And three’s a party: lysosomes, lipid droplets, and the ER in lipid trafficking and cell homeostasis

Sterols and fatty acids (FAs) are essential lipids that play fundamental roles in membrane dynamics and cellular homeostasis. Synthesized at the endoplasmic reticulum (ER) and cytoplasm, trafficked by proteins, and stored in lipid droplets (LDs), much work has been conducted examining how these lipids are shuttled from one location to another. Recent work has highlighted the importance of inter-organelle crosstalk in the regulation of sterol and FA homeostasis. In particular, three organelles—lysosomes, LDs, and the ER network—function together to regulate sterol subcellular distribution and utilization. This tri-organelle crosstalk also drives adaptions to stress and protects against FA-induced lipotoxicity. Here, we highlight recent work revealing how this unique organelle trio function together. We also discuss how LDs can modulate lysosome signaling to control growth, autophagy, and ER homeostasis.