Phospholipids and the Unfolded Protein Response

In evolutionary distant organisms, like yeast and mammals, the endoplasmic reticulum (ER) and mitochondria retain a unique composition of phospholipids and proteins to maintain organelle structure and function. Organellar phospholipid biosynthesis and remodeling are essential for protein synthesis, folding and secretion. Notably, proteotoxic and phospholipid bilayer stress has been associated with several pathologies such as cancer, obesity, diabetes and hepatic disorders. To restore homeostasis, a specialized transcriptional response, known as the unfolded protein response (UPR), is initiated upon ER (UPR^ER) or mitochondrial (UPR^mt) stress. While UPR^ER and UPR^mt sensing of unfolded protein accumulation has received much attention, how phospholipid bilayer stress is perceived and how it subsequently engages UPR signaling remain less understood. Indeed, both unfolded proteins and phospholipid bilayer stress engender a unique UPR-mediated transcriptional outcome. In turn, UPR activation has been reported to regulate phospholipid abundance. In this chapter, we survey recent findings on phospholipid biosynthesis and UPR signaling that highlight their extensive crosstalk and mutual regulation.