Lipid Sorting and Organelle Identity

Abstract

The sorting and trafficking of lipids between organelles gives rise to a dichotomy of bulk membrane properties between organelles of the secretory and endolysosome networks, giving rise to two "membrane territories" based on differences in lipid-packing density, net membrane charge, and bilayer leaflet asymmetries. The cellular organelle membrane dichotomy emerges from ER-to-PM anterograde membrane trafficking and the synthesis of sphingolipids and cholesterol flux at the trans-Golgi network, which constitutes the interface between the two membrane territories. Organelle homeostasis is maintained by vesicle-mediated retrieval of bulk membrane from the distal organelles of each territory to the endoplasmic reticulum or plasma membrane and by soluble lipid transfer proteins that traffic particular lipids. The concept of cellular membrane territories emphasizes the contrasting features of organelle membranes of the secretory and endolysosome networks and the essential roles of lipid-sorting pathways that maintain organelle function.

Figure 1.

The membrane territories of a cell. The diagram depicts the organization, key membrane properties, and membrane and lipid trafficking pathways that establish and maintain the membrane territories of the cell. The endoplasmic reticulum (ER), cis, and medial cisternae of the Golgi apparatus constitute the “ER territory” and the trans-Golgi network (TGN), plasma membrane (PM), and endolysosome organelles comprise the PM territory. The organelle membranes of the ER territory are characterized by their symmetry (i.e., the composition of each membrane leaflet is the same), relatively low-density lipid packing, and relatively low amounts of cholesterol and sphingolipids. In contrast, the organelle membranes of the PM territory are asymmetric, with the exofacial (outer) leaflet (dark blue) enriched in complex sphingolipids and the inner leaflet (red) containing negatively charged lipids, notably phosphatidylserine (PS) and phosphoinositides. PS is produced in the ER membrane, but it accumulates in the exofacial/lumenal leaflet until PS flippases, which localize to organelles of the PM territory, transfer PS from the exofacial leaflet to the cytoplasmic leaflet. Membrane recycling pathways are indicated that are used to return PM-derived lipids from the endosome to the PM. In the ER territory, the coatomer I vesicle coat protein complex sorts proteins and lipids into a vesicle mediated retrograde pathway that retains glycerolipids, allowing sphingolipids and cholesterol to follow anterograde membrane flow to the PM territory. Two lipids of the PM territory, cholesterol and ceramide (a building block of complex sphingolipids), are transferred from the ER to the TGN by soluble cholesterol (OSBP) and ceramide transfer proteins (CERTs) at the ER–Golgi membrane contact site.