Affinage

NPC2

NPC intracellular cholesterol transporter 2 · UniProt P61916

Length
151 aa
Mass
16.6 kDa
Annotated
2026-04-29
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NPC2 is a small soluble lysosomal glycoprotein essential for cholesterol egress from the endolysosomal compartment, functioning in the same non-redundant pathway as the transmembrane protein NPC1. NPC2 binds cholesterol with submicromolar affinity in a 1:1 stoichiometry within a deep hydrophobic pocket of its β-sandwich fold, extracts cholesterol from intralysosomal membranes via a collisional mechanism stimulated by bis(monoacylglycero)phosphate (BMP) and inhibited by sphingomyelin, and transfers cholesterol directionally to the N-terminal domain of NPC1 after docking onto NPC1's middle lumenal domain through a continuous transfer tunnel visualized at 2.4-Å resolution (PMID:10366780, PMID:17573352, PMID:18772377, PMID:22065762, PMID:27551080, PMID:20179319, PMID:31580258). Lysosomal targeting of NPC2 depends on mannose-6-phosphate modification of its Asn-39 N-glycan—enabled by the Golgi UDP-GlcNAc transporter TMEM241—and on cation-independent mannose-6-phosphate receptor recycling maintained by the GARP and BORC-ARL8-HOPS trafficking complexes (PMID:15542393, PMID:37890669, PMID:28658628, PMID:35653304). Loss-of-function mutations in NPC2 cause Niemann-Pick type C2 disease, characterized by lysosomal accumulation of unesterified cholesterol and progressive neurodegeneration (PMID:11125141).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1999 High

    Identifying NPC2 as a cholesterol-binding protein established the biochemical foundation for understanding its function, answering what small soluble lysosomal proteins could serve as sterol carriers.

    Evidence Cholesterol-binding assay with purified porcine HE1/NPC2 from epididymal fluid

    PMID:10366780

    Open questions at the time
    • Cellular function not yet defined
    • Human disease link not yet established
    • Mechanism of cholesterol transfer unknown
  2. 2000 High

    Demonstrating that NPC2 deficiency causes Niemann-Pick type C2 disease and that recombinant NPC2 rescues cholesterol accumulation in patient fibroblasts established NPC2 as the causal gene and proved its functional necessity for lysosomal cholesterol egress.

    Evidence Mutation analysis and fibroblast complementation with recombinant NPC2 protein

    PMID:11125141

    Open questions at the time
    • Mechanism of cholesterol mobilization unknown
    • Relationship to NPC1 undefined
  3. 2003 Medium

    Showing that NPC1 and NPC2 mutant cells both fail to generate regulatory oxysterols from LDL cholesterol placed both proteins upstream of SREBP/LXR signaling and suggested they operate in the same pathway, though their mechanistic relationship remained unclear.

    Evidence Oxysterol measurement and sterol regulatory assays in NPC1 and NPC2 mutant fibroblasts

    PMID:12719428

    Open questions at the time
    • Whether NPC1 and NPC2 act sequentially or in parallel was unresolved
    • Direct physical or functional interaction not demonstrated
  4. 2004 High

    Genetic epistasis in NPC1;NPC2 double-mutant mice—showing phenotypes identical to either single mutant—definitively placed NPC1 and NPC2 in the same non-redundant lipid transport pathway.

    Evidence Double-mutant mouse genetics with phenotypic, pathological, and biochemical analysis

    PMID:15071184

    Open questions at the time
    • Whether NPC2 acts upstream, downstream, or directly with NPC1 was unknown
    • Physical interaction not demonstrated
  5. 2004 High

    Identifying that the N-glycan on Asn-39 is solely responsible for mannose-6-phosphate-dependent lysosomal targeting of NPC2 established the glycosylation requirement for its correct subcellular delivery.

    Evidence Site-directed mutagenesis of glycosylation sites with immunocytofluorescence and functional rescue in NPC2-deficient fibroblasts

    PMID:15542393

    Open questions at the time
    • Upstream enzymes required for M6P modification unknown
    • Whether other sorting mechanisms contribute was unclear
  6. 2007 High

    The crystal structure of NPC2 bound to cholesterol sulfate revealed how cholesterol is buried in a deep hydrophobic pocket between two β-sheets with only the 3-OH group solvent-exposed, explaining the binding mechanism at atomic resolution.

    Evidence X-ray crystallography of apo and sterol-bound bovine NPC2

    PMID:17573352

    Open questions at the time
    • How cholesterol is released to membranes or NPC1 was unknown
    • No structure of NPC2 in complex with NPC1
  7. 2008 High

    Reconstituted transfer assays showed NPC2 accelerates cholesterol exchange between NPC1-NTD and membranes by >100-fold via a collisional (membrane-contact) mechanism stimulated by BMP/LBPA, establishing NPC2 as the kinetic driver of lysosomal cholesterol mobilization.

    Evidence In vitro [³H]cholesterol transfer assays between recombinant proteins and liposomes; FTIR and tryptophan fluorescence spectroscopy

    PMID:18772377 PMID:18823126

    Open questions at the time
    • Direct NPC2-NPC1 binding interface unknown
    • Which NPC1 domain mediates docking was unresolved
  8. 2010 High

    Systematic lipid composition studies showed BMP and ceramide stimulate while sphingomyelin inhibits NPC2-mediated inter-membrane cholesterol transfer, explaining how lysosomal lipid remodeling by acid sphingomyelinase gates cholesterol egress.

    Evidence Liposomal cholesterol transfer assays with defined lipid compositions

    PMID:20179319 PMID:25339683

    Open questions at the time
    • Structural basis of BMP–NPC2 interaction unknown
    • In vivo validation of lipid regulation incomplete
  9. 2011 High

    Demonstrating that NPC1's middle lumenal domain (MLD) directly binds cholesterol-loaded NPC2 at acidic pH resolved which NPC1 domain mediates the docking event and established pH-dependent directionality of the hand-off.

    Evidence Surface plasmon resonance and affinity chromatography with engineered soluble NPC1-MLD

    PMID:22065762

    Open questions at the time
    • Structural details of the NPC1-MLD:NPC2 interface unknown
    • How cholesterol moves from NPC2 to NPC1-NTD after docking was unresolved
  10. 2016 High

    The 2.4-Å crystal structure of the NPC1-MLD:NPC2 complex revealed a continuous hydrophobic tunnel connecting NPC2's cholesterol pocket to NPC1-NTD's sterol-binding site, providing the structural basis for directional cholesterol transfer.

    Evidence X-ray crystallography of NPC1-MLD:NPC2-cholesterol-3-O-sulfate complex with structural docking onto full-length NPC1

    PMID:27551080

    Open questions at the time
    • Dynamics of tunnel opening/closing not captured
    • No full-length NPC1:NPC2 complex structure
  11. 2017 High

    Identifying the GARP complex as essential for CI-MPR retrograde recycling and consequently NPC2 lysosomal delivery revealed the first upstream trafficking machinery required for NPC2 sorting.

    Evidence Amphotericin B selection screen; RNAi of GARP subunits; Vps54 mutant mice; CI-MPR mislocalization

    PMID:28658628

    Open questions at the time
    • Other trafficking complexes potentially involved were unknown
    • Whether GARP deficiency phenocopies NPC2 disease fully was untested
  12. 2019 High

    Mapping the NPC2 hydrophobic knob domain as the direct LBPA-binding site and showing that LBPA enrichment cannot rescue cholesterol clearance in NPC2-deficient cells established that BMP stimulation of cholesterol transfer requires direct NPC2–BMP interaction.

    Evidence Direct binding assay between NPC2 and LBPA; domain mapping; LBPA enrichment in NPC2-deficient fibroblasts

    PMID:31580258

    Open questions at the time
    • Structural basis of NPC2 knob–LBPA interaction at atomic level unknown
    • Whether BMP binding induces conformational change in NPC2 is unresolved
  13. 2022 High

    Showing that the BORC-ARL8-HOPS ensemble is required for CI-MPR recycling and NPC2 lysosomal delivery—while NPC1 localization is unaffected—distinguished the trafficking requirements of the two NPC pathway components.

    Evidence Depletion of BORC, ARL8, HOPS subunits with NPC2 localization, secretion, and CI-MPR degradation assays

    PMID:35653304

    Open questions at the time
    • Whether GARP and BORC-ARL8-HOPS act sequentially or in parallel is unclear
    • Relative contribution of each complex to NPC2 delivery not quantified
  14. 2023 High

    Identifying TMEM241 as the Golgi UDP-GlcNAc transporter required for mannose-6-phosphate modification of NPC2 completed the upstream biosynthetic pathway linking glycosylation machinery to NPC2 lysosomal sorting.

    Evidence Genome-wide CRISPR-Cas9 KO screen; TMEM241 localization; M6P modification assay; Tmem241-deficient mice

    PMID:37890669

    Open questions at the time
    • Whether TMEM241 affects other M6P-dependent cargo remains to be mapped
    • Structural mechanism of TMEM241-dependent NPC2 glycosylation unknown
  15. 2025 Medium

    NPC2 deficiency disrupts mitochondria–lysosome membrane contact sites and causes broad sphingolipid accumulation, extending NPC2's role beyond cholesterol to organelle contact-site maintenance and sphingolipid homeostasis.

    Evidence Proximity ligation assay and confocal imaging of organelle contacts; mass spectrometry lipidomics in NPC2-KO HEK293 cells

    PMID:39747180

    Open questions at the time
    • Whether contact-site disruption is a direct or indirect consequence of cholesterol accumulation is unclear
    • No reconstitution of NPC2-dependent contact-site formation

Open questions

Synthesis pass · forward-looking unresolved questions
  • A full-length NPC1:NPC2 complex structure, the conformational dynamics of cholesterol tunnel passage, and whether NPC2's role in mitochondria–lysosome contacts and sphingolipid metabolism is direct or secondary to cholesterol accumulation remain major open questions.
  • No full-length NPC1:NPC2 complex structure exists
  • Dynamics of cholesterol transfer through the tunnel not captured experimentally
  • Direct vs. indirect role of NPC2 in mitochondria-lysosome contacts unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008289 lipid binding 3 GO:0140104 molecular carrier activity 3
Localization
GO:0005764 lysosome 5 GO:0005576 extracellular region 2
Pathway
R-HSA-382551 Transport of small molecules 5 R-HSA-9609507 Protein localization 4 R-HSA-1430728 Metabolism 3 R-HSA-1643685 Disease 2
Partners
ARL8BNPC1TMEM241VPS53

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 NPC2 (HE1) is a ubiquitously expressed lysosomal cholesterol-binding protein whose deficiency causes Niemann-Pick type C2 disease; treatment of NPC2-deficient fibroblasts with exogenous recombinant NPC2 protein ameliorated lysosomal accumulation of LDL-derived cholesterol, establishing NPC2 as the causal gene and demonstrating its functional role in cholesterol egress from lysosomes. Biochemical identification, fibroblast complementation assay, mutation analysis Science High 11125141
1999 The porcine HE1/NPC2 homolog specifically binds cholesterol with high affinity (Kd = 2.3 µM) in a 1:1 stoichiometry, establishing NPC2 as a cholesterol-binding protein. Protein purification from porcine epididymal fluid, cholesterol-binding assay Biochimica et biophysica acta High 10366780
2004 Genetic epistasis in NPC1;NPC2 double-mutant mice shows phenotypes identical to either single mutant, providing genetic evidence that NPC1 and NPC2 function in the same, non-redundant pathway to facilitate lipid transport from the lysosome. Mouse genetics — generation of NPC2 hypomorph and NPC1;NPC2 double mutant; phenotypic analysis of disease onset, pathology, neuronal storage, lipid biochemistry Proceedings of the National Academy of Sciences of the United States of America High 15071184
2007 Crystal structure of bovine NPC2 bound to cholesterol-3-O-sulfate reveals cholesterol binds in a deep hydrophobic pocket between two β-sheets with only the sulfate exposed to solvent; two aromatic residues at the tunnel entrance are essential for NPC2 function, and the binding site is malleable, expanding upon sterol binding. X-ray crystallography (apo and sterol-bound NPC2 structures in the same crystal lattice) The Journal of biological chemistry High 17573352
2008 NPC2 facilitates bidirectional cholesterol transfer between NPC1's N-terminal domain (NTD) and phospholipid liposomes, accelerating transfer >100-fold; a naturally occurring human mutant NPC2 (Pro120Ser) that fails to bind cholesterol also fails to stimulate this transfer, establishing NPC2 as an essential mediator of the NPC1-NPC2 cholesterol hand-off mechanism. In vitro cholesterol transfer assay with [3H]cholesterol between recombinant proteins and liposomes; NPC2 mutant (P120S) functional analysis Proceedings of the National Academy of Sciences of the United States of America High 18772377
2008 NPC2 acts on cholesterol transfer via direct interaction with phospholipid membranes (collisional transfer mechanism); transfer rates are enhanced up to 2 orders of magnitude and are further stimulated by the lysosomal phospholipid lyso-bisphosphatidic acid (LBPA), as demonstrated by FTIR spectroscopy and tryptophan fluorescence spectral shifts. Fluorescence spectroscopy, FTIR spectroscopy; in vitro sterol transfer assays between membranes and NPC2 Biochemistry High 18823126
2011 NPC1's second (middle) lumenal domain (MLD) binds directly to NPC2 protein; binding is cholesterol-dependent (requires cholesterol on NPC2) and occurs only at acidic pH; disease-causing NPC1 domain 2 mutations reduce NPC2 binding, supporting a model where NPC1-MLD holds NPC2 in position for directional cholesterol transfer to NPC1's NTD. Surface plasmon resonance, affinity chromatography; engineered soluble NPC1 lumenal domain 2 with antiparallel coiled-coil sequences Proceedings of the National Academy of Sciences of the United States of America High 22065762
2016 Crystal structure (2.4-Å) of the NPC1-MLD:NPC2 complex reveals NPC1-MLD uses two protruding loops to bind NPC2; docking onto full-length NPC1 reveals a direct cholesterol transfer tunnel between NPC2 and NPC1-NTD cholesterol-binding pockets, supporting the 'hydrophobic hand-off' model. X-ray crystallography of NPC1-MLD:NPC2-cholesterol-3-O-sulfate complex; structural docking Proceedings of the National Academy of Sciences of the United States of America High 27551080
2006 Recombinant human NPC2 consists of multiple N-glycoforms: Asn-19 is not glycosylated, Asn-39 carries an Endo H-sensitive oligosaccharide, and Asn-116 is variably modified. All glycoforms bind cholesterol and can be endocytosed to rescue the cholesterol storage phenotype of NPC2-deficient fibroblasts. NPC2 binds sterols (cholesterol precursors, plant sterols, some oxysterols, cholesterol sulfate) but not glycolipids, phospholipids, or fatty acids. Mass spectrometry glycoform analysis; cation-exchange chromatography-based sterol binding assay; fibroblast complementation assay The Journal of biological chemistry High 17018531
2004 The N-glycan on Asn-58 (Asn-39 in mature protein) is solely responsible for proper lysosomal targeting of NPC2 and is crucial for its function; loss of this glycosylation prevents lysosomal delivery. The oligosaccharide chains are of the hybrid/high-mannose type with no complex chains. Site-directed mutagenesis of N-glycosylation sites; immunocytofluorescence; cDNA expression in NPC2-/- fibroblasts; cholesterol trafficking complementation assay Molecular genetics and metabolism High 15542393
2003 NPC1 and NPC2 mutant cells show impaired generation of LDL cholesterol-derived oxysterols (25-hydroxycholesterol and 27-hydroxycholesterol), preventing proper suppression of SREBP-dependent gene expression and LXR activation, placing both proteins in the pathway controlling sterol regulatory oxysterol generation. Oxysterol measurement in NPC1 and NPC2 mutant fibroblasts; sterol regulatory assays; LDL receptor activity measurement The Journal of biological chemistry Medium 12719428
2010 NPC2 specifically transfers cholesterol (but not ceramide, GM3, galactosylceramide, sulfatide, PE, or PS) between liposomal membranes; bis(monoacylglycero)phosphate (BMP) strongly stimulates NPC2-mediated cholesterol transfer, ceramide mildly stimulates it, and sphingomyelin strongly inhibits it; NPC2 also induces membrane fusion, stimulated by BMP and ceramide and inhibited by sphingomyelin. Liposomal cholesterol transfer assay with fluorescent acceptor liposomes and streptavidin-magnetic bead separation; membrane fusion assay Journal of lipid research High 20179319
2019 NPC2 directly interacts with LBPA (lysobisphosphatidic acid), and the NPC2 hydrophobic knob domain is the site of this interaction; enrichment of NPC2-deficient cells with LBPA (or its precursor PG) fails to clear cholesterol, demonstrating an obligate functional interaction between NPC2 and LBPA in intracellular cholesterol trafficking. Direct binding assay between NPC2 and LBPA; LBPA enrichment in NPC2-deficient human fibroblasts; domain-mapping experiments eLife High 31580258
2017 The GARP complex (containing VPS53 and other subunits) is required for NPC2 sorting to lysosomes via the cation-independent mannose-6-phosphate receptor (CI-MPR); GARP deficiency blocks CI-MPR retrieval to the trans-Golgi network, impairing NPC2 delivery and causing lysosomal cholesterol accumulation. Amphotericin B-based selection; whole-transcriptome sequencing; RNAi knockdown of GARP subunits; Vps54 mutant mice; filipin staining; CI-MPR localization Cell reports High 28658628
2022 The BORC-ARL8-HOPS ensemble is required for lysosomal cholesterol egress; depletion of BORC, ARL8, or HOPS decreases association of NPC2 with degradative compartments and increases NPC2 secretion by impairing CI-MPR recycling, while NPC1 localization is unaffected. Depletion experiments (BORC, ARL8, HOPS subunits); filipin cholesterol staining; NPC2 localization and secretion assays; CI-MPR degradation assay Molecular biology of the cell High 35653304
2023 TMEM241, a Golgi-localized UDP-GlcNAc transporter in the SLC35 family, is required for mannose-6-phosphate modification of NPC2 and its subsequent lysosomal targeting; TMEM241 ablation impairs NPC2 sorting to lysosomes and causes lysosomal cholesterol accumulation. Genome-wide CRISPR-Cas9 KO screen (amphotericin B selection); TMEM241 localization; M6P modification assay; Tmem241-deficient mice Journal of lipid research High 37890669
2003 NPC1 governs the endocytic transport of NPC2: in NPC1-mutant fibroblasts, NPC2 is upregulated and accumulates in cholesterol-storing late endocytic organelles, and NPC2 is present in an incompletely deglycosylated form in NPC1 late endosomes. Immunofluorescence microscopy; Western blotting; NPC1 mutation overexpression in fibroblasts Human molecular genetics Medium 12554680
2004 NPC2/HE1 protein is localized predominantly in neurons in the mouse brain (in contrast to NPC1, which is predominantly in astrocytes), and is found in the cytosol of dendrites and at postsynaptic densities (PSD), confirmed by electron microscopy and Western blot of PSD-enriched fractions. Immunohistochemistry; electron microscopic immunocytochemistry; subcellular fractionation and Western blot Neuroscience Medium 15381285
2011 Secreted NPC2 stimulates ABCG5/G8-mediated biliary cholesterol efflux but does not affect NPC1L1-mediated cholesterol uptake; hepatic NPC2 overexpression fails to increase biliary cholesterol secretion in ABCG5/G8-null mice, establishing a requirement for ABCG5/G8 in NPC2-stimulated biliary cholesterol secretion. Adenovirus-mediated hepatic Npc2 knockdown and overexpression in mice; biliary lipid characterization; in vitro cell-based cholesterol transporter activity assays Gastroenterology High 21315718
2014 ATRA-triggered antimicrobial activity against M. tuberculosis requires NPC2 expression; NPC2 knockdown abolishes ATRA-induced decrease in total cellular cholesterol content, increase in lysosomal acidification, and antimicrobial activity, placing NPC2 in the vitamin A antimicrobial pathway through cholesterol regulation. siRNA knockdown of NPC2 in primary human monocytes; cholesterol measurement; antimicrobial activity assay; lysosomal acidification assay Journal of immunology Medium 24501203
2017 Atomistic molecular dynamics simulations identify two NPC2 membrane-binding orientations: 'Prone' mode (cholesterol pocket faces membrane, involves loop insertion V59-M60-G61-I62-P63-V64-P65, associated with cholesterol uptake/release) and 'Supine' mode (pocket faces away); BMP specifically enables Prone mode binding while sphingomyelin counteracts it by hindering Prone without affecting Supine mode. Atomistic MD simulations; free energy calculations PLoS computational biology Low 29084218
2009 NPC2 interacts with the C2 domain of E3 ubiquitin ligase Nedd4L in the aldosterone-sensitive distal nephron (ASDN) as identified by yeast two-hybrid screening; NPC2 is co-localized with Nedd4L along ASDN and its expression is regulated by sodium intake in a Dahl salt-sensitive hypertension model. Yeast two-hybrid screening; co-localization by immunohistochemistry; Dahl rat salt-sensitive hypertension model Biochemical and biophysical research communications Low 19664597
2014 Acid sphingomyelinase (ASM) facilitates NPC2-mediated cholesterol transfer by hydrolyzing sphingomyelin to ceramide in inner lysosomal membranes; anionic lipids stimulate NPC2-mediated cholesterol transfer while sphingomyelin inhibits it, and ASM-mediated SM hydrolysis is required for physiological cholesterol secretion from late endosomes. Liposomal cholesterol transfer assay; ASM enzyme activity assay with various lipid compositions Journal of lipid research Medium 25339683
2009 NPC2 deficiency in female mice causes infertility due to anovulation and defective steroidogenesis; NPC2 localizes to theca and luteal cells (which use cholesterol for steroid synthesis), and NPC2-/- mice show accumulation of ovarian cholesterol, reduced serum estradiol and progesterone, and failure of follicular rupture. NPC2-/- mouse model; immunohistochemistry; steroid hormone measurements; superovulation experiments Molecular and cellular endocrinology Medium 19883728
2014 NPC2-deficient mouse spermatozoa have reduced cholesterol content and defective tyrosine phosphorylation patterns during capacitation, resulting in reduced in vitro fertilizing ability, establishing a role for epididymal NPC2 in regulating sperm cholesterol levels during epididymal maturation. NPC2-/- mouse model; Western blot and immunohistochemistry; biochemical and flow cytometry cholesterol measurement; in vitro fertilization assay Reproduction, fertility, and development Medium 24709320
2015 NPC2 secreted by premalignant lung tumour cells is taken up by immature macrophage-lineage cells (IMCs), where it suppresses secretion of the CCR1 ligand CCL6 at least partly by facilitating its lysosomal degradation, thereby restraining IMC recruitment to the tumour microenvironment. NPC2 loss-of-function in BRAF-driven mouse lung tumour model; ex vivo cell assays; cytokine secretion assays; CCL6 degradation assay EMBO molecular medicine Medium 26183450
2018 The non-canonical NF-κB pathway (via NF-κB2) directly regulates NPC2 expression: RNAi disruption of NF-κB2 or other pathway members causes cholesterol accumulation; LTβR/BaffR stimulation upregulates NPC2; NF-κB2 activates NPC2 transcription through direct binding to its promoter; NF-κB2-deficient zebrafish and mice show cholesterol accumulation. RNAi knockdown; chromatin immunoprecipitation (NF-κB2 binding to NPC2 promoter); receptor stimulation; NF-κB2-deficient zebrafish and mice; filipin staining Science China. Life sciences Medium 30091016
2004 Wild-type astrocytes and NPC1-/- astrocytes both secrete the NPC2 protein; the majority of sterols and NPC2 are secreted separately (in different lipoprotein-like particles), and sterol secretion does not require NPC1 function. Size-exclusion chromatography; electron microscopy; sterol secretion assay from primary murine embryonic astrocytes The Journal of biological chemistry Medium 15355983
2025 NPC2 deficiency disrupts contact sites between mitochondria and late endosomes/lysosomes; NPC2-/- HEK cells show swollen, lipid-dense acidic compartments and accumulation of glucosylsphingosine, glucosylceramides, sphingosine, and sphingomyelins as assessed by lipidomics, implicating NPC2 in mitochondria-lysosome membrane contact site formation and sphingolipid metabolic homeostasis. NPC2-/- HEK293 cells; proximity ligation assay/confocal imaging for organelle contact sites; mass spectrometry-based lipidomics Scientific reports Medium 39747180
2025 SARS-CoV-2 ORF3a blocks NPC2 lysosomal trafficking by binding HOPS subunit VPS39, trapping CI-MPR and retromer in endosomes/lysosomes; additionally ORF3a reduces BMP levels by decreasing lysosome-mitochondrion membrane contact sites, identifying VPS39 as a regulator of both NPC2 trafficking and BMP biosynthesis. Protein-protein interaction (ORF3a-VPS39 binding); retromer/CI-MPR localization; lipidomics; proteomics; organelle contact site quantification; VPS39 and retromer deletion bioRxivpreprint Medium 39605369
2016 NEGR1 (neuronal growth regulator 1) interacts with NPC2 and increases its protein stability; ectopic NEGR1 expression relieves abnormal cholesterol accumulation in endosomal compartments, and NEGR1-deficient mouse embryonic fibroblasts exhibit increased cholesterol levels. Co-immunoprecipitation; ectopic expression; cholesterol assay; NEGR1-deficient MEFs Biochemical and biophysical research communications Low 27940359
2025 ALKBH5-mediated m6A demethylation of NPC2 mRNA in a YTHDF2-dependent manner enhances NPC2 mRNA stability and promotes oxaliplatin resistance in colorectal cancer cells; inhibiting NPC2 or ALKBH5 re-sensitizes resistant cells to oxaliplatin in vitro and in vivo. m6A demethylation assay; ALKBH5/NPC2 knockdown; mRNA stability assay; in vitro and xenograft resistance models Functional & integrative genomics Medium 40681956

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 Identification of HE1 as the second gene of Niemann-Pick C disease. Science (New York, N.Y.) 678 11125141
2008 NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid bilayers, a step in cholesterol egress from lysosomes. Proceedings of the National Academy of Sciences of the United States of America 391 18772377
2004 Genetic evidence for nonredundant functional cooperativity between NPC1 and NPC2 in lipid transport. Proceedings of the National Academy of Sciences of the United States of America 287 15071184
2004 Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochimica et biophysica acta 223 15465426
2007 Structural basis of sterol binding by NPC2, a lysosomal protein deficient in Niemann-Pick type C2 disease. The Journal of biological chemistry 176 17573352
2003 NPC1 and NPC2 regulate cellular cholesterol homeostasis through generation of low density lipoprotein cholesterol-derived oxysterols. The Journal of biological chemistry 176 12719428
1999 A porcine homolog of the major secretory protein of human epididymis, HE1, specifically binds cholesterol. Biochimica et biophysica acta 163 10366780
2009 Niemann-Pick C2 (NPC2) and intracellular cholesterol trafficking. Biochimica et biophysica acta 162 19232397
2016 Clues to the mechanism of cholesterol transfer from the structure of NPC1 middle lumenal domain bound to NPC2. Proceedings of the National Academy of Sciences of the United States of America 147 27551080
2011 Niemann-Pick type C 1 function requires lumenal domain residues that mediate cholesterol-dependent NPC2 binding. Proceedings of the National Academy of Sciences of the United States of America 128 22065762
2001 Niemann-Pick disease type C: spectrum of HE1 mutations and genotype/phenotype correlations in the NPC2 group. American journal of human genetics 124 11567215
1996 Molecular cloning and characterization of HE1, a major secretory protein of the human epididymis. Biology of reproduction 113 8924505
2004 Structure and function of the NPC2 protein. Biochimica et biophysica acta 100 15465422
2006 NPC2, the protein deficient in Niemann-Pick C2 disease, consists of multiple glycoforms that bind a variety of sterols. The Journal of biological chemistry 96 17018531
2014 All-trans retinoic acid-triggered antimicrobial activity against Mycobacterium tuberculosis is dependent on NPC2. Journal of immunology (Baltimore, Md. : 1950) 90 24501203
2003 Defective endocytic trafficking of NPC1 and NPC2 underlying infantile Niemann-Pick type C disease. Human molecular genetics 81 12554680
2012 Drosophila melanogaster NPC2 proteins bind bacterial cell wall components and may function in immune signal pathways. Insect biochemistry and molecular biology 75 22580186
2008 Regulation of sterol transport between membranes and NPC2. Biochemistry 75 18823126
2014 Acid sphingomyelinase activity is regulated by membrane lipids and facilitates cholesterol transfer by NPC2. Journal of lipid research 71 25339683
2010 Role of endosomal membrane lipids and NPC2 in cholesterol transfer and membrane fusion. Journal of lipid research 66 20179319
2005 Niemann-Pick C disease: use of denaturing high performance liquid chromatography for the detection of NPC1 and NPC2 genetic variations and impact on management of patients and families. Molecular genetics and metabolism 66 16126423
2019 Intracellular cholesterol trafficking is dependent upon NPC2 interaction with lysobisphosphatidic acid. eLife 63 31580258
2007 Niemann-Pick C disease: functional characterization of three NPC2 mutations and clinical and molecular update on patients with NPC2. Clinical genetics 52 17470133
2006 NPC2 is expressed in human and murine liver and secreted into bile: potential implications for body cholesterol homeostasis. Hepatology (Baltimore, Md.) 51 16374838
2004 Niemann-Pick type C disease: importance of N-glycosylation sites for function and cellular location of the NPC2 protein. Molecular genetics and metabolism 51 15542393
2002 Frontal lobe atrophy due to a mutation in the cholesterol binding protein HE1/NPC2. Annals of neurology 51 12447927
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
2011 NPC2 regulates biliary cholesterol secretion via stimulation of ABCG5/G8-mediated cholesterol transport. Gastroenterology 46 21315718
2017 The GARP Complex Is Involved in Intracellular Cholesterol Transport via Targeting NPC2 to Lysosomes. Cell reports 42 28658628
2001 Cholesterol overload promotes morphogenesis of a Niemann-Pick C (NPC)-like compartment independent of inhibition of NPC1 or HE1/NPC2 function. The Journal of biological chemistry 42 11571306
2004 Secretion of sterols and the NPC2 protein from primary astrocytes. The Journal of biological chemistry 41 15355983
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 40 28082351
2016 Transcriptomic Biomarkers for Tuberculosis: Evaluation of DOCK9. EPHA4, and NPC2 mRNA Expression in Peripheral Blood. Frontiers in microbiology 39 27826286
2011 Regulation of the NPC2 protein-mediated cholesterol trafficking by membrane lipids. Journal of neurochemistry 38 21214551
2019 Sterol transfer by atypical cholesterol-binding NPC2 proteins in coral-algal symbiosis. eLife 37 31159921
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 36 19252935
2016 The new obesity-associated protein, neuronal growth regulator 1 (NEGR1), is implicated in Niemann-Pick disease Type C (NPC2)-mediated cholesterol trafficking. Biochemical and biophysical research communications 35 27940359
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
2013 Involvement of cathepsins B and L in inflammation and cholesterol trafficking protein NPC2 secretion in macrophages. Obesity (Silver Spring, Md.) 35 23666609
2011 Sterol transfer between cyclodextrin and membranes: similar but not identical mechanism to NPC2-mediated cholesterol transfer. Biochemistry 35 21740003
2013 Pulmonary abnormalities in animal models due to Niemann-Pick type C1 (NPC1) or C2 (NPC2) disease. PloS one 33 23843985
2006 HE1/NPC2 status in human reproductive tract and ejaculated spermatozoa: consequence of vasectomy. Molecular human reproduction 31 16772431
2007 Do mammalian NPC1 and NPC2 play a role in intestinal cholesterol absorption? The Biochemical journal 29 17880278
2019 The characteristics and biological significance of NPC2: Mutation and disease. Mutation research. Reviews in mutation research 27 31843136
2018 A pair of nonspecific phospholipases C, NPC2 and NPC6, are involved in gametophyte development and glycerolipid metabolism in Arabidopsis. The New phytologist 27 29655284
2014 Spermatozoa from mice deficient in Niemann-Pick disease type C2 (NPC2) protein have defective cholesterol content and reduced in vitro fertilising ability. Reproduction, fertility, and development 27 24709320
2013 Computational studies of the cholesterol transport between NPC2 and the N-terminal domain of NPC1 (NPC1(NTD)). Biochemistry 27 24001314
2017 Expression patterns of sterol transporters NPC1 and NPC2 in the cnidarian-dinoflagellate symbiosis. Cellular microbiology 26 28544363
2019 Insights into the Molecular Mechanisms of Cholesterol Binding to the NPC1 and NPC2 Proteins. Advances in experimental medicine and biology 25 31098815
2015 The cholesterol-binding protein NPC2 restrains recruitment of stromal macrophage-lineage cells to early-stage lung tumours. EMBO molecular medicine 25 26183450
2017 Relationship between HSP90a, NPC2 and L-PGDS proteins to boar semen freezability. Journal of animal science and biotechnology 24 28270911
2004 Neuronal localization and association of Niemann Pick C2 protein (HE1/NPC2) with the postsynaptic density. Neuroscience 24 15381285
2017 Concerted regulation of npc2 binding to endosomal/lysosomal membranes by bis(monoacylglycero)phosphate and sphingomyelin. PLoS computational biology 23 29084218
2005 Niemann-Pick type C disease: subcellular location and functional characterization of NPC2 proteins with naturally occurring missense mutations. Human mutation 23 15937921
2004 Vasectomy influences expression of HE1 but not HE2 and HE5 genes in human epididymis. Journal of andrology 23 14662784
2019 Non-specific phospholipases C, NPC2 and NPC6, are required for root growth in Arabidopsis. The Plant journal : for cell and molecular biology 22 31400172
2017 Pulmonary manifestations in Niemann-Pick type C disease with mutations in NPC2 gene: case report and review of literature. BMC medical genetics 21 28095804
2018 Attenuation of the Niemann-Pick type C2 disease phenotype by intracisternal administration of an AAVrh.10 vector expressing Npc2. Experimental neurology 18 29655638
2016 The NPC2 protein: A novel dog allergen. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology 18 26995145
2018 The non-canonical NF-κB pathway promotes NPC2 expression and regulates intracellular cholesterol trafficking. Science China. Life sciences 16 30091016
2009 Female infertility due to anovulation and defective steroidogenesis in NPC2 deficient mice. Molecular and cellular endocrinology 16 19883728
2022 BORC-ARL8-HOPS ensemble is required for lysosomal cholesterol egress through NPC2. Molecular biology of the cell 14 35653304
2021 npc2-Deficient Zebrafish Reproduce Neurological and Inflammatory Symptoms of Niemann-Pick Type C Disease. Frontiers in cellular neuroscience 14 33986646
2021 Secretory NPC2 Protein-Mediated Free Cholesterol Levels Were Correlated with the Sorafenib Response in Hepatocellular Carcinoma. International journal of molecular sciences 14 34445279
2019 Relative content of Niemann-Pick C2 protein (NPC2) in seminal plasma, but not that of spermadhesin AQN-1, is related to boar sperm cryotolerance. Theriogenology 14 31711697
2014 Niemann-Pick type C disease: a QM/MM study of conformational changes in cholesterol in the NPC1(NTD) and NPC2 binding pockets. Biochemistry 14 25251378
2013 Identification of mutation in NPC2 by exome sequencing results in diagnosis of Niemann-Pick disease type C. Molecular genetics and metabolism 14 23791309
2022 Retinoic acid restores the levels of cellular cholesterol in Leishmania donovani infected macrophages by increasing npc1 and npc2 expressions. Biochimie 13 35272007
2021 Cat-NPC2, a Newly Identified Allergen, With High Cross-Reactivity to Can f 7. Allergy, asthma & immunology research 13 33191681
2021 Niemann-Pick Type C 1 (NPC1) and NPC2 Gene Variability in Demented Patients with Evidence of Brain Amyloid Deposition. Journal of Alzheimer's disease : JAD 13 34420959
2023 Niemann-Pick Disease Type C (NPDC) by Mutation of NPC1 and NPC2: Aberrant Lysosomal Cholesterol Trafficking and Oxidative Stress. Antioxidants (Basel, Switzerland) 10 38136141
2022 Effects of Niemann-Pick type C2 (NPC2) gene transcripts silencing on behavior of Varroa destructor and molecular changes in the putative olfactory gene networks. Insect biochemistry and molecular biology 10 35926690
2009 Identification of NPC2 protein as interaction molecule with C2 domain of human Nedd4L. Biochemical and biophysical research communications 10 19664597
2018 Simulations of NPC1(NTD):NPC2 Protein Complex Reveal Cholesterol Transfer Pathways. International journal of molecular sciences 9 30181526
2014 Characterization of a spontaneous novel mutation in the NPC2 gene in a cat affected by Niemann Pick type C disease. PloS one 9 25396745
2009 Physiological and coordinate downregulation of the NPC1 and NPC2 genes are associated with the sequestration of LDL-derived cholesterol within endocytic compartments. Journal of cellular biochemistry 9 19746448
2005 [Fatal neonatal respiratory distress in Niemann-Pick C2 and prenatal diagnosis with mutations in gene HE1/NPC2]. Archives de pediatrie : organe officiel de la Societe francaise de pediatrie 9 15808435
2021 Transcriptomic Biomarkers for Tuberculosis: Validation of NPC2 as a Single mRNA Biomarker to Diagnose TB, Predict Disease Progression, and Monitor Treatment Response. Cells 7 34685683
2014 Effect of the replacement of aspartic acid/glutamic acid residues with asparagine/glutamine residues in RNase He1 from Hericium erinaceus on inhibition of human leukemia cell line proliferation. Bioscience, biotechnology, and biochemistry 7 25338779
2007 A role for NPC1 and NPC2 in intestinal cholesterol absorption--the hypothesis gutted. The Biochemical journal 7 17956226
2023 Exploration of NPC2 as a Potential Biomarker for Immunotherapy Using RNA-seq and Protein Data - A New Hypothesis. Endocrine, metabolic & immune disorders drug targets 6 37056065
2023 The Npc2Gt(LST105)BygNya mouse signifies pathological changes comparable to human Niemann-Pick type C2 disease. Molecular and cellular neurosciences 6 37454976
2025 Deficiency in NPC2 results in disruption of mitochondria-late endosome/lysosomes contact sites and endo-lysosomal lipid dyshomeostasis. Scientific reports 5 39747180
2024 Low expression of lysosome-related genes KCNE1, NPC2, and SFTPD promote cancer cell proliferation and tumor associated M2 macrophage polarization in lung adenocarcinoma. Heliyon 5 38509982
2023 TMEM241 is a UDP-N-acetylglucosamine transporter required for M6P modification of NPC2 and cholesterol transport. Journal of lipid research 5 37890669
2021 Pathophysiological In Vitro Profile of Neuronal Differentiated Cells Derived from Niemann-Pick Disease Type C2 Patient-Specific iPSCs Carrying the NPC2 Mutations c.58G>T/c.140G>T. International journal of molecular sciences 4 33924575
2009 Getting a "Hold" on NPC2. Cell metabolism 4 19723490
2025 SARS-CoV-2 ORF3a blocks lysosomal cholesterol egress by disrupting VPS39-regulated NPC2 trafficking and BMP metabolism. bioRxiv : the preprint server for biology 3 39605369
2024 NPC2, a seminal plasma protein with membrane cholesterol-binding ability, influences the cryotolerance and functionality of spermatozoa from Chino Santandereano bulls. Animal reproduction science 3 39798440
2023 Focusing on the Abnormal Events of NPC1, NPC2, and NPC1L1 in Pan-Cancer and Further Constructing LUAD and KICH Prediction Models. Journal of proteome research 3 38109854
2021 Identification and Classification of Rare Variants in NPC1 and NPC2 in Quebec. Scientific reports 3 33990640
2025 Genome-Wide Identification, Gene Duplication, and Expression Pattern of NPC2 Gene Family in Parnassius glacialis. Genes 2 40149401
2023 Novel Mutation in the Feline NPC2 Gene in Cats with Niemann-Pick Disease. Animals : an open access journal from MDPI 2 37458497
2021 NPC2 expression in thyroid tumors and its possible diagnostic utility. International journal of clinical and experimental pathology 2 33532030
2020 Existence and distribution of Niemann-Pick type 2C (NPC2) in prawn reproductive tract and its putative role as a cholesterol modulator during sperm transit in the vas deferens. Cell and tissue research 2 32556727
2010 Proteomic identification and characterization of secreted N-glycosylated NPC2 following cross-linking of the high-affinity receptor for IgE on mast cells. Cell biology international 2 20001954
2025 ALKBH5-mediated NPC2 mRNA m6A demethylation promotes resistance to oxaliplatin in colorectal cancer. Functional & integrative genomics 1 40681956
2019 X-Ray Crystallographic Structure of Hericium erinaceus Ribonuclease, RNase He1 in Complex with Zinc. Biological & pharmaceutical bulletin 1 31787719
2014 Mutagenesis of the novel Hericium erinaceus ribonuclease, RNase He1, reveals critical responsible residues for enzyme stability and activity. Biological & pharmaceutical bulletin 1 25366489