Affinage

NPC1

NPC intracellular cholesterol transporter 1 · UniProt O15118

Length
1278 aa
Mass
142.2 kDa
Annotated
2026-06-10
100 papers in source corpus 34 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NPC1 is a multi-pass transmembrane lysosomal/late-endosomal protein that mediates the export of cholesterol and sphingosine from the lumen of endolysosomes, the central function whose loss defines Niemann-Pick disease type C pathology (PMID:27238017, PMID:36893262). Its cryo-EM structure resolves 13 transmembrane segments adopting a resistance-nodulation-cell division (RND) fold, with TMs 3–7 forming a sterol-sensing domain (SSD) whose central lumenal tunnel serves as the conduit for sterol passage; blocking this tunnel with itraconazole abolishes cholesterol egress (PMID:27238017, PMID:31919352). NPC1 directly binds cholesterol and oxysterols in a buried hydrophobic pocket, with an additional cysteine-rich lumenal loop-1 sterol-binding site that is dispensable for transport (PMID:17989073, PMID:19029290, PMID:17989072), and it likewise binds sphingosine, the two lipids sharing a common export mechanism (PMID:36893262). Cholesterol export depends on inter-domain conformational dynamics: engineered disulfide constraints between lumenal domains abolish transport (PMID:32410728). Egress is licensed by GTP-loaded Rab7, which is activated by the Mon1-Ccz1-C18orf8 GEF complex (PMID:33144569), and culminates in direct lysosome-to-ER cholesterol transfer at membrane contact sites tethered through the ER sterol-transport protein Gramd1b (PMID:31537798). Loss of NPC1 export function triggers mTORC1 hyperactivation that drives lysosomal proteolytic failure and defective mitophagy (PMID:33308480), while in the CNS neuronal NPC1 deficiency is cell-autonomously sufficient to cause Purkinje cell loss and arrest oligodendrocyte maturation via H3K27me3 dysregulation (PMID:21856732, PMID:23593041, PMID:37407594). The most common disease allele, I1061T, is an ER-retained misfolded protein cleared by MARCH6-dependent ERAD and FAM134B-dependent ER-phagy (PMID:30202070). Independently of its transport role, NPC1 serves as the intracellular endosomal receptor for Ebola virus, binding cleaved glycoprotein through its lumenal domain C (PMID:27238017, PMID:23202491), and as an entry factor for hepatitis A virus via the HAVCR1-NPC1 pathway (PMID:32541946).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 Medium

    Established that NPC1's cysteine-rich lumenal loop is functionally required, linking the most common disease allele I1061T to loss of cholesterol-trafficking activity rather than mislocalization at this stage.

    Evidence Site-directed mutagenesis and complementation of NPC1-deficient CHO cells with zinc-binding assay

    PMID:10942596

    Open questions at the time
    • Did not resolve whether the loop binds sterol directly
    • Mechanism of how mutants fail transport unknown at the time
  2. 2003 High

    Placed ganglioside biosynthesis genetically upstream of cholesterol sequestration in NPC1-deficient neurons, clarifying the ordering of lipid storage events.

    Evidence NPC1-/- × GalNAcT-/- double-mutant mouse genetics with in situ filipin histochemistry

    PMID:12906793

    Open questions at the time
    • Molecular link between gangliosides and cholesterol retention not defined
    • Does not address NPC1's direct transport mechanism
  3. 2007 High

    Demonstrated that NPC1 directly binds cholesterol and oxysterols and localized a sterol-binding site to lumenal loop-1, but a mutation abolishing this binding still rescued transport, showing this site is not the essential transport conduit.

    Evidence Protein purification, radioligand binding, Q79A mutagenesis, and transport complementation in NPC1-deficient CHO cells

    PMID:17989072 PMID:17989073

    Open questions at the time
    • Did not identify the actual transport-relevant sterol path
    • Relationship between loop-1 binding and overall export unresolved
  4. 2008 High

    Showed purified full-length NPC1 binds cholesterol 1:1 in a deep hydrophobic pocket competed by 25-HC, defining a shared sterol pocket.

    Evidence FLAG-affinity purification with fluorescent sterol binding and photoaffinity labeling

    PMID:19029290

    Open questions at the time
    • Pocket location relative to membrane domains not structurally resolved
    • Transport directionality not addressed
  5. 2013 High

    Identified NPC1's lumenal domain C as necessary and sufficient for filovirus receptor activity, separating a viral function from cholesterol transport.

    Evidence NPC1/NPC1L1 chimera panel with viral infection and GP binding assays

    PMID:23202491

    Open questions at the time
    • Did not map single-residue determinants
    • Relationship to host trafficking cofactors unresolved
  6. 2016 High

    Resolved the full-length NPC1 architecture, defining the 13-TM RND fold, the SSD, and the structural basis of EBOV-GP binding to domain C, providing the framework for all subsequent mechanistic interpretation.

    Evidence Single-particle cryo-EM at 4.4 Å plus crystallography of domain C and EBOV-GP binding assays

    PMID:26846330 PMID:27238017

    Open questions at the time
    • Did not capture the sterol-transporting conformational states
    • Path of cholesterol through the protein not yet defined
  7. 2016 High

    Defined how azole antifungals inhibit NPC1 by binding the SSD, providing pharmacological probes that map the transport machinery.

    Evidence Mutagenesis, U18666A competition, docking, and photoaffinity cross-linking of NPC1 in nanodiscs with P691S validation

    PMID:27994139 PMID:28103683

    Open questions at the time
    • Atomic binding pose validated structurally only later
    • Whether inhibition reflects tunnel occlusion not directly shown here
  8. 2019 High

    Established that NPC1 tethers ER–endolysosome contact sites via Gramd1b to deliver cholesterol directly to the ER, defining the downstream destination of exported sterol.

    Evidence Reciprocal Co-IP, live imaging, and artificial MCS tethering rescue in NPC1-deficient cells

    PMID:31537798

    Open questions at the time
    • Stoichiometry and directionality of Gramd1b transfer not quantified
    • How NPC1 cytoplasmic transfer couples to Gramd1b unresolved
  9. 2020 High

    Defined the SSD central tunnel as the cholesterol conduit and showed inter-domain dynamics rather than NTD dissociation drive export.

    Evidence Cryo-EM with itraconazole, efflux assays, and engineered disulfide constraints

    PMID:31919352 PMID:32410728

    Open questions at the time
    • Full conformational cycle of transport not captured
    • Energetics of lumen-to-cytoplasm transfer unresolved
  10. 2020 High

    Identified active Rab7, controlled by the Mon1-Ccz1-C18orf8 GEF, as a direct licensing factor required for NPC1-dependent cholesterol export.

    Evidence Genome-wide CRISPR screen, Co-IP, and constitutively active Rab7 rescue

    PMID:33144569

    Open questions at the time
    • How Rab7 binding triggers transport competence mechanistically unknown
    • Spatial coordination with MCS tethering unresolved
  11. 2020 High

    Placed mTORC1 hyperactivation downstream of cholesterol accumulation as the driver of lysosomal proteolytic failure and defective mitophagy.

    Evidence Lysosomal proteomics and mTORC1 genetic/pharmacological epistasis in neuronal NPC models

    PMID:33308480

    Open questions at the time
    • Molecular link from cholesterol storage to mTORC1 activation not defined
    • Whether mTORC1 inhibition rescues neuropathology untested here
  12. 2018 High

    Defined the degradation routes of the I1061T misfolded mutant, identifying MARCH6-ERAD and FAM134B ER-phagy as complementary clearance pathways.

    Evidence MARCH6 and FAM134B knockouts, fractionation, in vivo mouse and patient tissue

    PMID:30202070

    Open questions at the time
    • Relative contribution of each pathway in patient cells not quantified
    • Whether blocking degradation restores function untested
  13. 2023 High

    Showed NPC1 also directly transports sphingosine, expanding its substrate scope and explaining lysosomal sphingosine accumulation that secondarily impairs cholesterol efflux.

    Evidence Photoactivatable sphingosine probes and photoaffinity labeling in NPC1-KO cells

    PMID:36893262

    Open questions at the time
    • Whether sphingosine and cholesterol use the identical tunnel not structurally resolved
    • Order of substrate handling unknown
  14. 2023 High

    Linked neuronal/oligodendrocyte NPC1 deficiency to an epigenetic mechanism, showing impaired H3K27me3-dependent silencing arrests oligodendrocyte maturation.

    Evidence snRNA-seq, H3K27me3 chromatin analysis, and GSK-J4 / cyclodextrin rescue in Npc1-/- mice

    PMID:37407594

    Open questions at the time
    • How cholesterol storage alters H3K27me3 metabolism unresolved
    • Generality to other cell types untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NPC1's lumen-to-cytoplasm sterol handoff is energetically driven and physically coupled to NPC2 delivery, Rab7 licensing, and Gramd1b acceptor transfer into a single transport cycle remains unresolved.
  • No structure of NPC1 captured mid-transport with substrate moving through the tunnel
  • Stoichiometric coupling of accessory factors to individual transport events undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 4 GO:0001618 virus receptor activity 3 GO:0005215 transporter activity 3 GO:0140104 molecular carrier activity 2
Localization
GO:0005764 lysosome 3 GO:0005768 endosome 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 3 R-HSA-382551 Transport of small molecules 3 R-HSA-9612973 Autophagy 2
Partners
CTSDGRAMD1BHAVCR1NPC2RAB7TMEM97VAMP4
Complex memberships
ER–lysosome membrane contact site

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2016 Cryo-EM structure of full-length human NPC1 at 4.4 Å revealed 13 transmembrane segments (TMs), three distinct lumenal domains A (NTD), C, and I, with TMs 2–13 forming a resistance-nodulation-cell division (RND) fold, TMs 3–7 constituting the sterol-sensing domain (SSD), and a trimeric EBOV cleaved glycoprotein (GPcl) binding to NPC1 domain C as a monomer. Single-particle electron cryo-microscopy (cryo-EM); biochemical binding assays Cell High 27238017
2020 Cryo-EM structure of NPC1 bound to itraconazole revealed that the drug binds within a central lumenal tunnel linked to the SSD; blocking this tunnel abolishes NPC1-mediated cholesterol egress, defining the SSD tunnel as the conduit for cholesterol transport. Cryo-EM structure determination; functional cholesterol efflux assays; site-directed mutagenesis Nature communications High 31919352
2016 Crystal structure of glycosylated NPC1 luminal domain C showed all seven N-glycosylation sites occupied, mapped disease mutations to a potential NPC2-binding face, and identified four residues (H418, Q421, F502, F504) critical for Ebola virus glycoprotein interaction. X-ray crystallography; computational docking; sequence analysis FEBS letters High 26846330
2007 NPC1 binds cholesterol and oxysterols (25-, 24-, 27-hydroxycholesterol) directly; the binding site for oxysterols differs from that for cholesterol, as excess cholesterol does not compete off 25-HC binding. NPC1 is not required for known oxysterol regulatory actions on SREBP processing or ACAT. Purification of NPC1 from rabbit liver membranes (~14,000-fold); radioligand binding assays with [³H]cholesterol and [³H]25-HC; competition assays The Journal of biological chemistry High 17989073
2007 The sterol-binding site of NPC1 is localized to luminal loop-1 (a 240-amino acid cysteine-rich domain), which binds [³H]cholesterol (Kd ~130 nM) and [³H]25-HC (Kd ~10 nM) as a soluble dimer. Mutation Q79A abolishes sterol binding to loop-1 yet still restores cholesterol transport in NPC1-deficient CHO cells, indicating this binding site is not essential for NPC1's transport function in fibroblasts. Recombinant protein production; radioligand binding assays; site-directed mutagenesis (Q79A); functional cholesterol transport complementation assay in NPC1-deficient CHO cells The Journal of biological chemistry High 17989072
2019 NPC1 tethers ER–endocytic organelle membrane contact sites (MCS) by interacting with the ER-localized sterol transport protein Gramd1b, and this interaction regulates cholesterol egress from lysosomes directly to the ER across MCS. Artificially tethering MCS rescued cholesterol accumulation in NPC1-deficient cells. Loss of NPC1 or Gramd1b expanded lysosome–mitochondria MCS in a STARD3-dependent manner. Co-immunoprecipitation; live-cell imaging; MCS artificial tethering; fractionation; NPC1-deficient cell lines Nature communications High 31537798
2020 Active Rab7 (GTP-loaded) directly interacts with the NPC1 cholesterol transporter and is required to license NPC1-dependent lysosomal cholesterol export; this function is controlled by the trimeric Mon1-Ccz1-C18orf8 (MCC) GEF that activates Rab7. Loss of MCC subunits abolishes lysosomal cholesterol export and is rescued by constitutively active Rab7. Genome-wide CRISPR screen; Co-immunoprecipitation; cholesterol reporter assay; Rab7 constitutively active rescue experiments Nature communications High 33144569
2020 Loss of NPC1-mediated cholesterol export causes mTORC1 hyperactivation, which drives lysosomal proteolytic impairment, hydrolase depletion, enhanced membrane damage, and defective mitophagy; genetic and pharmacological mTORC1 inhibition restores lysosomal proteolysis without correcting cholesterol storage, placing aberrant mTORC1 downstream of cholesterol accumulation. Proteomic profiling of NPC lysosomes; genetic mTORC1 inhibition (rapamycin); lysosomal proteolysis assays; mitophagy assays; neuronal NPC models Developmental cell High 33308480
2016 The antifungal drug itraconazole directly inhibits NPC1 by binding to its sterol-sensing domain (SSD); the binding site was mapped by mutagenesis, competition with U18666A, and molecular docking. Dual inhibition of NPC1 (cholesterol trafficking) and VDAC1 (AMPK activation) synergistically inhibits mTOR signaling and angiogenesis. Pharmacological inhibition assays; site-directed mutagenesis of SSD; competition binding with U18666A; molecular docking ACS chemical biology Medium 28103683
2016 Posaconazole (a triazole antifungal) and itraconazole directly bind to the NPC1 sterol-sensing domain to block lysosomal cholesterol export; a photoactivatable posaconazole derivative cross-linked specifically to purified NPC1 in lipid bilayer nanodiscs, and cross-linking was reduced by a P691S point mutation in the SSD. Photoactivatable cross-linking with posaconazole derivative P-X; NPC1 purification into nanodiscs; site-directed mutagenesis (P691S); competition with itraconazole and U18666A Proceedings of the National Academy of Sciences of the United States of America High 27994139
2018 The most common disease-causing NPC1 mutant I1061T is degraded by two complementary pathways: MARCH6-dependent ERAD followed by proteasomal degradation, and FAM134B-dependent selective ER autophagy (ER-phagy). Subcellular fractionation in mouse tissues confirmed ER retention of I1061T NPC1. Proteasome inhibitor studies; MARCH6 knockdown/knockout; ER-phagy (FAM134B) knockout; subcellular fractionation; in vivo mouse models; human tissue samples Nature communications High 30202070
2008 Purified full-length NPC1 directly binds fluorescent cholesterol analogs (dehydroergosterol, cholestatrienol, NBD-cholesterol) with apparent affinity ~0.5–6 µM (1:1 stoichiometry); bound cholesterol is buried in a deep hydrophobic pocket. Binding is competed by native cholesterol and 25-hydroxycholesterol, confirming a shared sterol-binding site. FLAG-tag affinity purification of NPC1; fluorescence binding and quenching assays; gel filtration; photoaffinity labeling with azido-cholesterol The Journal of biological chemistry High 19029290
2020 Inter-domain dynamics of NPC1 are required for cholesterol transport: introducing single disulfide bonds to constrain lumenal domains, or shortening a cytoplasmic loop, abolishes transport activity. The N-terminal domain need not dissociate from the rest of the protein for efficient export. Ezetimibe blocks NPC1L1 transport by binding simultaneously to residues at the interface of all three extracellular domains. Site-directed disulfide bond engineering; lysosomal cholesterol efflux assay; domain truncation mutagenesis; ezetimibe binding site mapping eLife High 32410728
2006 NPC1 undergoes ubiquitylation that is regulated by endosomal cholesterol levels: cholesterol depletion promotes NPC1 ubiquitylation, while the SSD mutant P691S fails to respond. Ubiquitylated NPC1 associates with the ESCRT component SKD1/Vps4; NPC2 is required to prevent NPC1 ubiquitylation under cholesterol-rich conditions. Co-immunoprecipitation; dominant-negative SKD1 expression; cholesterol depletion experiments; site-directed mutagenesis (P691S, ΔLLNF); NPC2-deficient patient fibroblasts Journal of cell science Medium 16757520
2016 TMEM97 is a cholesterol-responsive NPC1-binding protein that post-transcriptionally regulates NPC1 abundance; reducing TMEM97 increases NPC1 levels and restores cholesterol trafficking to the ER in NPC disease cells in an NPC1-dependent manner. TMEM97 lacking its ER-retention signal fails to regulate NPC1 availability. RNA interference; Co-immunoprecipitation; cholesterol trafficking assays (filipin staining, ER cholesterol measurement); domain deletion of TMEM97 ER-retention signal Human molecular genetics Medium 27378690
2023 NPC1 directly binds sphingosine using lysosome-targeted photoactivatable sphingosine probes; absence of NPC1 causes lysosomal sphingosine accumulation. Artificial elevation of lysosomal sphingosine impairs cholesterol efflux, consistent with sphingosine and cholesterol sharing a common NPC1-mediated export mechanism. Caged, photocrosslinkable sphingosine and cholesterol probes; photoaffinity labeling; subcellular fractionation; NPC1 knockout cells Proceedings of the National Academy of Sciences of the United States of America High 36893262
2015 NPC1 aids transfer of LDL-derived cholesterol across the lysosomal glycocalyx: inhibiting O-linked glycosylation in NPC1-deficient fibroblasts reduced lysosomal cholesterol content by ≥30% and increased ER cholesterol delivery, indicating that cells become less dependent on NPC1 when glycocalyx density is reduced. Pharmacological inhibition of O-glycosylation; CRISPR-generated NPC1-deficient CHO cells; biochemical lysosome cholesterol measurement; [¹⁴C]-oleate esterification assay Proceedings of the National Academy of Sciences of the United States of America Medium 26578804
2013 NPC1 is an intracellular endosomal receptor for Ebola virus; its second luminal domain (domain C) is necessary and sufficient for filovirus receptor activity. NPC1L1 lacks receptor activity because its domain C does not bind viral GP; a chimera bearing NPC1's domain C conferred near-wild-type filovirus infection. NPC1/NPC1L1 chimera panel; viral infection assays; GP binding assays Viruses High 23202491
2015 A single amino acid at position 503 in NPC1 bidirectionally controls binding to EBOV glycoprotein and viral receptor activity; this residue is in domain C and its mutation does not perturb NPC1 endosomal localization or cholesterol trafficking function. NPC1 viper-human chimeras and point mutants; viral infection assays; GP binding assays; cholesterol trafficking assays mSphere Medium 27303731
2015 TIM-1 and NPC1 colocalize and physically interact in intracellular vesicles where EBOV glycoprotein-mediated membrane fusion occurs; a TIM-1-specific monoclonal antibody that disrupts TIM-1–NPC1 interaction also prevents GP-mediated membrane fusion, implicating this protein–protein interaction in filovirus fusion. Co-immunoprecipitation; colocalization by fluorescence microscopy; monoclonal antibody blocking; pseudovirus fusion assays Journal of virology Medium 25855742
2015 Ebolavirus enters cells through endolysosomes that co-contain both NPC1 and TPC2, directly observed by live-cell imaging, contradicting a model of entry through NPC1-negative organelles. Live-cell imaging; co-localization of NPC1 and TPC2 with viral entry sites Journal of virology Medium 26468524
2012 NPC1-bearing vesicles (lacking lysosomal markers) traffick to Anaplasma phagocytophilum bacterial inclusions; NPC1 function is required for bacterial cholesterol acquisition and infection. The trans-Golgi SNAREs VAMP4 and syntaxin 16, which associate with NPC1 on LDL-cholesterol vesicles, are recruited to bacterial inclusions and VAMP4 is required for bacterial infection. siRNA knockdown; immunofluorescence co-localization; cholesterol-traffic inhibitor U18666A; infection assays Cellular microbiology Medium 22212234
2013 In NPC1-deficient cells, neuronal deletion of Npc1 alone is sufficient to arrest oligodendrocyte maturation and cause myelination failure, associated with decreased Fyn kinase activation. Oligodendrocyte-specific Npc1 deletion causes delayed early myelination and late loss of myelin proteins followed by secondary Purkinje neuron degeneration. Conditional cell-type-specific Npc1 knockout (neuron-specific and oligodendrocyte-specific Cre); Fyn kinase activity assays; histological and electron microscopic analysis of myelin PLoS genetics High 23593041
2011 Neuronal-specific deletion of Npc1 is sufficient to cause NPC neuropathology (Purkinje cell loss, axonal spheroids, reactive gliosis), establishing that neuronal NPC1 deficiency—not astrocytic—drives CNS disease. Adult-onset global deletion produces the same phenotype as germline deletion, showing no significant developmental component. Conditional neuron-specific and astrocyte-specific Npc1 knockout; behavioral testing; neuropathological analysis Human molecular genetics High 21856732
2012 Targeting ER calcium levels with ryanodine receptor (RyR) antagonists increased steady-state levels of the I1061T NPC1 mutant protein, promoted its trafficking to late endosomes/lysosomes, and rescued aberrant storage of cholesterol and sphingolipids; overexpression of calnexin (a calcium-dependent ER chaperone) produced similar rescue, implicating ER calcium-dependent chaperoning in I1061T NPC1 proteostasis. RyR antagonist pharmacology; calnexin overexpression; immunofluorescence of NPC1 localization; filipin cholesterol staining; patient fibroblasts Human molecular genetics Medium 22505584
2019 NPC1 is present in the postsynaptic compartment and is locally translated during long-term potentiation (LTP). NPC1 mediates cholesterol mobilization at synapses and is required for surface delivery of CYP46A1 and GluA1 receptors necessary for LTP; the NPC1nmf164 mutation reduces synaptic NPC1 via enhanced protein degradation, shortens postsynaptic densities, and impairs LTP. Immunofluorescence and subcellular fractionation of synaptic compartments; local translation assay; LTP electrophysiology; GluA1 surface biotinylation; NPC1nmf164 mutant mice EMBO reports Medium 31535451
2015 NPC1 loss in microglia causes cell-autonomous enhanced phagocytic uptake, impaired myelin turnover, accumulation of multivesicular bodies, and impaired lipid trafficking to lysosomes, while lysosomal degradation function is preserved. Npc1-/- microglial isolation; proteomics; phagocytosis assays; electron microscopy; lipid trafficking assays Nature communications Medium 33627648
2000 Mutation of cysteine residues in the cysteine-rich luminal loop of NPC1 produces proteins that fail to correct cholesterol trafficking in NPC1-deficient cells; the I1061T mutation (most common disease allele, also in this loop) similarly inactivates the protein. All such mutants localize to cholesterol-engorged lysosomes, and the loop binds zinc via a zinc-NTA agarose assay. Site-directed mutagenesis; complementation of NPC1-deficient CT60 CHO cells; immunofluorescence localization; zinc-NTA agarose binding Experimental cell research Medium 10942596
2015 NPC1 loss of function in microglia (mouse model and patient-derived macrophages) is cell-autonomous: NPC1-deficient macrophages from NPC patients show molecular and functional cholesterol trafficking defects. Patient-derived blood macrophages; lipid accumulation assays; protein expression analysis Nature communications Medium 33627648
2015 NPC1 interacts with cathepsin D at the lysosome; NPC1-deficient fibroblasts accumulate procathepsin D with reduced mature cathepsin D and diminished activity, while increasing NPC1 levels with proteasome inhibitor bortezomib restores cathepsin D activity. Affinity chromatography with NPC1 loop-I peptide bait; LC-MS/MS identification; co-immunoprecipitation validation; cathepsin D activity assays; patient fibroblasts; bortezomib rescue Proteomics Medium 26507101
2003 Cholesterol sequestration in NPC1-deficient neurons is ganglioside-dependent: mice doubly deficient in NPC1 and GM2/GD2 synthase (GalNAcT) lacked both neuronal GM2 accumulation and free cholesterol storage, establishing that gangliosides are required upstream of cholesterol sequestration in NPC1-deficient neurons. Double-mutant mouse genetics (NPC1-/- × GalNAcT-/-); immunocytochemistry and filipin histochemistry in situ Current biology High 12906793
2023 NPC1 deficiency in oligodendrocyte progenitor cells impairs their maturation in vitro and in vivo through diminished H3K27me3-dependent gene silencing (epigenetic regulation); this is rescued by GSK-J4 (H3K27 demethylase inhibitor) or by mobilizing stored cholesterol with 2-hydroxypropyl-β-cyclodextrin. Single-nucleus RNA-seq; in vitro oligodendrocyte differentiation; H3K27me3 chromatin analysis; GSK-J4 pharmacological rescue; cyclodextrin cholesterol mobilization; Npc1-/- conditional mice Nature communications High 37407594
2022 NPC1-mediated cholesterol homeostasis in endosomes is required for reovirus core particle delivery into the cytoplasm: NPC1-deficient cells block reovirus infection at the post-uncoating membrane penetration step, and this defect is rescued by cholesterol-solubilizing cyclodextrin. NPC1 is not required for virus attachment, internalization, or capsid uncoating. CRISPR and RNAi screens; infectious subvirion particle (ISVP) bypass assay; hydroxypropyl-β-cyclodextrin rescue; NPC1-knockout cells; reovirus infection assays PLoS pathogens High 35263388
2005 Drosophila NPC1a (ortholog of human NPC1) promotes efficient intracellular trafficking of sterols required for ecdysone synthesis in the ring gland; NPC1a null larvae are lethal but rescued by high-cholesterol diet, 20-hydroxyecdysone, or NPC1a expression specifically in the ring gland, while total cholesterol levels in mutant larvae are unchanged. Drosophila genetic null allele; dietary rescue; tissue-specific transgenic rescue; cholesterol quantification Genetics Medium 16079224
2020 NPC1 is the intracellular receptor used by HAVCR1 (TIM-1) for hepatitis A virus (exo-HAV) infection: CRISPR-Cas9 knockout of either HAVCR1 or NPC1 blocks membrane fusion and RNA delivery from exosomes carrying HAV, establishing that the HAVCR1-NPC1 pathway mediates an envelope-glycoprotein-independent viral fusion mechanism. CRISPR-Cas9 knockout of HAVCR1 and NPC1; exo-HAV infection assays; methylene blue RNA inactivation; membrane fusion assays Nature microbiology Medium 32541946

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2016 Structural Insights into the Niemann-Pick C1 (NPC1)-Mediated Cholesterol Transfer and Ebola Infection. Cell 256 27238017
2019 NPC1 regulates ER contacts with endocytic organelles to mediate cholesterol egress. Nature communications 231 31537798
2004 Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochimica et biophysica acta 224 15465426
2007 Purified NPC1 protein: II. Localization of sterol binding to a 240-amino acid soluble luminal loop. The Journal of biological chemistry 185 17989072
2019 NPC intracellular cholesterol transporter 1 (NPC1)-mediated cholesterol export from lysosomes. The Journal of biological chemistry 176 30710017
2003 NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of low density lipoprotein cholesterol-derived oxysterols. The Journal of biological chemistry 176 12719428
2007 Purified NPC1 protein. I. Binding of cholesterol and oxysterols to a 1278-amino acid membrane protein. The Journal of biological chemistry 175 17989073
2020 NPC1-mTORC1 Signaling Couples Cholesterol Sensing to Organelle Homeostasis and Is a Targetable Pathway in Niemann-Pick Type C. Developmental cell 161 33308480
2001 Niemann-Pick C1 disease: correlations between NPC1 mutations, levels of NPC1 protein, and phenotypes emphasize the functional significance of the putative sterol-sensing domain and of the cysteine-rich luminal loop. American journal of human genetics 161 11333381
2007 Genetic variations and treatments that affect the lifespan of the NPC1 mouse. Journal of lipid research 133 18077828
2007 Liver X receptor activation enhances cholesterol loss from the brain, decreases neuroinflammation, and increases survival of the NPC1 mouse. The Journal of neuroscience : the official journal of the Society for Neuroscience 128 18160655
2015 Filovirus receptor NPC1 contributes to species-specific patterns of ebolavirus susceptibility in bats. eLife 105 26698106
2000 Niemann-pick type C1 (NPC1) overexpression alters cellular cholesterol homeostasis. The Journal of biological chemistry 104 10964915
1999 Mutations in NPC1 highlight a conserved NPC1-specific cysteine-rich domain. American journal of human genetics 104 10521290
2018 Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD. Nature communications 102 30202070
2021 Loss of NPC1 enhances phagocytic uptake and impairs lipid trafficking in microglia. Nature communications 93 33627648
2013 Npc1 acting in neurons and glia is essential for the formation and maintenance of CNS myelin. PLoS genetics 90 23593041
2004 The NPC1 protein: structure implies function. Biochimica et biophysica acta 90 15465421
2005 Mutations of a Drosophila NPC1 gene confer sterol and ecdysone metabolic defects. Genetics 84 16079224
1999 NPC1 gene mutations in Japanese patients with Niemann-Pick disease type C. Human genetics 83 10480349
2013 Cholesterol-binding molecules MLN64 and ORP1L mark distinct late endosomes with transporters ABCA3 and NPC1. Journal of lipid research 82 23709693
2016 Reduction of TMEM97 increases NPC1 protein levels and restores cholesterol trafficking in Niemann-pick type C1 disease cells. Human molecular genetics 81 27378690
2020 A trimeric Rab7 GEF controls NPC1-dependent lysosomal cholesterol export. Nature communications 78 33144569
2008 Astrocyte-only Npc1 reduces neuronal cholesterol and triples life span of Npc1-/- mice. Journal of neuroscience research 78 18500759
2003 Cholesterol accumulation in NPC1-deficient neurons is ganglioside dependent. Current biology : CB 69 12906793
2015 Interaction between TIM-1 and NPC1 Is Important for Cellular Entry of Ebola Virus. Journal of virology 67 25855742
2013 NPC1, intracellular cholesterol trafficking and atherosclerosis. Clinica chimica acta; international journal of clinical chemistry 67 24296264
2016 Simultaneous Targeting of NPC1 and VDAC1 by Itraconazole Leads to Synergistic Inhibition of mTOR Signaling and Angiogenesis. ACS chemical biology 65 28103683
2015 Ebolavirus Glycoprotein Directs Fusion through NPC1+ Endolysosomes. Journal of virology 64 26468524
2020 Structural basis for itraconazole-mediated NPC1 inhibition. Nature communications 63 31919352
2019 NPC1 enables cholesterol mobilization during long-term potentiation that can be restored in Niemann-Pick disease type C by CYP46A1 activation. EMBO reports 60 31535451
2015 Glycosylation inhibition reduces cholesterol accumulation in NPC1 protein-deficient cells. Proceedings of the National Academy of Sciences of the United States of America 59 26578804
2011 Temporal and cell-specific deletion establishes that neuronal Npc1 deficiency is sufficient to mediate neurodegeneration. Human molecular genetics 56 21856732
2020 Exosome mimicry by a HAVCR1-NPC1 pathway of endosomal fusion mediates hepatitis A virus infection. Nature microbiology 54 32541946
2016 Triazoles inhibit cholesterol export from lysosomes by binding to NPC1. Proceedings of the National Academy of Sciences of the United States of America 54 27994139
2008 Characterization of fluorescent sterol binding to purified human NPC1. The Journal of biological chemistry 54 19029290
2005 NPC1 late endosomes contain elevated levels of non-esterified ('free') fatty acids and an abnormally glycosylated form of the NPC2 protein. The Biochemical journal 50 15896196
2002 NPC1: Complete genomic sequence, mutation analysis, and characterization of haplotypes. Human mutation 50 11754101
2023 Lysosome-targeted multifunctional lipid probes reveal the sterol transporter NPC1 as a sphingosine interactor. Proceedings of the National Academy of Sciences of the United States of America 48 36893262
2018 The Extending Spectrum of NPC1-Related Human Disorders: From Niemann-Pick C1 Disease to Obesity. Endocrine reviews 47 29325023
2017 AAV9-NPC1 significantly ameliorates Purkinje cell death and behavioral abnormalities in mouse NPC disease. Journal of lipid research 46 28053186
2001 Isolation of NPC1-deficient Chinese hamster ovary cell mutants by gene trap mutagenesis. Journal of biochemistry 45 11388901
2010 Npc1 haploinsufficiency promotes weight gain and metabolic features associated with insulin resistance. Human molecular genetics 44 21036943
2000 Determinants of NPC1 expression and action: key promoter regions, posttranscriptional control, and the importance of a "cysteine-rich" loop. Experimental cell research 44 10942596
2005 NPC1 gene deficiency leads to lack of neural stem cell self-renewal and abnormal differentiation through activation of p38 mitogen-activated protein kinase signaling. Stem cells (Dayton, Ohio) 43 16099992
2021 Enrichment of NPC1-deficient cells with the lipid LBPA stimulates autophagy, improves lysosomal function, and reduces cholesterol storage. The Journal of biological chemistry 41 34023384
2017 FTY720/fingolimod increases NPC1 and NPC2 expression and reduces cholesterol and sphingolipid accumulation in Niemann-Pick type C mutant fibroblasts. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 41 28082351
2010 Increased expression of the lysosomal cholesterol transporter NPC1 in Alzheimer's disease. Biochimica et biophysica acta 41 20497909
2017 Rare Loss-of-Function Variants in NPC1 Predispose to Human Obesity. Diabetes 38 28130309
2011 Requirement of Npc1 and availability of cholesterol for early embryonic cell movements in zebrafish. Journal of lipid research 38 21576600
2016 Structure of glycosylated NPC1 luminal domain C reveals insights into NPC2 and Ebola virus interactions. FEBS letters 37 26846330
2009 Molecular analysis of NPC1 and NPC2 gene in 34 Niemann-Pick C Italian patients: identification and structural modeling of novel mutations. Neurogenetics 37 19252935
2015 Quantitative Proteomics of Human Fibroblasts with I1061T Mutation in Niemann-Pick C1 (NPC1) Protein Provides Insights into the Disease Pathogenesis. Molecular & cellular proteomics : MCP 36 25873482
2009 Decreased Npc1 gene dosage in mice is associated with weight gain. Obesity (Silver Spring, Md.) 36 19910939
2014 Diagnosis of Niemann-Pick disease type C with 7-ketocholesterol screening followed by NPC1/NPC2 gene mutation confirmation in Chinese patients. Orphanet journal of rare diseases 35 24915861
2012 Niemann-Pick C1 (NPC1)/NPC1-like1 chimeras define sequences critical for NPC1's function as a flovirus entry receptor. Viruses 35 23202491
2002 Sterols and intracellular vesicular trafficking: lessons from the study of NPC1. Steroids 35 12398991
2000 Regional and developmental expression of the Npc1 mRNA in the mouse brain. Journal of neurochemistry 33 10936208
2012 Ryanodine receptor antagonists adapt NPC1 proteostasis to ameliorate lipid storage in Niemann-Pick type C disease fibroblasts. Human molecular genetics 32 22505584
2009 NPC1 repression contributes to lipid accumulation in human macrophages exposed to environmental aryl hydrocarbons. Cardiovascular research 31 19131362
2020 Inter-domain dynamics drive cholesterol transport by NPC1 and NPC1L1 proteins. eLife 30 32410728
2007 Spontaneous atherothrombosis and medial degradation in Apoe-/-, Npc1-/- mice. Circulation 30 17984379
2021 Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup. Life science alliance 29 34183444
2012 Subversion of NPC1 pathway of cholesterol transport by Anaplasma phagocytophilum. Cellular microbiology 29 22212234
2007 Do mammalian NPC1 and NPC2 play a role in intestinal cholesterol absorption? The Biochemical journal 29 17880278
2020 Molecular Genetics of Niemann-Pick Type C Disease in Italy: An Update on 105 Patients and Description of 18 NPC1 Novel Variants. Journal of clinical medicine 28 32138288
2019 Insights into the Molecular Mechanisms of Cholesterol Binding to the NPC1 and NPC2 Proteins. Advances in experimental medicine and biology 27 31098815
2016 A Single Residue in Ebola Virus Receptor NPC1 Influences Cellular Host Range in Reptiles. mSphere 27 27303731
2006 Cholesterol depletion facilitates ubiquitylation of NPC1 and its association with SKD1/Vps4. Journal of cell science 27 16757520
2017 Expression patterns of sterol transporters NPC1 and NPC2 in the cnidarian-dinoflagellate symbiosis. Cellular microbiology 26 28544363
2010 Pre-synaptic defects of NPC1-deficient hippocampal neurons are not directly related to plasma membrane cholesterol. Journal of neurochemistry 26 20456004
2011 The cholesterol trafficking protein NPC1 is required for Drosophila spermatogenesis. Developmental biology 25 21215267
2010 br regulates the expression of the ecdysone biosynthesis gene npc1. Developmental biology 25 20621708
2023 The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells. Nature communications 24 37407594
2023 An overview of the role of Niemann-pick C1 (NPC1) in viral infections and inhibition of viral infections through NPC1 inhibitor. Cell communication and signaling : CCS 24 38098077
2011 Proteins that bind and move lipids: MsbA and NPC1. Critical reviews in biochemistry and molecular biology 24 22117698
2022 NPC1 Confers Metabolic Flexibility in Triple Negative Breast Cancer. Cancers 22 35884604
2020 STARD1 and NPC1 expression as pathological markers associated with astrogliosis in post-mortem brains from patients with Alzheimer's disease and Down syndrome. Aging 22 31902793
2016 Diversity of glycosphingolipid GM2 and cholesterol accumulation in NPC1 patient-specific iPSC-derived neurons. Brain research 22 27923633
2010 Epistasis between intracellular cholesterol trafficking-related genes (NPC1 and ABCA1) and Alzheimer's disease risk. Journal of Alzheimer's disease : JAD 21 20571217
2005 Six novel NPC1 mutations in Chinese patients with Niemann-Pick disease type C. Journal of neurology, neurosurgery, and psychiatry 21 15774455
2018 Lovastatin promotes myelin formation in NPC1 mutant oligodendrocytes. Journal of the neurological sciences 20 29406968
2023 Activation of invasion by oncogenic reprogramming of cholesterol metabolism via increased NPC1 expression and macropinocytosis. Oncogene 19 37420029
2022 Reovirus infection is regulated by NPC1 and endosomal cholesterol homeostasis. PLoS pathogens 19 35263388
2022 MiR-25 blunts autophagy and promotes the survival of Mycobacterium tuberculosis by regulating NPC1. iScience 19 35586071
2020 Variants in the Niemann-Pick type C gene NPC1 are not associated with Parkinson's disease. Neurobiology of aging 19 32371106
2018 Single-Nucleotide Polymorphisms in Human NPC1 Influence Filovirus Entry Into Cells. The Journal of infectious diseases 19 30010949
2017 RNA sequencing of esophageal adenocarcinomas identifies novel fusion transcripts, including NPC1-MELK, arising from a complex chromosomal rearrangement. Cancer 19 28640357
2016 Role of STARD4 and NPC1 in intracellular sterol transport. Biochemistry and cell biology = Biochimie et biologie cellulaire 19 27421092
2012 Tracking sphingosine metabolism and transport in sphingolipidoses: NPC1 deficiency as a test case. Traffic (Copenhagen, Denmark) 19 22607065
2019 Hepatic and neuronal phenotype of NPC1-/- mice. Heliyon 18 30923761
2012 Mammalian NPC1 genes may undergo positive selection and human polymorphisms associate with type 2 diabetes. BMC medicine 18 23153210
2009 NO-1886 up-regulates Niemann-Pick C1 protein (NPC1) expression through liver X receptor alpha signaling pathway in THP-1 macrophage-derived foam cells. Cardiovascular drugs and therapy 18 19229602
2000 Regional distribution of NPC1 protein in monkey brain. Journal of neurocytology 17 11387550
2022 Annexin A6 and NPC1 regulate LDL-inducible cell migration and distribution of focal adhesions. Scientific reports 16 35022465
2020 NPC1 silent variant induces skipping of exon 11 (p.V562V) and unfolded protein response was found in a specific Niemann-Pick type C patient. Molecular genetics & genomic medicine 16 32931663
2022 NPC1 Deficiency Contributes to Autophagy-Dependent Ferritinophagy in HEI-OC1 Auditory Cells. Frontiers in molecular biosciences 15 35936782
2018 Phylogeny and evolution of the cholesterol transporter NPC1 in insects. Journal of insect physiology 15 29649482
2015 Identification of lysosomal Npc1-binding proteins: Cathepsin D activity is regulated by NPC1. Proteomics 15 26507101
2008 Liver X receptor agonist T0901317 reduces atherosclerotic lesions in apoE-/- mice by up-regulating NPC1 expression. Science in China. Series C, Life sciences 15 18785587

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