Multiple Endoplasmic Reticulum‐Localized Protein Complexes Respond to Phospholipid Metabolism and Regulate Gene Expression by Distinct Mechanisms

Abstract

Recent work has shown that the addition of inositol to growing yeast cells induces a rapid and profound alteration in the pattern of synthesis and turnover of the major membrane phospholipids, which results in the repression of phospholipid biosynthetic genes. In the present study we extended this work by profiling changes in genome-wide expression that accompany alterations in phospholipid metabolism induced by inositol supplementation. We observed multiple expression patterns for distinct sets of genes responding to signals emanating from the endoplasmic reticulum (ER), the major site of phospholipid synthesis. One set included genes that are regulated by the transcription factor Opi1p, a transcription factor that directly senses changes in phosphatidic acid levels induced by changes in phospholipid metabolism. Another set included genes important for ER homeostasis that are regulated by the unfolded protein response (UPR) pathway. Both sets of genes are rapidly repressed upon inositol supplementation; however, we show that the UPR response is separable from the one mediated by Opi1p. Finally, we detected a novel response from another set of genes important for membrane remodeling. We show that this response is specifically regulated by Mga2p, a transcription factor that is synthesized as an inactive precursor in the ER, but whose soluble form is transcriptionally active, and we show that this responsive is mediated through the LORE element found in the promoters of this set of genes. Overall, these results indicate that altering membrane lipid composition has acute effects on global gene expression patterns and suggest that the interplay among several distinct ER membrane-localized signaling pathways contributes to this response. The work was supported by NIH grant GM19629 to SAH.