Pascual, Florencia. Regulation of the PAH1-encoded phosphatidate phosphatase and its role in lipid metabolism in yeast. Retrieved from https://doi.org/doi:10.7282/T3862DGN
DescriptionThe yeast PAH1-encoded phosphatidate phosphatase (PAP) catalyzes the penultimate step in the synthesis of triacylglycerol (TAG). PAP plays a crucial role in lipid homeostasis by controlling the relative proportions of its substrate phosphatidate (PA) and its product diacylglycerol (DAG). The cellular amounts of these lipid intermediates influence the synthesis of TAG and the pathways by which membrane phospholipids are synthesized. The importance of this enzyme is exemplified by the severe phenotypes of the pah1 mutant that include deregulation of phospholipid synthesis, an aberrant expansion of the nuclear/ER membrane, a decrease in lipid droplet formation, a massive reduction in TAG content, defects in vacuole homeostasis and fusion, and increased sensitivity to lipotoxicity. On the other hand, the attenuation of PAH1-encoded PAP function is also essential to normal cell physiology. Indeed, the overexpression of an unregulated form of PA phosphatase inhibits cell growth, and this is attributed to the depletion of PA needed for phospholipid synthesis via CDP-DAG and the accumulation of DAG to a toxic level. TAG accumulates in the stationary phase of growth, and the lipid analysis of the pah1 mutant established the essential role of Pah1p PAP in this process. While Pah1p PAP activity was elevated in stationary phase cells, the expression of PAH1 mRNA and Pah1p was maximal in the exponential phase, but declined as cells entered the stationary phase. The levels of Pah1p were stabilized in stationary phase cells treated with the proteasome inhibitor MG132 as well as in several mutants that exhibit a decrease in proteasome function. Catalytic site mutant forms of Pah1p exhibited increased stability in stationary phase, indicating that the balance of PA and DAG acts as a signal for the degradation of the enzyme. Additionally, Pah1p levels were also stabilized in cells overexpressing DGK1, pointing to PA as a possible regulator of Pah1p stability. This work reveals a novel mechanism for the control of Pah1p PAP function in yeast.