ArticleThe EMBO journal2021
NPC1 regulates the distribution of phosphatidylinositol 4-kinases at Golgi and lysosomal membranes.
Article in The EMBO journal, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 31 citations in OpenAlex.
- E-Syt1 recruits PI4KA to endoplasmic reticulum-plasma membrane junctions to enhance PI4P synthesis.Science China. Life sciences · 2026Article
- Subcellular Cartography of the Phosphoinositide Multiverse.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2026Review
- A clickable CoQ imaging probe reveals that cellular uptake and lysosomal trafficking depend on CD36 and NPC1.Redox biology · 2026Article
- Mass spectrometry-based lipid analysis in NPC1 disease: Methods for phosphoinositide quantification, lipid imaging, and myelin lipid profiling.Methods in enzymology · 2026Article
- Article
- Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.Nature communications · 2025Article
- Lysosome heterogeneity and diversity mapped through its distinct cellular functions.Cellular and molecular life sciences : CMLS · 2025Review
- Advances in mass spectrometry of lipids for the investigation of Niemann-pick type C disease.Lipids in health and disease · 2025Review
- Unveiling the crossroads of STING signaling pathway and metabolic reprogramming: the multifaceted role of the STING in the TME and new prospects in cancer therapies.Cell communication and signaling : CCS · 2025Review
- Unifying biology of neurodegeneration in lysosomal storage diseases.Journal of inherited metabolic disease · 2025Review
- Endo-lysosomal dysfunction and neuronal-glial crosstalk in Niemann-Pick type C disease.Philosophical transactions of the Royal Society of London. Series B, Biological sciences · 2024Review
- Phosphoinositide switches in cell physiology - From molecular mechanisms to disease.The Journal of biological chemistry · 2024Review
- Unraveling the Connection: Cholesterol, Calcium Signaling, and Neurodegeneration.Neuroscience insights · 2024Article
- PI4P STimulatING innate immune activation: beyond the Golgi.Cellular & molecular immunology · 2023Article
- Niemann-Pick Disease Type C (NPDC) by Mutation ofAntioxidants (Basel, Switzerland) · 2023Review
- NPC1-dependent alterations in KNature communications · 2023Article
- CaAdvances in experimental medicine and biology · 2023Article
- Alterations in Cholesterol and Phosphoinositides Levels in the Intracellular Cholesterol Trafficking Disorder NPC.Advances in experimental medicine and biology · 2023Article
- Phosphoinositide transport and metabolism at membrane contact sites.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2022Review
- Impaired Retromer Function in Niemann-Pick Type C Disease Is Dependent on Intracellular Cholesterol Accumulation.International journal of molecular sciences · 2021Article
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
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-PI4KIIα and PI4KIIIβ-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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Registered trials
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