Self-organization of apical membrane protein sorting in epithelial cells

Abstract

Polarized epithelial cells are characterized by the asymmetric distribution of proteins between apical and basolateral domains of the plasma membrane. This asymmetry is highly conserved and is fundamental to epithelial cell physiology, development, and homeostasis. How proteins are segregated for apical or basolateral delivery, a process known as sorting, has been the subject of considerable investigation for decades. Despite these efforts, the rules guiding apical sorting are poorly understood and remain controversial. Here, we consider mechanisms of apical membrane protein sorting and argue that they are largely driven by self-organization and biophysical principles. The preponderance of data to date is consistent with the idea that apical sorting is not ruled by a dedicated protein-based sorting machinery and relies instead on the concerted effects of oligomerization, phase separation of lipids and proteins in membranes, and pH-dependent glycan interactions.

Keywords: V-ATPase; apical sorting; epithelial cell; oligomerization; zebrafish.

Figure 1.. Biophysical principles of apical sorting in polarized epithelial cells.

(A) Phase separation of cholesterol (orange groups), saturated sphingolipids (blue membrane) and glycolipids (purple groups) promote the formation of lipid rafts. Greater lateral packing and bilayer thickness of lipid rafts results in higher affinity of membrane proteins with longer transmembrane domains (dark grey rectangles). Lipid modifications, including GPI-anchors (light blue groups) and palmitoylation (not depicted), also increase cargo affinity with lipid rafts to promote apical sorting. (B) Luminal acidification of the TGN by the V-H⁺ATPase is required for biosynthetic sorting of O-glycosylated membrane proteins. This may be facilitated by protonation of acidic glycan chains (gray branches) to promote CCIs of glycans. Membrane lipid composition may also enhance apical sorting through interactions with transmembrane domains. (C) Many features of apical sorting, such as lipid rafts, V-H⁺ATPase activity, and oligomerization, also promote membrane remodeling that may act in budding and carrier formation.