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The endoplasmic reticulum (ER) forms direct membrane contact sites with the plasma membrane (PM) in eukaryotic cells. These ER-PM contact sites play essential roles in lipid homeostasis, ion dynamics, and cell signaling, which are carried out by protein-protein or protein-lipid interactions. Distinct tethering factors dynamically control the architecture of ER-PM junctions in response to intracellular signals or external stimuli. The physiological roles of ER-PM contact sites are dependent on a variety of regulators that individually or cooperatively perform functions in diverse cellular processes. This review focuses on proteins functioning at ER-PM contact sites and highlights the recent progress in their mechanisms and physiological roles.

The endoplasmic reticulum (ER)-plasma membrane (PM) contact sites (EPCSs) are structurally conserved in eukaryotes. The Arabidopsis ER-anchored synaptotagmin 1 (SYT1), enriched in EPCSs, plays a critical role in plant abiotic stress tolerance. It has become clear that SYT1 interacts with PM to mediate ER-PM connectivity. However, whether SYT1 performs additional functions at EPCSs remains unknown. Here, we report that SYT1 efficiently transfers phospholipids between membranes. The lipid transfer activity of SYT1 is highly dependent on phosphatidylinositol 4,5-bisphosphate [PI(4,5)P 2 ], a signal lipid accumulated at the PM under abiotic stress. Mechanically, while SYT1 transfers lipids fundamentally through the synaptotagmin-like mitochondrial-lipid-binding protein (SMP) domain, the efficient lipid transport requires the C2A domain-mediated membrane tethering. Interestingly, we observed that Ca 2+ could stimulate SYT1-mediated lipid transport. In addition to PI(4,5)P 2 , the Ca 2+ activation requires the phosphatidylserine, another negatively charged lipid on the opposed membrane. Together, our studies identified Arabidopsis SYT1 as a lipid transfer protein at EPCSs and demonstrated that it takes conserved as well as divergent mechanisms with other extend-synaptotagmins. The critical role of lipid composition and Ca 2+ reveals that SYT1-mediated lipid transport is highly regulated by signals in response to abiotic stresses.