ER-PM contacts regulate apical domain formation in hepatocytes

Apico-basal membrane polarity is fundamental for epithelial cell development and function. Polarity factors including the small GTPase Cdc42, the Par3/Par6/aPKC complex, and cytoskeletal proteins are recruited by the anionic lipids phosphatidylinositol 4,5-bisphosphate and phosphatidylserine. But how these lipids accumulate at polarised sites remains unclear. We have examined roles of contacts between the endoplasmic reticulum and plasma membrane (ER-PM contacts) in generating lipid gradients during apical domain formation. Comprehensive electron microscopy analyses in hepatocytes and epithelial spheroids revealed two distinct ER-PM contact architectures that are spatially linked to apical and baso-lateral domains. Moreover, apical domain formation was delayed in HepG2 cells upon modulating the ER-PM contact proteins E-Syt1 and ORP5. We propose ER-PM contacts regulate apico-basal polarity via the lipid transfer proteins E-Syt1 and ORP5. Importantly, our findings suggest that the spatial organisation of ER-PM contacts is a conserved feature of polarised epithelial cells.