Septins in the Middle—Makers and Breakers of Membrane Contact Sites

Intracellular communication in neurons requires precise coordination of signals across geometrically complex and highly compartmentalized cellular architectures. Membrane contact sites (MCS)-specialized junctions where two organelles are closely apposed without undergoing fusion-have emerged as key organizational hubs enabling efficient exchange of ions, lipids, and metabolites, yet the cytoskeletal proteins that organize and regulate these junctions remain poorly understood. Here, we review evidence that septins-a conserved family of heteromeric GTP-binding proteins that assemble into filamentous oligomers and polymers-function as integral components of MCS in neurons and beyond. Septins associate with hyperboloid, hourglass-shaped membrane curvatures and distinct membrane domains and organelles through polybasic motifs, amphipathic helices, and transmembrane domains. We review how septins establish diffusion barriers at endoplasmic reticulum (ER)-plasma membrane (PM) contacts in budding yeast and consider evidence that analogous mechanisms operate at dendritic branch points and spine necks in mammalian neurons. We examine septin roles in regulating store-operated calcium entry at ER-PM contacts and explore how septins regulate membrane contacts at presynaptic active zones. Additionally, we highlight how septins organize membrane contacts between host organelles and intracellular pathogens, scaffolding autophagic, mitochondrial, and lysosomal membranes for bacterial clearance. Collectively, these findings support the view that septins constitute a versatile and underappreciated class of MCS tethers whose paralog- and isoform-specific complex compositions may confer spatial and functional selectivity for distinct MCS, opening new avenues for understanding organelle connectivity in health and disease.