Phosphatidate-mediated regulation of lipid synthesis at the nuclear/endoplasmic reticulum membrane

Abstract

In yeast and higher eukaryotes, phospholipids and triacylglycerol are derived from phosphatidate at the nuclear/endoplasmic reticulum membrane. In de novo biosynthetic pathways, phosphatidate is channeled into membrane phospholipids via its conversion to CDP-diacylglycerol. Its dephosphorylation to diacylglycerol is required for the synthesis of triacylglycerol as well as for the synthesis of phosphatidylcholine and phosphatidylethanolamine via the Kennedy pathway. In addition to the role of phosphatidate as a precursor, it is a regulatory molecule in the transcriptional control of phospholipid synthesis genes via the Henry regulatory circuit. Pah1 phosphatidate phosphatase and Dgk1 diacylglycerol kinase are key players that function counteractively in the control of the phosphatidate level at the nuclear/endoplasmic reticulum membrane. Loss of Pah1 phosphatidate phosphatase activity not only affects triacylglycerol synthesis but also disturbs the balance of the phosphatidate level, resulting in the alteration of lipid synthesis and related cellular defects. The pah1Δ phenotypes requiring Dgk1 diacylglycerol kinase exemplify the importance of the phosphatidate level in the misregulation of cellular processes. The catalytic function of Pah1 requires its translocation from the cytoplasm to the nuclear/endoplasmic reticulum membrane, which is regulated through its phosphorylation in the cytoplasm by multiple protein kinases as well as through its dephosphorylation by the membrane-associated Nem1-Spo7 protein phosphatase complex. This article is part of a Special Issue entitled Endoplasmic reticulum platforms for lipid dynamics edited by Shamshad Cockcroft and Christopher Stefan.

Keywords: Diacylglycerol; Diacylglycerol kinase; Phosphatidate; Phosphatidate phosphatase; Phospholipid; Triacylglycerol.

Fig. 1.

Synthesis of phospholipids and TAG and model for the regulation of Pah1 PA phosphatase. The figure depicts the pathways for the synthesis of lipids and their precursors that occur in the nuclear/ER membrane (green), in the mitochondria (blue), and in the cytoplasm (tan). A greater detail of lipid synthetic pathways may be found elsewhere [32,33,176,234]. The phosphorylated form of Pah1 is indicated by the white circles within the ellipse surrounding Pah1 and lipid droplets are indicated by the yellow circles emanating from the nuclear/ER. Gro, glycerol; Ins, inositol; Glc, glucose; Etn, ethanolamine; P-Etn, phosphoethanolamine; Cho, choline; P-Cho, phosphocholine; LDs, lipid droplets.

Fig. 2.

Henry regulatory circuit for the PA-mediated regulation of UASINO-containing lipid synthesis genes during growth. The model depicts the regulation that occurs in the exponential and stationary phases of growth. Details are described in the text and elsewhere [32,33,37].

Fig. 3.

Phenotypes and cellular defects caused by the pah1Δ mutation.

Fig. 4.

Model for the regulation of lipid synthesis by PKA. The phosphorylations of the Nem1-Spo7 protein phosphatase complex, Pah1, and Opi1 by PKA have negative effects on their functions. The positive effect Nem1-Spo7 has on Pah1 function is attenuated (indicated by the dashed grey arrow) by its phosphorylation. The phosphorylations of Ura7, Cho1, and Cki1 have positive effects on their functions. The net effect of these phosphorylations is an increase in phospholipids (blue arrow) and a decrease in TAG (orange arrow).