ATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair
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Stefano De Tito Eugenia AlmacellasiCanals Daniel Dai Yu Emily Millard Wenxin Zhang Cecilia de Heus Christophe Queval Javier Hervas Enrica Pellegrino Ioanna Panagi Ditte Fogde Teresa LM Thurston Judith Klumperman Maximiliano Gutierrez Sharon ToozeAbstract
Lysosome damage activates multiple pathways to prevent lysosome-dependent cell death, including a repair mechanism involving endoplasmic reticulum (ER)-lysosome membrane contact sites, phosphatidylinositol 4-kinase-2a (PI4K2A), phosphatidylinositol-4 phosphate (PI4P), and oxysterol-binding protein-like proteins (OSBPLs) lipid transfer proteins. PI4K2A localizes to the trans-Golgi network and endosomes, yet how it is delivered to damaged lysosomes remains unknown. During acute sterile damage and damage caused by intracellular bacteria, we show that ATG9A-containing vesicles perform a critical role in delivering PI4K2A to damaged lysosomes. ADP ribosylation factor interacting protein 2 (ARFIP2), a component of ATG9A vesicles, binds and sequesters PI4P on lysosomes, balancing OSBPL-dependent lipid transfer and promoting the retrieval of ATG9A vesicles through the recruitment of the adaptor protein complex-3 (AP-3). Our results identify a role for mobilized ATG9A vesicles and ARFIP2 in lysosome homeostasis after damage and bacterial infection.
Journal details
Journal
Developmental Cell
Volume
60
Issue number
20
Pages
2744-2760 .e9
Available online
Publication date
Full text links
Publisher website (DOI)
10.1016/j.devcel.2025.05.007
Figshare
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Europe PubMed Central
40460835
Pubmed
40460835
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Publishing history
The publication was previously a preprint.
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