SCS3 and YFT2 Link Transcription of Phospholipid Biosynthetic Genes to ER Stress and the UPR

Abstract

The ability to store nutrients in lipid droplets (LDs) is an ancient function that provides the primary source of metabolic energy during periods of nutrient insufficiency and between meals. The Fat storage-Inducing Transmembrane (FIT) proteins are conserved ER–resident proteins that facilitate fat storage by partitioning energy-rich triglycerides into LDs. FIT2, the ancient ortholog of the FIT gene family first identified in mammals has two homologs in Saccharomyces cerevisiae (SCS3 and YFT2) and other fungi of the Saccharomycotina lineage. Despite the coevolution of these genes for more than 170 million years and their divergence from higher eukaryotes, SCS3, YFT2, and the human FIT2 gene retain some common functions: expression of the yeast genes in a human embryonic kidney cell line promotes LD formation, and expression of human FIT2 in yeast rescues the inositol auxotrophy and chemical and genetic phenotypes of strains lacking SCS3. To better understand the function of SCS3 and YFT2, we investigated the chemical sensitivities of strains deleted for either or both genes and identified synthetic genetic interactions against the viable yeast gene-deletion collection. We show that SCS3 and YFT2 have shared and unique functions that connect major biosynthetic processes critical for cell growth. These include lipid metabolism, vesicular trafficking, transcription of phospholipid biosynthetic genes, and protein synthesis. The genetic data indicate that optimal strain fitness requires a balance between phospholipid synthesis and protein synthesis and that deletion of SCS3 and YFT2 impacts a regulatory mechanism that coordinates these processes. Part of this mechanism involves a role for SCS3 in communicating changes in the ER (e.g. due to low inositol) to Opi1-regulated transcription of phospholipid biosynthetic genes. We conclude that SCS3 and YFT2 are required for normal ER membrane biosynthesis in response to perturbations in lipid metabolism and ER stress.

Salinomycin induces endoplasmic reticulum stress-mediated autophagy and apoptosis through generation of reactive oxygen species in human glioma U87MG cells

“…Accumulating evidence indicates that apoptosis is also regulated by ER stress (6,21). ER is a key organelle with protein processing, intracellular calcium storage, as well as signaling regulation functions in eukaryotic cells (31). Although the anticancer effects of salinomycin have been established in a variety of preclinical studies using many different cancer types, there are few studies on the effects of salinomycin on glioma cancer cells (6).…”

The collaborative work of droplet assembly

“…Expression of the two yeast genes in human embryonic kidney cell line promotes LD formation, and the expression of human FIT2 in yeast rescues inositol auxotrophy, a behavior of the yeast knockouts [73]. …”

Postnatal Deletion of Fat Storage-inducing Transmembrane Protein 2 (FIT2/FITM2) Causes Lethal Enteropathy

“…Fat storage-inducing transmembrane protein 2 (FIT2/ FITM2) is an evolutionarily conserved and ubiquitously expressed ER membrane protein that has been implicated in regulating cytosolic LD formation in mammals and phospholipid metabolism in the yeast Saccharomyces cerevisiae (3,4). FIT2 is part of a two-gene family with 35% identity with FIT1.…”