Navigating lipid droplet proteins – part I: ER targeting routes of lipid droplet-destined membrane proteins

Lipid droplets (LDs) are cytosolic lipid storage organelles that derive from the endoplasmic reticulum (ER). Their biogenesis and function are essential for maintaining cellular lipid homeostasis and require a spatiotemporally co-ordinated recruitment of specific membrane proteins to the LD surface. Many LD-destined proteins are inserted into the ER phospholipid bilayer in a monotopic hairpin topology before they can partition to the LD monolayer. About a third of all cellular proteins enter the ER during their biogenesis, either as ER-resident or as secretory proteins. Decades of research have provided a solid understanding of which molecular machineries ensure ER targeting fidelity of transmembrane-spanning proteins. The molecular mechanisms underlying the biogenesis of LD-destined monotopic proteins, however, are only beginning to emerge. In this first part of the bipartite review 'Navigating lipid droplet proteins,' we provide an overview of the general principles underlying protein targeting to the ER. We highlight recent advances and current challenges regarding the specific mechanisms for LD-destined proteins and discuss their physiological implications. The molecular mechanisms underlying the subsequent ER-to-LD protein partitioning are at the heart of the second part of this bipartite review.