Multiple endoplasmic reticulum-to-nucleus signaling pathways coordinate phospholipid metabolism with gene expression by distinct mechanisms.

In many organisms the coordinated synthesis of membrane lipids is controlled by feedback systems that regulate the transcription of target genes. However, a complete description of the transcriptional changes that accompany the remodeling of membrane phospholipids has not been reported. To identify metabolic signaling networks that coordinate phospholipid metabolism with gene expression, we profiled the sequential and temporal changes in genome-wide expression that accompany alterations in phospholipid metabolism induced by inositol supplementation in yeast. This analysis identified six distinct expression responses, which included phospholipid biosynthetic genes regulated by Opi1p, endoplasmic reticulum (ER) luminal protein folding chaperone and oxidoreductase genes regulated by the unfolded protein response pathway, lipid-remodeling genes regulated by Mga2p, as well as genes involved in ribosome biogenesis, cytosolic stress response, and purine and amino acid metabolism. We also report that the unfolded protein response pathway is rapidly inactivated by inositol supplementation and demonstrate that the response of the unfolded protein response pathway to inositol is separable from the response mediated by Opi1p. These data indicate that altering phospholipid metabolism produces signals that are relayed through numerous distinct ER-to-nucleus signaling pathways and, thereby, produce an integrated transcriptional response. We propose that these signals are generated in the ER by increased flux through the pathway of phosphatidylinositol synthesis.