Molecular mechanisms of inter-organelle ER–PM contact sites

Observed for decades by electron microscopy but mostly ignored, inter-organelle membrane contact sites (MCSs) are now emerging as major sites for the exchange of cellular components in eukaryotic cells. Although new MCSs are continually characterized, those formed between the endoplasmic reticulum (ER) and the plasma membrane (PM) are currently the best defined. Here, we focus on ER–PM contact sites as a model system for understanding the molecular mechanisms that govern inter-organelle junctions. Through tight inter-organelle tethering, ER–PM proteins generate a unique microenvironment optimized for processes like lipid and ion transport. Several MCS proteins also boast potential membrane remodeling domains, which may promote curvature and lipid transfer between juxtaposed bilayers. Finally, we discuss challenges and future directions for the MCS field.