The ultrastructural organization of endoplasmic reticulum-plasma membrane contacts is conserved in epithelial cells

Contacts between the endoplasmic reticulum and the plasma membrane (ER-PM contacts) have important roles in membrane lipid and calcium dynamics, yet their organization in polarized epithelial cells has not been thoroughly described. Here we examine ER-PM contacts in hepatocytes in mouse liver using electron microscopy, providing the first comprehensive ultrastructural study of ER-PM contacts in a mammalian epithelial tissue. Our quantitative analyses reveal strikingly distinct ER-PM contact architectures spatially linked to apical, lateral, and basal PM domains. Notably, we find that an extensive network of ER-PM contacts exists at lateral PM domains that form intercellular junctions between hepatocytes. Moreover, the spatial organization of ER-PM contacts is conserved in epithelial spheroids, suggesting that ER-PM contacts may serve conserved roles in epithelial cell architecture. Consistent with this notion, we show that ORP5 activity at ER-PM contacts modulates the apical-basolateral aspect ratio in HepG2 cells. Thus ER-PM contacts have a conserved distribution and crucial roles in PM domain architecture across epithelial cell types.