Linking proteostasis and lipid metabolism maintains cellular FITness

Lipid droplets originate from the endoplasmic reticulum (ER) and are the main organelles for storing neutral lipids inside the cell. Fat storage-inducing transmembrane (FIT) proteins have known roles in the formation of lipid droplets, but there is still a great deal to learn about how lipid droplet formation and FIT proteins influence cellular physiology. In this study, Guillaume Thibault and colleagues (Yap et al., 2020) carry out detailed genetic and biochemical analyses to investigate the function of the yeast FIT2 homologs SCS3 and YFT2 (collectively ScFIT). They first establish that in the absence of Ire1, the sole inducer of the unfolded protein response (UPR) in yeast, Scs3 is essential for cell viability. Using a conditional temperature sensitive scs3 allele allows them to reveal that the loss of Scs3 leads to accumulation of triacylglycerol in the ER in cells devoid of a functional UPR, confirming its key role in lipid metabolism. Furthermore, Scs3 is required to maintain lipid droplet morphology and phospholipid homeostasis. The authors then screen for ScFIT interactors and, surprisingly, find multiple proteostasis machinery components. Indeed, ScFIT mutants display a global reduction in ubiquitylated proteins and an impaired clearance of ER degradation pathway (ERAD) proteins. Taken together, these findings suggest a model where ScFIT proteins not only influence lipid homeostasis at the ER, but also play a role in ER stress pathways and protein quality control.