ER mediates spatial regulation of lysosome-endosome interactions via motion switch at junction sites

Membrane-bound intracellular organelles engage in extensive direct interactions through membrane contact or fusion to work together for vital physiological functions. However, how their interactions are regulated is unclear. Lysosomes, for example, interact with ER and endosomes through membrane contact or fusion/fission to receive macromolecular cargos for recycling and degradation. The interactions are thought to be spatially regulated because participating lysosomes and endosomes must be positioned in close proximity. But the mechanism of spatial regulation is unknown. In this study, we examined how individual lysosomes and endosomes move along the endoplasmic reticulum (ER) network and found primarily two modes of movement. In the fast mode they explore different regions. In the slow mode they often pause and become confined near ER junctions to come near each other for interactions. The pause and confinement of lysosomes and endosomes occur in ER regions with elevated network density and connectivity and are mediated by condensation of the actin cytoskeleton, in which the VAP-STARD3-YWHAH pathway plays a key role. Together, these results reveal that ER mediates spatial regulation of lysosome-endosome interactions. Other organelles such as lipid droplets and peroxisomes are also found to pause near ER junctions. Overall, our findings suggest a general ER-mediated mechanism for spatial regulation of organelle interactions.