Work

NSF is required for diverse endocytic modes by promoting fusion and fission pore closure in secretory cells

Year: 2026

Type: article

Abstract: The ATPase N-ethylmaleimide-sensitive factor (NSF), known for disassembling SNARE complexes, plays key roles in neurotransmitter release, neurotransmitter (AMPA, GABA, and dopamine) receptor trafficking, and synaptic plasticity, and its dysfunction or mutation is linked to neurological disorders. These roles are largely attributed to SNARE-mediated exocytosis. Here, we reveal an unexpected role for NSF: mediating diverse modes of endocytosis-including slow, fast, ultrafast, overshoot, and bulk-by driving closure of both fusion and fission pores. This function was consistently observed across large calyx nerve terminals, small hippocampal boutons, and chromaffin cells using capacitance recordings, synapto-pHluorin imaging, electron microscopy, and multi-color pore-closure imaging. Results were robust across four NSF inhibitors, gene knockout, knockdown, and mutations. Furthermore, NSF facilitates content release. These findings establish NSF as a central regulator of membrane fission, kiss-and-run fusion, endocytosis, and exo-endocytosis coupling, providing a mechanistic basis for its diverse roles in synaptic transmission, receptor trafficking, and disease.

Source: iScience

DOI: 10.1016/j.isci.2026.115510