The non-fusogenic Sec22b–Stx1 SNARE complex has been shown to be involved in plasma membrane (PM) expansion and neurite growth by promoting endoplasmic reticulum (ER)–PM contacts at growth cones. However, the underlying mechanism is still not completely understood. Now, Thierry Galli and colleagues (Gallo et al., 2020) show that the ER lipid-transfer proteins (LTPs) extended synaptotagmins (E-Syts) interact with the Sec22b–Stx1 complex to control neurite growth. By using super-resolution microscopy, the authors show that Sec22b and E-Syts are in close proximity in neurites. The N-terminal longin domain of Sec22b regulates the interaction with E-Syts. Overexpression of E-Syts in HeLa cells increases the proximity of complexes between Sec22b and Stx3, a closely related homologue of Stx1, whereas simultaneous knockdown of the three E-Syt isoforms (E-Syt1, E-Syt2 and E-Syt3) results in decreased proximity. In addition, overexpression of E-Syt2 in HeLa cells and cultured neurons induces formation of filopodia, which is dependent on its lipid-transfer and ER-binding capacities. Finally, inhibiting the interaction between Sec22b and Stx1, or increasing their distance within the complex, which both reduce the proximity between the ER and the PM, abolishes filopodia formation in cultured neurons. Together, these data unveil a new interaction between LTPs and non-fusogenic SNARE complexes that is important for PM expansion and axonal growth.
