September 19, 2025 - Seminar -Tweek/LPD-3-Mediated ER-PM Contact Site Formation Facilitates Lipid Transfer and Glial Phagocytosis during Neuronal Remodeling

Published: Sept. 8, 2025
Kang

Yunsik Kang, Ph.D.

Abstract

Neuronal remodeling during development produces substantial cellular debris, which glial cells must phagocytose to maintain tissue homeostasis and guide proper circuit formation. In Drosophila, astrocytes transform into phagocytes during the larva-to-adult transition, phagocytosing synaptic, axonal, and dendritic debris. We show that Tweek, a bridge-like lipid transfer protein (BLTP), is essential for endoplasmic reticulum (ER)- plasma membrane (PM) contact formation in astrocytes, facilitating the lipid transfer required for phagocytic function. Loss of Tweek disrupts lipid distribution and ER-PM contacts, and mutations in the mammalian homolog of Tweek (BLTP1), linked to Alkuraya-Kucinskas syndrome, result in similar defects in phagocytosis. Structural studies of the C. elegans Tweek homolog, LPD-3, reveal an elongated lipid-filled tunnel coordinated by ionizable residues, along with two interacting  proteins,  Intake  and  Spigot,  that  regulate  lipid  entry  and  ER-PM  contact formation, respectively. This work provides structural and mechanistic insights into the conserved role of Tweek/LPD-3/BLTP1 in lipid transfer and glial phagocytosis, establishing a foundation for further studies of BLTPs.