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Autophagy, Sep 16 2025, | https://doi.org/10.1080/15548627.2025.2559689 SCAMP5 regulates AP-4-dependent sorting and trafficking of ATG9A for presynaptic autophagy via PI4KB/PI4KIIIβ recruitment and PtdInsP4 production at the TGN

Seung Hyun Ryu ^{1 2 †}, Jungmihn Lee ^{1 †}, Unghwi Lee ^{1 3}, Kitae Kim ¹, Go-Eun Jun ¹, Jeongmin Oh¹, Sang-Eun Lee ^{1 4 *}, Sunghoe Chang^{1 2 *}

¹Department of Physiology and Biomedical Sciences, Seoul National University College of Medicine, Seoul, South Korea.
²Interdisciplinary Program in Neuroscience, Seoul National University, Seoul, South Korea.
³Department of Biochemistry and Biophysics, Kavli Institute for Fundamental Neuroscience, University of California, San Francisco, CA, USA.
⁴Department of Life Sciences, CHA University, Seongnam-si, Gyeonggi-do, South Korea.

^†These authors contributed equally
^*Corresponding authors: correspondence to Sang-Eun Lee or Sunghoe Chang

Abstract

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.

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