ATG9A and ARFIP2 cooperate to regulate PI4P levels for lysosomal repair
业务
细胞生物学
化学
生物
作者
Stefano De Tito,Eugènia Almacellas,Daniel Dai Yu,Wenxin Zhang,Elaine Millard,Javier H. Hervás,Enrica Pellegrino,Ioanna Panagi,Ditte Fodge,Teresa L. M. Thurston,Maximiliano G. Gutiérrez,Sharon A. Tooze
标识
DOI:10.1101/2024.07.23.604321
摘要
Lysosome damage activates multiple pathways to prevent lysosome-dependent cell death, including a repair mechanism involving ER-lysosome membrane contact sites, phosphatidylinositol 4-kinase-2a (PI4K2A), phosphatidylinositol-4 phosphate (PI4P) and oxysterol-binding protein-related proteins (ORPs), lipid transfer proteins. PI4K2A localizes to 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 ORP-dependent lipid transfer and promoting retrieval of ATG9A vesicles through recruitment of the adaptor protein complex-3 (AP-3). Our results reveal a role for mobilized ATG9A vesicles and ARFIP2 in lysosome homeostasis after damage and bacterial infection.