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Journal Club

NPC1 regulates the distribution of phosphatidylinositol 4-kinases at Golgi and lysosomal membranes

EMBO J (2021)e105990



The lysosomal Niemann-Pick Type C1 (NPC1) transporter is essential for the egress of cholesterol from the lysosome to other cellular membranes. This study shows that NPC1 tunes the composition of Golgi-endoplasmic reticulum (ER) and lysosome-ER membrane contact sites (MCS) to regulate intracellular trafficking and growth signaling in mammalian cells.

  • Phosphatidylinositol 4-phosphate (PtdIns4P) levels are increased at Golgi and lysosomal membranes in NPC1 patient-derived cells and in the brain of an NPC1 mouse model.

  • High levels of PtdIns4P are due to increased recruitment of PI4KIIα and PI4KIIIβ kinases at Golgi and lysosomal membranes.

  • Palmitoyl acyltransferase DHHC3 and multi-functional adaptor protein ACBD3 mediate recruitment of PI4KIIα and PI4KIIIβ to Golgi-ER and lysosome-ER MCS.

  • PtdIns4P increases anterograde secretion from the Golgi, and mTORC1 recruitment to lysosomes.

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