期刊
EMBO JOURNAL
卷 40, 期 13, 页码 -出版社
WILEY
DOI: 10.15252/embj.2020105990
关键词
membrane contact sites; mTORC; neurodegeneration; Niemann‐ Pick Type C; phosphoinositides
资金
- Ara Parseghian Medical Research Foundation
- University of California funds
- National Institutes of Health [R01 GM127513, R01 NS109176, R01 HL06773, R01 AG063796]
- Pharmacology National Institutes of Health T32 training award [T32GM099608]
In this study, it was found that dysfunction of the lysosomal Niemann-Pick C1 (NPC1) cholesterol transporter initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4-phosphate (PtdIns4P) countertransport cycle between the Golgi-endoplasmic reticulum and lysosome-endoplasmic reticulum membrane contact sites. These disruptions in signaling pathways lead to abnormal intracellular trafficking and growth signaling.
Cholesterol and phosphoinositides (PI) are two critically important lipids that are found in cellular membranes and dysregulated in many disorders. Therefore, uncovering molecular pathways connecting these essential lipids may offer new therapeutic insights. We report that loss of function of lysosomal Niemann-Pick Type C1 (NPC1) cholesterol transporter, which leads to neurodegenerative NPC disease, initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4-phosphate (PtdIns4P) countertransport cycle between Golgi-endoplasmic reticulum (ER), as well as lysosome-ER membrane contact sites (MCS). Central to these disruptions is increased recruitment of phosphatidylinositol 4-kinases-PI4KII alpha and PI4KIII beta-which boosts PtdIns4P metabolism at Golgi and lysosomal membranes. Aberrantly increased PtdIns4P levels elevate constitutive anterograde secretion from the Golgi complex, and mTORC1 recruitment to lysosomes. NPC1 disease mutations phenocopy the transporter loss of function and can be rescued by inhibition or knockdown of either key phosphoinositide enzymes or their recruiting partners. In summary, we show that the lysosomal NPC1 cholesterol transporter tunes the molecular content of Golgi and lysosome MCS to regulate intracellular trafficking and growth signaling in health and disease.
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