biostudies-literatureUnknownDe Tito SCancer Research UKEuropean Research CouncilMedical Research CouncilDutch Research Council (NWO)Wellcome TrustBiotechnology and Biological Sciences Research CouncilLysosome 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 Developmental cellS1534-5807(25)00318-1https://www.ebi.ac.uk/biostudies/studies/S-EPMC7617826biostudies-literatureATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair.PMC7617826BB/R011834/1788708CC2081CC2134184.034.014de Heus CPellegrino EDe Tito SAlmacellas EHervas JHKlumperman JTooze SAZhang WDai Yu DGutierrez MMillard EThurston TLMPanagi IFogde DQueval CfalseATG9A and ARFIP2 cooperate to control PI4P levels for lysosomal repair.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 2025-01-01T00:00:00Z2025 May2026-06-02T08:44:41.426Z2026-04-16T03:12:48.362ZS-EPMC76178264046083510.1016/j.devcel.2025.05.007