SCAMP5 regulates AP-4-dependent sorting and trafficking of ATG9A for presynaptic autophagy via PI4KB/PI4KIIIβ recruitment and PtdInsP4 production at the TGN.

Neuronal autophagosome formation at distant presynaptic sites relies on ATG9A trafficking, a process mediated by AP-4 at the trans-Golgi network (TGN), but the molecular mechanisms governing its sorting for presynaptic delivery have remained elusive. Here, we uncover an unexpected role for SCAMP5, a key regulator of synaptic vesicle dynamics, in orchestrating presynaptic macroautophagy/autophagy through its actions at the TGN. SCAMP5 depletion severely impairs autophagosome formation at presynaptic boutons. Mechanistically, we identify SCAMP5 as a novel binding partner of PI4KB/PI4KIIIβ (phosphatidylinositol 4-kinase beta), where it controls PI4KB recruitment to the TGN and subsequent phosphatidylinositol-4-phosphate (PtdIns4P) production. As PtdIns4P is essential for AP-4 recruitment, SCAMP5 depletion disrupts AP-4-mediated ATG9A trafficking to presynaptic sites, thereby compromising presynaptic autophagy and subsequent protein turnover. Our findings establish that SCAMP5 coordinates ATG9A-dependent presynaptic autophagy through PI4KB recruitment and PtdIns4P production at the TGN, revealing a novel pathway critical for maintaining presynaptic protein homeostasis.