Lipidome remodeling in response to nutrient replenishment requires the tRNA modifier Deg1/Pus3 in yeast

Abstract

In the yeast Saccharomyces cerevisiae, the absence of the pseudouridine synthase Pus3/Deg1, which modifies tRNA positions 38 and 39, results in increased lipid droplet (LD) content and translational defects. In addition, starvation‐like transcriptome alterations and induced protein aggregation were observed. In this study, we show that the deg1 mutant increases specific misreading errors. This could lead to altered expression of the main regulators of neutral lipid synthesis which are the acetyl‐CoA carboxylase (Acc1), an enzyme that catalyzes a key step in fatty acid synthesis, and its regulator, the Snf1/AMPK kinase. We demonstrate that upregulation of the neutral lipid content of LD in the deg1 mutant is achieved by a mechanism operating in parallel to the known Snf1/AMPK kinase‐dependent phosphoregulation of Acc1. While in wild‐type cells removal of the regulatory phosphorylation site (Ser‐1157) in Acc1 results in strong upregulation of triacylglycerol (TG), but not steryl esters (SE), the deg1 mutation more specifically upregulates SE levels. In order to elucidate if other lipid species are affected, we compared the lipidomes of wild type and deg1 mutants, revealing multiple altered lipid species. In particular, in the exponential phase of growth, the deg1 mutant shows a reduction in the pool of phospholipids, indicating a compromised capacity to mobilize acyl‐CoA from storage lipids. We conclude that Deg1 plays a key role in the coordination of lipid storage and mobilization, which in turn influences lipid homeostasis. The lipidomic effects in the deg1 mutant may be indirect outcomes of the activation of various stress responses resulting from protein aggregation.

Key enzymes involved in the utilization of fatty acids by Saccharomyces cerevisiae: a review

“…First, fatty acyl-CoA and glycerol-3-phosphate (Glyc-3-P) synthesized lysophosphatidic acid (LPA) through G3P acyltransferases encoded by SCT1 (GAT2) and GPT2 (GAT1) in the endoplasmic reticulum ( Yasukawa et al, 2023 ), and LPA and fatty acyl-CoA formed PA through the LPA acyltransferase Slc1p/Slc4p in the endoplasmic reticulum, and then formed cytidine diphosphate diacylglycerol (CDP-DAG). CDP-DAG is a precursor for the synthesis of PL, which forms PI, PS, PE, PC under the action of celluloalcohol ( Matos et al, 2023 ). PA can be cleaved into diacylglycerol (DAG) by phospholipidase phosphatase Pah1p, which is then combined with fatty acyl-CoA to act as a storage lipid in cells ( Speer et al, 2024 ).…”