Yeast FIT2 homolog is necessary to maintain cellular proteostasis by regulating lipid homeostasis

Lipid droplets (LDs) have long been regarded as inert cytoplasmic organelles with the primary function of housing excess intracellular lipids. More recently, LDs have been strongly implicated in conditions of lipid and protein dysregulation. The fat storage inducing transmembrane (FIT) family of proteins comprises of evolutionarily conserved endoplasmic reticulum (ER)-resident proteins that have been reported to induce LD formation. Here, we establish a model system to study the role ofS. cerevisiae FIThomologues (ScFIT),SCS3andYFT2, in proteostasis and stress response pathways. While LD biogenesis and basal ER stress-induced unfolded protein response (UPR) remain unaltered inScFITmutants,SCS3was found to be essential for proper stress-induced UPR activation and for viability in the absence of the sole yeast UPR transducer IRE1. Devoid of a functional UPR,scs3mutants exhibited accumulation of triacylglycerol within the ER along with aberrant LD morphology, suggesting a UPR-dependent compensatory mechanism for LD maturation. Additionally,SCS3was necessary to maintain phospholipid homeostasis. Strikingly, the absence of the ScFIT proteins results in the downregulation of the closely-related Heat Shock Response (HSR) pathway. In line with this observation, global protein ubiquitination and the turnover of both ER and cytoplasmic misfolded proteins is impaired inScFITcells, while a screen for interacting partners of Scs3 identifies components of the proteostatic machinery as putative targets. Taken together, these suggest that ScFIT proteins may modulate proteostasis and stress response pathways with lipid metabolism at the interface between the two cellular processes.