Phosphatidate Phosphatase Plays Role in Zinc-mediated Regulation of Phospholipid Synthesis in Yeast

Soto‐Cardalda, Anibal; Fakas, Stylianos; Pascual, Florencia; Choi, Hyeon‐Son; Carman, George M.

doi:10.1074/jbc.m111.313130

Cited by 48 publications

(62 citation statements)

References 73 publications

(133 reference statements)

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“…ATP and CTP, nucleotides that serve as precursors in membrane phospholipid synthesis (5,6), inhibit PAP activity by a complex mechanism that affects catalytic efficiency and by chelation of Mg 2ϩ (57). Expression of the PAP-encoding gene PAH1 is regulated by growth phase and nutrient availability (13,58). Its expression is induced as yeast cells progress into the stationary phase when TAG synthesis is increased at the expense of membrane phospholipids (11), and the growth phase regulation is enhanced by inositol supplementation (13,58).…”

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“…Expression of the PAP-encoding gene PAH1 is regulated by growth phase and nutrient availability (13,58). Its expression is induced as yeast cells progress into the stationary phase when TAG synthesis is increased at the expense of membrane phospholipids (11), and the growth phase regulation is enhanced by inositol supplementation (13,58). The PAH1 expression is also induced when exponential phase cells are deprived of the essential mineral zinc.…”

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“…The PAH1 expression is also induced when exponential phase cells are deprived of the essential mineral zinc. Unlike the growth phase regulation, the zincmediated regulation of PAP channels its product DAG to the synthesis of phosphatidylcholine via the CDP-choline branch of the Kennedy pathway (13,58). Regulation of the PAH1 expression by growth phase and nutrient status involves transcription factors (e.g.…”

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“…The induced expression of PAH1 in the stationary phase and by nutrient status correlates with elevated levels of PAP activity, but the overall abundance of Pah1 is shown to decline (13,39,40,58). Considering that only the membrane-associated Pah1 is physiologically active, the enigmatic regulation seems to ensure that the enzyme level is appropriately controlled on the membrane to preserve PA for phospholipid synthesis and/or prevent the toxic effects of DAG (7,45).…”

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Phosphorylation Regulates the Ubiquitin-independent Degradation of Yeast Pah1 Phosphatidate Phosphatase by the 20S Proteasome

Hsieh

Han

et al. 2015

Journal of Biological Chemistry

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Background: Yeast Pah1 phosphatidate phosphatase required for triacylglycerol synthesis is subject to proteasome-mediated degradation. Results: Pah1 is degraded by the 20S proteasome in a ubiquitin-independent manner that is governed by its phosphorylation state. Conclusion: 20S proteasomal degradation of Pah1 is regulated by phosphorylation and dephosphorylation. Significance: Pah1 function in lipid metabolism is regulated by the 20S proteasome.

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Phosphorylation Regulates the Ubiquitin-independent Degradation of Yeast Pah1 Phosphatidate Phosphatase by the 20S Proteasome

Hsieh

Han

et al. 2015

Journal of Biological Chemistry

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“…The lack of DGK1 does not impart a striking phenotype under standard laboratory culture conditions, but its overexpression causes many of the pah1⌬ phenotypes that are attributed to an elevated PA content (1). Of the transcriptional (71,77) and biochemical (49, 78 -81) mechanisms that control Pah1 PA phosphatase, phosphorylation/dephosphorylation (19, 44 -48, 66, 82) has the greatest impact on the functional role of the enzyme in lipid metabolism. In this work, we showed that Dgk1 DAG kinase, which counteracts the function of Pah1 PA phosphatase in controlling the levels of PA and DAG, is also phosphorylated and regulated by CKII.…”

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Phosphorylation of Dgk1 Diacylglycerol Kinase by Casein Kinase II Regulates Phosphatidic Acid Production in Saccharomyces cerevisiae

Qiu

Hassaninasab

Han

et al. 2016

Journal of Biological Chemistry

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Edited by Dennis VoelkerIn the yeast Saccharomyces cerevisiae, Dgk1 diacylglycerol (DAG) kinase catalyzes the CTP-dependent phosphorylation of DAG to form phosphatidic acid (PA). The enzyme in conjunction with Pah1 PA phosphatase controls the levels of PA and DAG for the synthesis of triacylglycerol and membrane phospholipids, the growth of the nuclear/endoplasmic reticulum membrane, and the formation of lipid droplets. Little is known about how DAG kinase activity is regulated by posttranslational modification. In this work, we examined the phosphorylation of Dgk1 DAG kinase by casein kinase II (CKII). When phosphate groups were globally reduced using nonspecific alkaline phosphatase, Triton X-100-solubilized membranes from DGK1-overexpressing cells showed a 7.7-fold reduction in DAG kinase activity; the reduced enzyme activity could be increased 5.5-fold by treatment with CKII. Dgk1(1-77) expressed heterologously in Escherichia coli was phosphorylated by CKII on a serine residue, and its phosphorylation was dependent on time as well as on the concentrations of CKII, ATP, and Dgk1(1-77). We used site-specific mutagenesis, coupled with phosphorylation analysis and phosphopeptide mapping, to identify Ser-45 and Ser-46 of Dgk1 as the CKII target sites, with Ser-46 being the major phosphorylation site. In vivo, the S46A and S45A/S46A mutations of Dgk1 abolished the stationary phase-dependent stimulation of DAG kinase activity. In addition, the phosphorylation-deficient mutations decreased Dgk1 function in PA production and in eliciting pah1⌬ phenotypes, such as the expansion of the nuclear/endoplasmic reticulum membrane, reduced lipid droplet formation, and temperaturesensitivity.ThisworkdemonstratesthattheCKII-mediatedphosphorylation of Dgk1 regulates its function in the production of PA.The yeast 2 Dgk1 DAG 3 kinase, an integral membrane enzyme catalyzing the CTP-dependent phosphorylation of DAG to PA (1, 2), and Pah1 PA phosphatase, a peripheral membrane enzyme catalyzing the Mg 2ϩ -dependent dephosphorylation of PA to DAG (3), have emerged as key regulators of the essential lipid intermediates PA and DAG ( Fig. 1) (4, 5). PA is used for the synthesis of all membrane phospholipids via CDP-DAG (CDP-DAG Pathway) or DAG (Kennedy Pathway) and for the synthesis of TAG via DAG (4, 5) (Fig. 1). In addition, the mobilization of TAG to produce DAG and its subsequent phosphorylation to PA for the synthesis of membrane phospholipids (Fig. 1) play an important role in the growth resumption of yeast cells that exit stasis (e.g. stationary phase) (6). Moreover, PA and DAG serve as signaling molecules that control transcription, membrane proliferation, vesicular trafficking, and the activation of cell growth (7-16).Disturbing the PA/DAG balance in yeast, as caused by the lack of Pah1 PA phosphatase activity, results in the abnormal regulation of phospholipid synthesis gene expression and phospholipid content, the aberrant growth of the nuclear/ER membrane, vacuole fragmentation, a defect in lipid droplet formation, an acute se...

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Lipid biosynthesis in yeasts: A comparison of the lipid biosynthetic pathway between the model nonoleaginous yeast Saccharomyces cerevisiae and the model oleaginous yeast Yarrowia lipolytica

Fakas

2016

Engineering in Life Sciences

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Lipid biosynthesis and its regulation have been studied mostly in the nonoleaginous yeast Saccharomyces cerevisiae that serves as a model for eukaryotic cells. On the other hand, the yeast Yarrowia lipolytica has been put forward as a model for oleaginous microorganisms because its genetics is known and tools for its genetic manipulation are becoming increasingly available. A comparison of the lipid biosynthetic pathways that function in these two microorganisms shows many similarities in key biosynthetic and regulatory steps. An example is the enzyme phosphatidic acid phosphatase that controls the synthesis of triacylglycerol (TAG) in both yeasts. Controlling the TAG synthesis is crucial for metabolic engineering efforts that aim to increase the production of microbial lipids (i.e. single cell oils) because TAG comprises the final product of these processes. At the same time the comparison reveals fundamental differences (e.g. in the generation of acetyl‐CoA for lipid biosynthesis) stemming from the oleaginous nature of Y. lipolytica. These differences warranty more studies in Y. lipolytica where the biochemistry and molecular biology of oleaginicity can be further explored.

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Phosphatidate Phosphatase Plays Role in Zinc-mediated Regulation of Phospholipid Synthesis in Yeast

Cited by 48 publications

References 73 publications

Phosphorylation Regulates the Ubiquitin-independent Degradation of Yeast Pah1 Phosphatidate Phosphatase by the 20S Proteasome

Phosphorylation Regulates the Ubiquitin-independent Degradation of Yeast Pah1 Phosphatidate Phosphatase by the 20S Proteasome

Phosphorylation of Dgk1 Diacylglycerol Kinase by Casein Kinase II Regulates Phosphatidic Acid Production in Saccharomyces cerevisiae

Lipid biosynthesis in yeasts: A comparison of the lipid biosynthetic pathway between the model nonoleaginous yeast Saccharomyces cerevisiae and the model oleaginous yeast Yarrowia lipolytica

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