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Updated: Sep 19, 2025

Author Spotlight: Imaging ATG9A, a Multi-Spanning Membrane Protein
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Author Spotlight: Imaging ATG9A, a Multi-Spanning Membrane Protein

Published on: June 16, 2023

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ATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair

Stefano De Tito1, Eugenia Almacellas1, Daniel Dai Yu1

  • 1Molecular Cell Biology of Autophagy Laboratory, The Francis Crick Institute, London, UK.

Developmental Cell
|June 3, 2025
PubMed

Insights

Mobilized ATG9A vesicles deliver PI4K2A to damaged lysosomes, preventing cell death. ARFIP2 on these vesicles balances lipid transfer and aids vesicle retrieval, maintaining lysosome homeostasis during damage and infection.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Lysosome damage can trigger cell death pathways.
  • Endoplasmic reticulum (ER)-lysosome contact sites are involved in lysosome repair.
  • Phosphatidylinositol 4-kinase-2a (PI4K2A) is crucial for this repair but its delivery to damaged lysosomes is unclear.

Purpose of the Study:

  • To investigate the mechanism of PI4K2A delivery to damaged lysosomes.
  • To elucidate the role of ATG9A vesicles in lysosome repair.
  • To understand the function of ARFIP2 in lysosome homeostasis.

Main Methods:

  • Cellular imaging and microscopy techniques.
  • Genetic manipulation of ATG9A and ARFIP2.
  • Analysis of lipid transfer proteins and membrane contact sites.

Main Results:

  • ATG9A-containing vesicles deliver PI4K2A to damaged lysosomes during sterile damage and bacterial infection.
  • ARFIP2 binds and sequesters PI4P on lysosomes, regulating lipid transfer.
  • ARFIP2 recruits AP-3, promoting ATG9A vesicle retrieval.

Conclusions:

  • Mobilized ATG9A vesicles are essential for delivering PI4K2A to damaged lysosomes.
  • ARFIP2 plays a key role in balancing lysosome repair and vesicle trafficking.
  • These findings reveal a novel mechanism for maintaining lysosome homeostasis after damage and infection.
Keywords:
AP-3ARFIP2ATG9API4K2API4Pautophagylysosomal damagelysosomemembrane trafficking

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