2006.06.011

Cited by 71 publications

(61 citation statements)

References 162 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…) phenotype is classically associated with insufficient INO1 transcriptional derepression during inositol starvation due to regulatory and signaling defects (40). In contrast to previously studied Ino Ϫ mutants, the slt2⌬ mutant, which is defective in PKC signaling (Fig.…”

mentioning

confidence: 42%

Interruption of Inositol Sphingolipid Synthesis Triggers Stt4p-dependent Protein Kinase C Signaling

Jesch

Gaspar

Stefan

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

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.The protein kinase C (PKC) pathway, also 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). Signals produced on the cell surface are amplified and relayed by PKC to downstream targets through a three-component MAPK phosphorylation cascade composed of the MEK kinase Bck1p, the redundant MEKs Mkk1p and Mkk2p, and the MAPK Slt2p (Fig. 1A). Pkc1p homologs in mammals are directly regulated by lipids, including diacylglycerol (DAG) 2 produced by hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P 2 ), anionic phospholipids, and sphingolipids (7,8). Nevertheless, these lipid metabolites do not appear to play identical roles in yeast PKC activation.In yeast, the phosphorylated derivatives of phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PI4P) and PI(4,5)P 2 , are essential for PKC signaling during heat stress (9). PI4P is produced on the plasma membrane by the PI 4-kinase Stt4p and is subsequently phosphorylated to PI(4,5)P 2 by the PI4P 5-kinase Mss4p. Stt4p was originally identified in a genetic screen for mutants that are hypersensitive to staurosporine, a specific inhibitor of PKC (10). Mutations in both STT4 and MSS4 cause cell lysis phenotypes associated with defects in cell wall integrity signaling, and these defects are suppressed by overexpression of PKC1 (10, 11). Stt4p-dependent pools of PI4P and PI(4,5)P 2 are proposed to regulate PKC signaling by plasma membrane recruitment of the guanine nucleotide exchange factor Rom2p, where it carries out multiple function...

show abstract

mentioning

confidence: 42%

Interruption of Inositol Sphingolipid Synthesis Triggers Stt4p-dependent Protein Kinase C Signaling

Jesch

Gaspar

Stefan

et al. 2010

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…The expression of phospholipid synthesis genes is controlled by multiple factors, including nutrient availability, growth stage, pH, and temperature (1,2,9,16,28,32). The mechanisms responsible for the regulation of gene expression include a number of cis-and trans-acting elements (7,9).…”

Section: Genetic and Biochemical Mechanisms For The Regulation Of Phomentioning

confidence: 99%

“…In addition, elevated PA content stimulates PS synthase activity (44), which would favor the synthesis of PC via the CDP-DAG pathway. Moreover, 2 The PAH1-encoded PA phosphatase is a Mg 21 -dependent enzyme that is involved in de novo lipid synthesis. It is distinct from the DPP1-and LPP1-encoded lipid phosphate phosphatase enzymes that dephosphorylate PA and a host of lipid phosphate molecules by a catalytic mechanism that does not require Mg 21 (5).…”

Section: Roles Of Pa Phosphatase and Dag Kinase Inmentioning

confidence: 99%

“…1) (1, 2). Its tractable genetics has facilitated the identification and characterization of nearly all of the structural and regulatory genes that are involved in de novo phospholipid synthesis (2,3). Moreover, the purification and characterization of several key phospholipid synthesis enzymes have led to an understanding of the biochemical regulation of phospholipid synthesis (1,4,5).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Regulation of phospholipid synthesis in yeast

Carman

Han

2009

Journal of Lipid Research

100

109

View full text Add to dashboard Cite

Phospholipid synthesis in the yeast Saccharomyces cerevisiae is a complex process that involves regulation by both genetic and biochemical mechanisms. The activity levels of phospholipid synthesis enzymes are controlled by gene expression (e.g., transcription) and by factors (lipids, water-soluble phospholipid precursors and products, and covalent modification of phosphorylation) that modulate catalysis. Phosphatidic acid, whose levels are controlled by the biochemical regulation of key phospholipid synthesis enzymes, plays a central role in the regulation of phospholipid synthesis gene expression.-Carman, G. M., and G-S. Han. Regulation of phospholipid synthesis in yeast. J. Lipid Res. 2009. 50: S69-S73.

show abstract

“…In the absence of lipid precursors, Opi1, which may interact with Ino2 in the nucleus to block transcription, is retained in the endoplasmic reticulum by binding to PA (33). The presence of inositol leads to rapid consumption of PA pools in the ER and subsequent translocation of Opi1 into the nucleus to repress Ino2/Ino4-dependent transcription (33,36,37). Defective PE to PC methylation in cho2 or opi3 mutants leads to PA accumulation and, accordingly, to derepression of phospholipid biosynthetic genes, in particular INO1, which encodes inositol 3-phosphate synthase, the most highly regulated gene in this regulatory circuit (38,39).…”

mentioning

confidence: 99%

S-Adenosyl-L-homocysteine Hydrolase, Key Enzyme of Methylation Metabolism, Regulates Phosphatidylcholine Synthesis and Triacylglycerol Homeostasis in Yeast

Malanovic

Streith

Wolinski

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

In eukaryotes, S-adenosyl-L-homocysteine hydrolase (Sah1) offers a single way for degradation of S-adenosyl-L-homocysteine, a product and potent competitive inhibitor of S-adenosyl-L-methionine (AdoMet)-dependent methyltransferases. De novophosphatidylcholine(PC)synthesisrequiresthreeAdoMetdependent methylation steps. Here we show that down-regulation of SAH1 expression in yeast leads to accumulation of S-adenosyl-L-homocysteine and decreased de novo PC synthesis in vivo. This decrease is accompanied by an increase in triacylglycerol (TG) levels, demonstrating that Sah1-regulated methylation has a major impact on cellular lipid homeostasis. TG accumulation is also observed in cho2 and opi3 mutants defective in methylation of phosphatidylethanolamine to PC, confirming that PC de novo synthesis and TG synthesis are metabolically coupled through the efficiency of the phospholipid methylation reaction. Indeed, because both types of lipids share phosphatidic acid as a precursor, we find in cells with down-regulated Sah1 activity major alterations in the expression of the INO1 gene as well as in the localization of Opi1, a negative regulatory factor of phospholipid synthesis, which binds and is retained in the endoplasmic reticulum membrane by phosphatidic acid in conjunction with VAMP/ synaptobrevin-associated protein, Scs2. The addition of homocysteine, by the reversal of the Sah1-catalyzed reaction, also leads to TG accumulation in yeast, providing an attractive model for the role of homocysteine as a risk factor of atherosclerosis in humans.

show abstract

The emergence of yeast lipidomics

Cited by 71 publications

References 162 publications

Interruption of Inositol Sphingolipid Synthesis Triggers Stt4p-dependent Protein Kinase C Signaling

Interruption of Inositol Sphingolipid Synthesis Triggers Stt4p-dependent Protein Kinase C Signaling

Regulation of phospholipid synthesis in yeast

S-Adenosyl-L-homocysteine Hydrolase, Key Enzyme of Methylation Metabolism, Regulates Phosphatidylcholine Synthesis and Triacylglycerol Homeostasis in Yeast

Contact Info

Product

Resources

About