Npc1 encodes NPC intracellular cholesterol transporter 1, a 1277-residue polytopic glycoprotein of the limiting membrane of late endosomes and lysosomes, with a signal peptide, 13 transmembrane helices, three large lumenal domains and a sterol-sensing domain, and it belongs to the patched family. It is the membrane half of a two-protein cholesterol export machine. Cholesterol liberated from endocytosed LDL in the acidic lysosomal lumen is bound by the small soluble protein NPC2, which docks on the second (middle) lumenal domain of NPC1 in a cholesterol-dependent, pH-dependent manner; the sterol is then handed off through a transfer tunnel into the cholesterol-binding pocket of the NPC1 N-terminal domain, held in the orientation set by the C-terminal lumenal domain, and delivered into the limiting membrane. From there NPC1 supplies cholesterol to the rest of the cell, including by tethering lysosome-endoplasmic reticulum membrane contact sites and passing sterol to GRAMD1B, so that lysosomal cholesterol reaches the metabolically active pool. The cholesterol-binding site is indispensable: knocking the binding-dead P202A/F203A substitutions into mouse Npc1 reproduces the phenotype of complete deficiency. A second activity of the same transport function restrains growth signalling, as NPC1 binds the lysosomal transmembrane protein SLC38A9 and prevents lysosomal cholesterol from activating mTORC1. NPC1 is also the intracellular receptor for the proteolytically primed Ebola virus glycoprotein, a requirement independent of its sterol transport activity. Loss of Npc1 in mouse sequesters unesterified cholesterol and glycosphingolipids in late endosomes and lysosomes, expands the whole-animal sterol pool, and causes hepatosplenomegaly, progressive Purkinje-cell loss, ataxia and death at around 2-3 months; export-promoting cyclodextrin prevents the neurodegeneration. Smaller pools of the protein are detected at the plasma membrane and in caveolin-1-containing rafts, and the protein transits the endoplasmic reticulum and Golgi as a heavily N-glycosylated biosynthetic intermediate.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001889 liver development | IMP PMID:21289032 Quantitative role of LAL, NPC2, and NPC1 in lysosomal choles... | MARK AS OVER ANNOTATED | Summary: IMP to liver development from the quantitative LAL/NPC2/NPC1 lysosomal cholesterol-processing study in mice. Reason: What this study measures in liver is lysosomal sterol processing and whole-animal sterol pool size in npc1-/- mice, not organ development. NPC1 loss produces hepatic cholesterol storage and secondary liver pathology, so a developmental reading is not flatly wrong, but the gene product performs no step of liver development; the informative terms are the cholesterol-transport and homeostasis terms it already carries. The full text is not in our cache, so the row is marked over-annotated rather than removed, and the term is flagged upstream for review. Supporting Evidence: PMID:21289032 endosomal/lysosomal (E/L) compartment by the sequential action of lysosomal acid PMID:21289032 processing and export of sterol |
| GO:0005319 lipid carrier activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro IPR004765 (NPC1 family) maps to the generic lipid carrier activity term. Reason: Correct but less specific than the evidence supports: NPC1 carries cholesterol specifically, and GO:0120020 cholesterol transfer activity (a descendant of GO:0005319 via sterol transfer activity) is already asserted for this gene by ISS/ISO/IEA. Refine the family-level mapping to the cholesterol-specific child. Proposed replacements: cholesterol transfer activity Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Important for cholesterol binding and cholesterol PMID:18772377 NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol |
| GO:0005515 protein binding | IPI PMID:16757520 Cholesterol depletion facilitates ubiquitylation of NPC1 and... | REMOVE | Summary: IPI with Vps4b/SKD1: cholesterol depletion drives NPC1 ubiquitylation and association with SKD1/Vps4 on endosomal membranes. Reason: Bare GO:0005515 protein binding carries no functional information and is removed under the protein-binding policy. Removal does not question the reported interaction: cholesterol depletion does promote NPC1 ubiquitylation and SKD1 association, but that observation is about ESCRT-dependent turnover of NPC1 and supports no more informative molecular-function term for NPC1 itself. Supporting Evidence: PMID:16757520 depletion of cellular cholesterol facilitated ubiquitylation of NPC1 PMID:16757520 SKD1(E235Q) associated with NPC1 on the endosomal membrane |
| GO:0005515 protein binding | IPI PMID:22065762 Niemann-Pick type C 1 function requires lumenal domain resid... | MODIFY | Summary: IPI with bovine NPC2: NPC1 lumenal domain 2 binds NPC2 directly, only at acidic pH and only when NPC2 carries cholesterol. Reason: The cited paper supports a specific molecular function rather than bare protein binding: the cholesterol-dependent NPC1-MLD/NPC2 interaction is the hand-off step by which cholesterol is transferred onto NPC1, and disease mutations in domain 2 that weaken NPC2 binding abolish function while still reaching lysosomes. Replace the uninformative term with cholesterol transfer activity. Proposed replacements: cholesterol transfer activity Supporting Evidence: PMID:22065762 we show here that the second lumenal domain of NPC1 binds directly to NPC2 protein PMID:22065762 Binding to NPC1 domain 2 requires the presence of cholesterol on PMID:22065762 R581Q showed the same punctate, lysosomal distribution as the wild-type protein PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol file:mouse/Npc1/Npc1-uniprot.txt Interacts (via the second lumenal domain) with NPC2 |
| GO:0005515 protein binding | IPI PMID:34237247 Global mapping of Salmonella enterica-host protein-protein i... | REMOVE | Summary: IPI with the Salmonella secreted effector SseJ from a global host-pathogen interactome screen. Reason: Bare GO:0005515 protein binding is uninformative and is removed under the protein-binding policy. The interactome hit itself is not disputed, but a xeno interaction detected in a proteome-scale screen supports no molecular-function term for mouse Npc1. Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt O35604; A0A0F6B1Q8: sseJ; Xeno; NbExp=3 |
| GO:0005576 extracellular region | IDA PMID:22065762 Niemann-Pick type C 1 function requires lumenal domain resid... | REMOVE | Summary: IDA to extracellular region from the NPC1 lumenal-domain-2/NPC2 binding study. Reason: The extracellular signal is a property of the experimental construct, not of NPC1. The authors built a soluble domain-2 fragment by replacing transmembrane domains 2 and 3 with an antiparallel coiled coil and adding a preprotrypsin signal peptide, then purified it from conditioned medium. Native NPC1 is a multi-pass lysosomal/late-endosomal membrane protein with no secreted form, so the location claim is contradicted by the record itself. Full text was read before removing this experimental row. Supporting Evidence: PMID:22065762 a soluble NPC1 lumenal domain 2 was engineered by replacing adjacent transmembrane domains with antiparallel coiled-coil sequences PMID:22065762 the protein was efficiently processed for secretion and could be collected from the conditioned medium file:mouse/Npc1/Npc1-uniprot.txt Multi-pass membrane protein file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005635 nuclear envelope | IDA PMID:20457914 A molecular mechanism underlying the neural-specific defect ... | MARK AS OVER ANNOTATED | Summary: IDA to nuclear envelope attributed to the torsinA mutant mouse paper. Reason: Nuclear envelope is at best an over-reading of the ER/perinuclear signal reported for NPC1 (and largely for mislocalized mutant NPC1). NPC1 functions in the limiting membrane of late endosomes and lysosomes; no assay places an NPC1 activity at the nuclear envelope. The term is not flatly impossible - the NE is continuous with the ER, through which NPC1 is synthesized - so the rows are marked over-annotated rather than removed. In addition, the cited reference is about torsinA/LAP1 and nuclear-membrane blebbing in Tor1a mutant mice; Npc1 is not mentioned anywhere in the cached full text, so the reference is flagged upstream for checking. Supporting Evidence: PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to file:mouse/Npc1/Npc1-uniprot.txt Multi-pass membrane protein file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005635 nuclear envelope | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of the human nuclear envelope annotation. Reason: Nuclear envelope is at best an over-reading of the ER/perinuclear signal reported for NPC1 (and largely for mislocalized mutant NPC1). NPC1 functions in the limiting membrane of late endosomes and lysosomes; no assay places an NPC1 activity at the nuclear envelope. The term is not flatly impossible - the NE is continuous with the ER, through which NPC1 is synthesized - so the rows are marked over-annotated rather than removed. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS SOURCE BUT NOT TARGET The human nuclear-envelope IDA (PMID:12554680) rests on ER/perinuclear staining, largely of mislocalized mutant NPC1; the compartment claim is an over-reading rather than a functional location. Supporting Evidence: PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005635 nuclear envelope | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Mouse-human ortholog transfer of the human nuclear envelope annotation. Reason: Nuclear envelope is at best an over-reading of the ER/perinuclear signal reported for NPC1 (and largely for mislocalized mutant NPC1). NPC1 functions in the limiting membrane of late endosomes and lysosomes; no assay places an NPC1 activity at the nuclear envelope. The term is not flatly impossible - the NE is continuous with the ER, through which NPC1 is synthesized - so the rows are marked over-annotated rather than removed. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS SOURCE BUT NOT TARGET Same human IDA source; the ortholog transfer carries the over-reading with it. Supporting Evidence: PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005635 nuclear envelope | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Curator sequence-similarity transfer of the human nuclear envelope annotation. Reason: Nuclear envelope is at best an over-reading of the ER/perinuclear signal reported for NPC1 (and largely for mislocalized mutant NPC1). NPC1 functions in the limiting membrane of late endosomes and lysosomes; no assay places an NPC1 activity at the nuclear envelope. The term is not flatly impossible - the NE is continuous with the ER, through which NPC1 is synthesized - so the rows are marked over-annotated rather than removed. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS SOURCE BUT NOT TARGET Same human IDA source, transferred by curator judgement of sequence similarity. Supporting Evidence: PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005764 lysosome | IDA PMID:10787428 Localization of the murine Niemann-Pick C1 protein to two di... | ACCEPT | Summary: Mouse NPC1 cosediments with LAMP1-containing membranes and colocalizes with LAMP1-positive compartments, increasingly so after LDL loading. Reason: Lysosome is a root organelle term and is informative in its own right (projects/ORGANELLES.md): it is kept beside the lysosomal membrane rows rather than refined to them. This is the compartment where NPC1 receives cholesterol from NPC2 and exports it, so the location is core. Supporting Evidence: PMID:10787428 Incubation of fibroblasts with low density lipoprotein (LDL) increases PMID:10787428 colocalization of NPC1 with LAMP1-containing compartments file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005764 lysosome | IDA PMID:21289032 Quantitative role of LAL, NPC2, and NPC1 in lysosomal choles... | ACCEPT | Summary: NPC1 acts in the lysosome in the sequential LAL/NPC2/NPC1 pathway that processes and exports lipoprotein-derived cholesterol. Reason: Lysosome is a root organelle term and is informative in its own right (projects/ORGANELLES.md): it is kept beside the lysosomal membrane rows rather than refined to them. This is the compartment where NPC1 receives cholesterol from NPC2 and exports it, so the location is core. Here the row records where the activity happens, which matches the genetic and pharmacological dissection of the pathway. Supporting Evidence: PMID:21289032 endosomal/lysosomal (E/L) compartment by the sequential action of lysosomal acid PMID:21289032 processing and export of sterol |
| GO:0005764 lysosome | IDA PMID:21896731 Amino acid substitution in NPC1 that abolishes cholesterol b... | ACCEPT | Summary: Cholesterol-binding-site knock-in mice (Npc1 P202A/F203A) accumulate cholesterol in lysosomes, where NPC1 resides. Reason: Lysosome is a root organelle term and is informative in its own right (projects/ORGANELLES.md): it is kept beside the lysosomal membrane rows rather than refined to them. This is the compartment where NPC1 receives cholesterol from NPC2 and exports it, so the location is core. Supporting Evidence: PMID:21896731 npc1(pf/pf) mice accumulated excess cholesterol in lysosomes PMID:21896731 reproduce the phenotype of complete NPC1 deficiency when knocked into the mouse file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005764 lysosome | IDA PMID:22065762 Niemann-Pick type C 1 function requires lumenal domain resid... | ACCEPT | Summary: Full-length NPC1-GFP shows punctate lysosomal distribution. Reason: Lysosome is a root organelle term and is informative in its own right (projects/ORGANELLES.md): it is kept beside the lysosomal membrane rows rather than refined to them. This is the compartment where NPC1 receives cholesterol from NPC2 and exports it, so the location is core. Supporting Evidence: PMID:22065762 R581Q showed the same punctate, lysosomal distribution as the wild-type protein file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005765 lysosomal membrane | EXP PMID:21896731 Amino acid substitution in NPC1 that abolishes cholesterol b... | ACCEPT | Summary: Experimental lysosomal membrane localization in the cholesterol-binding-site knock-in study. Reason: The lysosomal limiting membrane is NPC1 core functional location: a 13-transmembrane glycoprotein whose lumenal domains receive cholesterol from NPC2 and deliver it into the membrane for export. Curated UniProt subcellular location and the structural/genetic literature agree. Supporting Evidence: PMID:21896731 a lysosomal membrane protein, abolish its cholesterol binding activity and file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005765 lysosomal membrane | EXP PMID:22065762 Niemann-Pick type C 1 function requires lumenal domain resid... | ACCEPT | Summary: Experimental lysosomal membrane localization of full-length NPC1 in the NPC2-binding study. Reason: The lysosomal limiting membrane is NPC1 core functional location: a 13-transmembrane glycoprotein whose lumenal domains receive cholesterol from NPC2 and deliver it into the membrane for export. Curated UniProt subcellular location and the structural/genetic literature agree. Supporting Evidence: PMID:22065762 R581Q showed the same punctate, lysosomal distribution as the wild-type protein file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005765 lysosomal membrane | EXP PMID:27551080 Clues to the mechanism of cholesterol transfer from the stru... | ACCEPT | Summary: Experimental lysosomal membrane localization of mouse NPC1 MLD mutants in the NPC1-MLD/NPC2 structure paper. Reason: The lysosomal limiting membrane is NPC1 core functional location: a 13-transmembrane glycoprotein whose lumenal domains receive cholesterol from NPC2 and deliver it into the membrane for export. Curated UniProt subcellular location and the structural/genetic literature agree. Supporting Evidence: PMID:27551080 Colocalization with endogenous lysosome-associated membrane protein 2 (LAMP2) confirmed that the mutant NPC1 protein was indeed correctly delivered to lysosomes file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005765 lysosomal membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automatic methods (including the UniProt SL-0157 lysosome membrane keyword) place NPC1 in the lysosomal membrane. Reason: The lysosomal limiting membrane is NPC1 core functional location: a 13-transmembrane glycoprotein whose lumenal domains receive cholesterol from NPC2 and deliver it into the membrane for export. Curated UniProt subcellular location and the structural/genetic literature agree. The electronic row agrees with the three experimental rows for the same term. Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane file:mouse/Npc1/Npc1-uniprot.txt Multi-pass membrane protein |
| GO:0005765 lysosomal membrane | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse-human ortholog transfer of lysosomal membrane localization. Reason: The lysosomal limiting membrane is NPC1 core functional location: a 13-transmembrane glycoprotein whose lumenal domains receive cholesterol from NPC2 and deliver it into the membrane for export. Curated UniProt subcellular location and the structural/genetic literature agree. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 lysosomal membrane localization is experimentally established and the mouse protein has its own EXP rows for the same term. Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005765 lysosomal membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of lysosomal membrane localization. Reason: The lysosomal limiting membrane is NPC1 core functional location: a 13-transmembrane glycoprotein whose lumenal domains receive cholesterol from NPC2 and deliver it into the membrane for export. Curated UniProt subcellular location and the structural/genetic literature agree. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 lysosomal membrane localization, transferred by sequence similarity; mouse NPC1 also carries direct evidence. Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005768 endosome | IDA PMID:10787428 Localization of the murine Niemann-Pick C1 protein to two di... | MODIFY | Summary: IDA endosome localization of murine NPC1 by fractionation and microscopy. Reason: Correct but less specific than the evidence supports. NPC1 resides in the limiting membrane of late endosomes, and GO:0031902 late endosome membrane is already asserted for this gene; the endosome row is refined to it rather than kept at the generic compartment. (Endosome is not one of the five root organelle terms exempted by projects/ORGANELLES.md.) Proposed replacements: late endosome membrane Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Late endosome membrane PMID:10787428 colocalization of NPC1 with LAMP1-containing compartments |
| GO:0005768 endosome | IDA PMID:16757520 Cholesterol depletion facilitates ubiquitylation of NPC1 and... | MODIFY | Summary: IDA endosome localization: NPC1 and SKD1/Vps4 associate on the endosomal membrane. Reason: Correct but less specific than the evidence supports. NPC1 resides in the limiting membrane of late endosomes, and GO:0031902 late endosome membrane is already asserted for this gene; the endosome row is refined to it rather than kept at the generic compartment. (Endosome is not one of the five root organelle terms exempted by projects/ORGANELLES.md.) Proposed replacements: late endosome membrane Supporting Evidence: PMID:16757520 SKD1(E235Q) associated with NPC1 on the endosomal membrane file:mouse/Npc1/Npc1-uniprot.txt Late endosome membrane |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of the human ER localization (human IDA, PMID:12554680). Reason: Endoplasmic reticulum is a root organelle term, so it is kept rather than refined or dismissed (projects/ORGANELLES.md). NPC1 is a co-translationally inserted, N-glycosylated multi-pass protein that transits the ER, mutant forms accumulate there, and NPC1 engages lysosome-ER membrane contact sites with GRAMD1B. None of that makes the ER where the cholesterol hand-off happens, so the location is kept as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 ER localization rests on direct imaging; the claim holds for mouse NPC1 as a biosynthetic/contact-site location rather than the site of the transport activity. Supporting Evidence: PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to file:mouse/Npc1/Npc1-uniprot.txt Mediates cholesterol transfer from lysosomes to endoplasmic reticulum by tethering |
| GO:0005783 endoplasmic reticulum | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Mouse-human ortholog transfer of the human ER localization. Reason: Endoplasmic reticulum is a root organelle term, so it is kept rather than refined or dismissed (projects/ORGANELLES.md). NPC1 is a co-translationally inserted, N-glycosylated multi-pass protein that transits the ER, mutant forms accumulate there, and NPC1 engages lysosome-ER membrane contact sites with GRAMD1B. None of that makes the ER where the cholesterol hand-off happens, so the location is kept as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 ER localization rests on direct imaging; the claim holds for mouse NPC1 as a biosynthetic/contact-site location rather than the site of the transport activity. Supporting Evidence: PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to file:mouse/Npc1/Npc1-uniprot.txt Mediates cholesterol transfer from lysosomes to endoplasmic reticulum by tethering |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator sequence-similarity transfer of the human ER localization. Reason: Endoplasmic reticulum is a root organelle term, so it is kept rather than refined or dismissed (projects/ORGANELLES.md). NPC1 is a co-translationally inserted, N-glycosylated multi-pass protein that transits the ER, mutant forms accumulate there, and NPC1 engages lysosome-ER membrane contact sites with GRAMD1B. None of that makes the ER where the cholesterol hand-off happens, so the location is kept as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 ER localization rests on direct imaging; the claim holds for mouse NPC1 as a biosynthetic/contact-site location rather than the site of the transport activity. Supporting Evidence: PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to file:mouse/Npc1/Npc1-uniprot.txt Mediates cholesterol transfer from lysosomes to endoplasmic reticulum by tethering |
| GO:0005794 Golgi apparatus | IDA PMID:10787428 Localization of the murine Niemann-Pick C1 protein to two di... | KEEP AS NON CORE | Summary: IDA Golgi apparatus localization of murine NPC1 by immunofluorescence and fractionation. Reason: Golgi apparatus is a root organelle term and is kept rather than refined (projects/ORGANELLES.md). NPC1 is a glycoprotein that acquires endoglycosidase H-resistant, Golgi-processed oligosaccharides, so a Golgi pool is expected along the biosynthetic route; the same study reports that the major NPC1-containing structures do not coincide with the main organelle markers, so the Golgi is a transit compartment rather than where NPC1 acts. Experimental row, full text unavailable, so it is kept rather than removed. Supporting Evidence: PMID:22065762 That the protein passed through the Golgi complex is confirmed by the presence of endoglycosidase H-resistant oligosaccharide chains PMID:10787428 do not colocalize with major file:mouse/Npc1/Npc1-uniprot.txt N-glycosylated |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA plasma membrane from the PANTHER NPC1/NPC1L1 node. Reason: Plasma membrane is true of this gene - a fraction of murine NPC1 is detected at the cell surface and in caveolin-1-containing rafts, which is what the IDA row for the same term records - so the claim is kept, consistently with the other four rows, as a peripheral location. It is not core: the cholesterol hand-off from NPC2 occurs in the acidic lysosomal lumen. Worth noting for the phylogenetic reading is that the node behind this row also covers NPC1L1 (UniProtKB:Q9UHC9 is in the WITH/FROM), the apical enterocyte sterol permease whose activity really is plasma-membrane based; that branch, not NPC1, is where a plasma-membrane site of action is established. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000083973 · PTN000083973 SUPPORTS TRANSFER The NPC1/NPC1L1 node is well grounded; a plasma-membrane pool of NPC1 is independently observed in mouse, though the NPC1L1 branch is where plasma-membrane sterol transport is actually characterized. Supporting Evidence: PMID:10787428 a fraction of NPC1 cosediments with caveolin-1 in rafts PMID:10821832 this glycoprotein contains 13 transmembrane domains, 3 large and 4 small luminal file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0005886 plasma membrane | IDA PMID:10787428 Localization of the murine Niemann-Pick C1 protein to two di... | KEEP AS NON CORE | Summary: IDA plasma membrane: a raft/caveolin-1-associated NPC1 pool in mouse liver membranes and fibroblasts. Reason: A fraction of NPC1 is detected at the cell surface and in detergent-resistant, caveolin-1-containing rafts, and epitope-accessibility topology mapping also exploited a surface pool. This is a real but peripheral localization: the cholesterol hand-off from NPC2 happens in the acidic lysosomal lumen, so the plasma membrane is kept as a non-core location. Supporting Evidence: PMID:10787428 a fraction of NPC1 cosediments with caveolin-1 in rafts PMID:10821832 this glycoprotein contains 13 transmembrane domains, 3 large and 4 small luminal |
| GO:0005886 plasma membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of the human plasma membrane localization. Reason: A fraction of NPC1 is detected at the cell surface and in detergent-resistant, caveolin-1-containing rafts, and epitope-accessibility topology mapping also exploited a surface pool. This is a real but peripheral localization: the cholesterol hand-off from NPC2 happens in the acidic lysosomal lumen, so the plasma membrane is kept as a non-core location. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 cell-surface/plasma-membrane detection is direct; the mouse protein has its own IDA row for the same term. Non-core either way. Supporting Evidence: PMID:10787428 a fraction of NPC1 cosediments with caveolin-1 in rafts PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to |
| GO:0005886 plasma membrane | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Mouse-human ortholog transfer of the human plasma membrane localization. Reason: A fraction of NPC1 is detected at the cell surface and in detergent-resistant, caveolin-1-containing rafts, and epitope-accessibility topology mapping also exploited a surface pool. This is a real but peripheral localization: the cholesterol hand-off from NPC2 happens in the acidic lysosomal lumen, so the plasma membrane is kept as a non-core location. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 cell-surface/plasma-membrane detection is direct; the mouse protein has its own IDA row for the same term. Non-core either way. Supporting Evidence: PMID:10787428 a fraction of NPC1 cosediments with caveolin-1 in rafts PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to |
| GO:0005886 plasma membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator sequence-similarity transfer of the human plasma membrane localization. Reason: A fraction of NPC1 is detected at the cell surface and in detergent-resistant, caveolin-1-containing rafts, and epitope-accessibility topology mapping also exploited a surface pool. This is a real but peripheral localization: the cholesterol hand-off from NPC2 happens in the acidic lysosomal lumen, so the plasma membrane is kept as a non-core location. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 cell-surface/plasma-membrane detection is direct; the mouse protein has its own IDA row for the same term. Non-core either way. Supporting Evidence: PMID:10787428 a fraction of NPC1 cosediments with caveolin-1 in rafts PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to |
| GO:0006897 endocytosis | IMP PMID:15078881 Accumulation of glycosphingolipids in Niemann-Pick C disease... | MARK AS OVER ANNOTATED | Summary: IMP endocytosis from the study of glycosphingolipid accumulation and disrupted endosomal transport in NPC cells. Reason: The reduced uptake of a fluid-phase marker in NPC1-deficient cells is a consequence of accumulated glycosphingolipid in mislocalized membrane microdomains - the paper itself attributes the trafficking deficit to the stored lipid, and inhibiting glycosphingolipid synthesis reverses it. NPC1 performs no step of endocytosis; it acts downstream, after endocytosed LDL cholesterol has reached the lysosome. Necessity for a normal endocytic phenotype is not participation. Supporting Evidence: PMID:15078881 endocytic uptake of a fluid phase marker PMID:15078881 accumulating GSL is part of a mislocalized membrane PMID:21289032 endosomal/lysosomal (E/L) compartment by the sequential action of lysosomal acid |
| GO:0006914 autophagy | ISO PMID:19074461 Tau deletion exacerbates the phenotype of Niemann-Pick type ... | MODIFY | Summary: ISO autophagy, transferred from the human ortholog on the basis of the Npc1/Mapt double-mutant study. Reason: The relationship between NPC1 and autophagy is regulatory and negative: loss of NPC1 raises Beclin-1 and LC3-II and increases flux, so the wild-type protein restrains macroautophagy rather than carrying it out. The gene already has IMP and IGI rows for GO:0016242 negative regulation of macroautophagy from the same group, which is the claim the evidence supports; the bare autophagy term asserts participation in the process itself. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS SOURCE BUT NOT TARGET The human source annotation records the same phenotype (increased autophagy on NPC1 loss); the direction of the relationship, not the organism, is what the term gets wrong. Proposed replacements: negative regulation of macroautophagy Supporting Evidence: PMID:17468177 associated with increased expression of Beclin-1 PMID:17468177 like npc1(-/-) mice fibroblasts, showed increased PMID:19074461 reduction of tau expression in a cellular model of NPC decreases induction and |
| GO:0007041 lysosomal transport | ISS GO_REF:0000024 | MODIFY | Summary: ISS lysosomal transport, transferred from UniProtKB:Q7TMD4. Reason: The claim is right but general: NPC1 mediates a specific lysosomal transport step, the export of cholesterol from the lysosome towards the ER, for which GO:0090120 (a descendant of GO:0007041 via intracellular cholesterol transport) is already asserted for this gene. Refine to the specific term. Note also that the ISS donor Q7TMD4 is a second, unreviewed UniProt entry for the same mouse gene, so this is a within-gene transfer rather than a cross-species inference. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:Q7TMD4 · Npc1 SUPPORTS TRANSFER Q7TMD4 is an unreviewed UniProt entry for the same mouse Npc1 gene; its IMP (PMID:15071184) shows NPC1 and NPC2 acting in concert in lysosomal lipid export, which supports the claim but at a coarser term than the evidence allows. Proposed replacements: lysosome to ER cholesterol transport Supporting Evidence: PMID:21289032 processing and export of sterol PMID:15071184 function in concert to facilitate the intracellular transport of file:mouse/Npc1/Npc1-uniprot.txt Mediates cholesterol transfer from lysosomes to endoplasmic reticulum by tethering |
| GO:0007628 adult walking behavior | IGI PMID:19074461 Tau deletion exacerbates the phenotype of Niemann-Pick type ... | MARK AS OVER ANNOTATED | Summary: IGI adult walking behavior from Npc1/Mapt double-null mice. Reason: Gait abnormality in Npc1-null (and Npc1;Mapt double-null) mice is the behavioural readout of Purkinje-cell loss caused by lysosomal cholesterol sequestration. NPC1 executes no step of locomotion; the phenotype establishes that the gene is required for a normal nervous system, which is not participation in walking behaviour. Supporting Evidence: PMID:19074461 NPC1/tau double null mutants are generated in PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration file:mouse/Npc1/Npc1-uniprot.txt Causes age-dependent loss of Purkinje cells, loss of body weight and leads then to ataxia and premature |
| GO:0008206 bile acid metabolic process | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: ISS bile acid metabolic process, transferred from UniProtKB:Q7TMD4 (donor IMP, PMID:16374838). Reason: The donor paper is about NPC2 in bile and plasma; its NPC1 observation is that hepatic NPC2 protein rises sharply in NPC1-deficient mice. No bile acid species or bile acid enzyme step is assigned to NPC1, which transports cholesterol rather than metabolizing it. Biliary lipid secretion is altered in Npc1 mutant mice, so the term is not flatly wrong, but it overstates the gene role. The donor row full text is not available to us, so the row is marked over-annotated rather than removed. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: UniProtKB:Q7TMD4 · Npc1 SUPPORTS SOURCE BUT NOT TARGET Q7TMD4 (unreviewed mouse Npc1) carries GO:0008206 IMP from PMID:16374838, a study of NPC2 secretion into bile in which the NPC1-deficient mouse serves as the genetic background; bile acid metabolism itself is not assayed for NPC1. Supporting Evidence: PMID:16374838 hepatic NPC2 protein expression was dramatically PMID:21289032 processing and export of sterol |
| GO:0009101 glycoprotein biosynthetic process | IEA GO_REF:0000107 | REMOVE | Summary: Ensembl Compara transfer of human glycoprotein biosynthetic process. Reason: NPC1 is a substrate of glycosylation, not a participant in glycoprotein biosynthesis. The human source annotation comes from the topology study, which identified NPC1 own N-glycosylated lumenal loops to map its 13-transmembrane architecture; being N-glycosylated is exactly what being a substrate means, and NPC1 catalyses no step of glycan assembly or transfer and supplies no scaffold or cofactor for one. The comparator check agrees: substrates are not annotated to their modifying pathway in this way, while the glycosyltransferases and OST subunits that do the work are. Both mouse rows are electronic propagations of that misreading, so they are removed. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:O15118 · NPC1 SOURCE BAD Human NPC1 GO:0009101 IDA (PMID:10821832) treats NPC1 own glycosylation as participation in glycoprotein biosynthesis. Supporting Evidence: PMID:10821832 this glycoprotein contains 13 transmembrane domains, 3 large and 4 small luminal file:mouse/Npc1/Npc1-uniprot.txt N-glycosylated |
| GO:0009101 glycoprotein biosynthetic process | ISO GO_REF:0000119 | REMOVE | Summary: Mouse-human ortholog transfer of human glycoprotein biosynthetic process. Reason: NPC1 is a substrate of glycosylation, not a participant in glycoprotein biosynthesis. The human source annotation comes from the topology study, which identified NPC1 own N-glycosylated lumenal loops to map its 13-transmembrane architecture; being N-glycosylated is exactly what being a substrate means, and NPC1 catalyses no step of glycan assembly or transfer and supplies no scaffold or cofactor for one. The comparator check agrees: substrates are not annotated to their modifying pathway in this way, while the glycosyltransferases and OST subunits that do the work are. Both mouse rows are electronic propagations of that misreading, so they are removed. Propagation Review Root cause: SOURCE BAD Failure modes: ROLE CONFLATION Sources checked: UniProtKB:O15118 · NPC1 SOURCE BAD Same human IDA row; the substrate/participant conflation transfers with it. Supporting Evidence: PMID:10821832 this glycoprotein contains 13 transmembrane domains, 3 large and 4 small luminal file:mouse/Npc1/Npc1-uniprot.txt N-glycosylated |
| GO:0009410 response to xenobiotic stimulus | IDA PMID:10787428 Localization of the murine Niemann-Pick C1 protein to two di... | KEEP AS NON CORE | Summary: IDA response to xenobiotic stimulus: chloroquine (and progesterone) treatment redistributes NPC1 to LAMP1-positive compartments. Reason: NPC1 responds to, and contributes to the handling of, lysosomotropic xenobiotics: chloroquine treatment shifts its distribution, and NPC1 knockdown raises cellular chloroquine accumulation and abolishes the protection conferred by alpha-tocopherol transfer protein. A genuine but peripheral role next to the cholesterol-export function. Supporting Evidence: PMID:10787428 can be further enhanced by treating fibroblasts with progesterone or PMID:10787428 colocalization of NPC1 with LAMP1-containing compartments PMID:22147702 These results indicate that NPC1 is involved in α-TTP-mediated prevention of CQ accumulation |
| GO:0010467 gene expression | IMP PMID:21289032 Quantitative role of LAL, NPC2, and NPC1 in lysosomal choles... | MARK AS OVER ANNOTATED | Summary: IMP gene expression from the quantitative lysosomal cholesterol-processing study. Reason: GO:0010467 gene expression is both uninformative and the wrong kind of claim here. What the cited studies show is that transcript or protein levels change in Npc1-mutant tissue - lysosomal enzyme mRNAs in liver, cerebellar EAAT and beta-III-spectrin protein. Those are downstream consequences of lysosomal cholesterol storage; NPC1 performs no step of transcription or translation. Supporting Evidence: PMID:21289032 endosomal/lysosomal (E/L) compartment by the sequential action of lysosomal acid PMID:21289032 processing and export of sterol |
| GO:0010467 gene expression | IMP PMID:29463856 Impact of Reduced Cerebellar EAAT Expression on Purkinje Cel... | MARK AS OVER ANNOTATED | Summary: IMP gene expression from the cerebellar EAAT expression study in Npc1-/- mice. Reason: GO:0010467 gene expression is both uninformative and the wrong kind of claim here. What the cited studies show is that transcript or protein levels change in Npc1-mutant tissue - lysosomal enzyme mRNAs in liver, cerebellar EAAT and beta-III-spectrin protein. Those are downstream consequences of lysosomal cholesterol storage; NPC1 performs no step of transcription or translation. Supporting Evidence: PMID:29463856 EAAT1, EAAT2, EAAT4, and βIII-spectrin levels in NPC1-/-mice PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration |
| GO:0010878 cholesterol storage | IMP PMID:21697390 Unesterified cholesterol accumulation in late endosomes/lyso... | KEEP AS NON CORE | Summary: IMP cholesterol storage: Npc1-/- mice sequester unesterified cholesterol in late endosomes/lysosomes. Reason: Where cellular cholesterol is stored does depend on NPC1, and the term captures that regulatory relationship, but the activity NPC1 performs is the transfer and export step; storage is the state that results when it fails. Kept as a non-core process term beside the transport and homeostasis terms. Supporting Evidence: PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration PMID:21697390 a compound known to prevent this C accumulation |
| GO:0012501 programmed cell death | IMP PMID:21697390 Unesterified cholesterol accumulation in late endosomes/lyso... | MARK AS OVER ANNOTATED | Summary: IMP programmed cell death from the neurodegeneration/cyclodextrin rescue study. Reason: Neuronal death in Npc1-/- mice follows lysosomal cholesterol sequestration and is prevented by driving cholesterol out of the compartment with HP-beta-cyclodextrin. NPC1 executes no step of programmed cell death; the knockout phenotype shows the gene is required for neuronal survival, which is necessity rather than participation. Supporting Evidence: PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration PMID:21697390 a compound known to prevent this C accumulation |
| GO:0015485 cholesterol binding | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cholesterol binding from the PANTHER NPC1 family node. Reason: Core molecular function. NPC1 N-terminal domain has a dedicated cholesterol-binding pocket that engages the 3-beta-hydroxyl end of the sterol, and in the mouse the P202A/F203A substitutions that abolish binding reproduce complete NPC1 deficiency, so the binding site is genetically required for function. The phylogenetic placement is sound: cholesterol binding by the N-terminal domain is a property of the family, and mouse NPC1 has its own experimental grounding for it. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000083973 · PTN000083973 SUPPORTS TRANSFER The NPC1/NPC1L1 node inherits an N-terminal sterol-binding domain; cholesterol binding is shared across the clade and is directly demonstrated for the mouse protein. Supporting Evidence: PMID:21896731 reproduce the phenotype of complete NPC1 deficiency when knocked into the mouse PMID:21896731 the cholesterol binding site in the N-terminal domain of NPC1 is file:mouse/Npc1/Npc1-uniprot.txt Important for cholesterol binding and cholesterol |
| GO:0015485 cholesterol binding | ISO GO_REF:0000119 | ACCEPT | Summary: ISO cholesterol binding, transferred from human NPC1. Reason: Core molecular function. NPC1 N-terminal domain has a dedicated cholesterol-binding pocket that engages the 3-beta-hydroxyl end of the sterol, and in the mouse the P202A/F203A substitutions that abolish binding reproduce complete NPC1 deficiency, so the binding site is genetically required for function. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 cholesterol binding is experimentally established (NTD structures and transfer assays); the mouse protein has its own knock-in evidence for the same site. Supporting Evidence: PMID:21896731 the cholesterol binding site in the N-terminal domain of NPC1 is file:mouse/Npc1/Npc1-uniprot.txt Important for cholesterol binding and cholesterol |
| GO:0015918 sterol transport | IBA GO_REF:0000033 | MODIFY | Summary: IBA sterol transport from a deep PANTHER node spanning NPC1-family members across fungi, worms, flies and vertebrates. Reason: True but less specific than the evidence supports. The sterol NPC1 moves is cholesterol, and the destination-specific terms GO:0032367 intracellular cholesterol transport (a descendant of GO:0015918) and GO:0090120 lysosome to ER cholesterol transport are already asserted for this gene. Refine rather than keep the generic parent. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000847349 · PTN000847349 SUPPORTS TRANSFER The ancestral node legitimately asserts sterol transport, since the clade includes members whose sterol ligand is not cholesterol (e.g. yeast NCR1 ergosterol); for mouse NPC1 the cholesterol-specific child is the right level. Proposed replacements: intracellular cholesterol transport Supporting Evidence: PMID:21289032 processing and export of sterol PMID:21896731 the cholesterol binding site in the N-terminal domain of NPC1 is PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol |
| GO:0015918 sterol transport | IMP PMID:21289032 Quantitative role of LAL, NPC2, and NPC1 in lysosomal choles... | MODIFY | Summary: IMP sterol transport from the quantitative LAL/NPC2/NPC1 study. Reason: True but less specific than the evidence supports. The sterol NPC1 moves is cholesterol, and the destination-specific terms GO:0032367 intracellular cholesterol transport (a descendant of GO:0015918) and GO:0090120 lysosome to ER cholesterol transport are already asserted for this gene. Refine rather than keep the generic parent. Proposed replacements: intracellular cholesterol transport Supporting Evidence: PMID:21289032 endosomal/lysosomal (E/L) compartment by the sequential action of lysosomal acid PMID:21289032 processing and export of sterol |
| GO:0016020 membrane | IDA PMID:10787428 Localization of the murine Niemann-Pick C1 protein to two di... | MODIFY | Summary: IDA membrane localization of murine NPC1 from subcellular fractionation. Reason: Generic membrane is less specific than the evidence supports, and GO:0016020 is not one of the root organelle terms exempted by projects/ORGANELLES.md. NPC1 is a multi-pass protein of the lysosomal limiting membrane, a term this gene already carries with three EXP rows; refine to it. Proposed replacements: lysosomal membrane Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane file:mouse/Npc1/Npc1-uniprot.txt Multi-pass membrane protein PMID:10787428 colocalization of NPC1 with LAMP1-containing compartments |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: InterPro IPR004765 maps the NPC1 family to membrane. Reason: Generic membrane is less specific than the evidence supports, and GO:0016020 is not one of the root organelle terms exempted by projects/ORGANELLES.md. NPC1 is a multi-pass protein of the lysosomal limiting membrane, a term this gene already carries with three EXP rows; refine to it. Proposed replacements: lysosomal membrane Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane file:mouse/Npc1/Npc1-uniprot.txt Multi-pass membrane protein |
| GO:0016125 sterol metabolic process | IMP PMID:21289032 Quantitative role of LAL, NPC2, and NPC1 in lysosomal choles... | MARK AS OVER ANNOTATED | Summary: IMP sterol metabolic process from the quantitative LAL/NPC2/NPC1 study. Reason: NPC1 transports cholesterol; it catalyses no step of sterol metabolism. The cited studies measure sterol pool size, cholesterol synthesis and SREBP2/LXR target genes in Npc1-deficient mice: sterol metabolism is remodelled because the transport step has failed. That makes the term a secondary, phenotype-level reading rather than a false one, so the rows are marked over-annotated and the informative claim is carried by the transport and homeostasis terms. Supporting Evidence: PMID:21289032 endosomal/lysosomal (E/L) compartment by the sequential action of lysosomal acid PMID:21289032 processing and export of sterol |
| GO:0016125 sterol metabolic process | IMP PMID:21697390 Unesterified cholesterol accumulation in late endosomes/lyso... | MARK AS OVER ANNOTATED | Summary: IMP sterol metabolic process from the neurodegeneration/cyclodextrin study. Reason: NPC1 transports cholesterol; it catalyses no step of sterol metabolism. The cited studies measure sterol pool size, cholesterol synthesis and SREBP2/LXR target genes in Npc1-deficient mice: sterol metabolism is remodelled because the transport step has failed. That makes the term a secondary, phenotype-level reading rather than a false one, so the rows are marked over-annotated and the informative claim is carried by the transport and homeostasis terms. Supporting Evidence: PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration PMID:21697390 a compound known to prevent this C accumulation |
| GO:0016242 negative regulation of macroautophagy | IGI PMID:17468177 Autophagy in Niemann-Pick C disease is dependent upon Beclin... | KEEP AS NON CORE | Summary: IGI negative regulation of macroautophagy with Becn1. Reason: A genuine genetic result kept as non-core: NPC1-deficient mouse and human fibroblasts show elevated Beclin-1 and LC3-II and increased long-lived protein degradation, and the effect depends on Beclin-1, so wild-type NPC1 restrains macroautophagy. The link runs through the lipid trafficking defect rather than through an autophagy activity of NPC1 itself, which is why this is peripheral to the core cholesterol-transfer function. Supporting Evidence: PMID:17468177 associated with increased expression of Beclin-1 PMID:17468177 like npc1(-/-) mice fibroblasts, showed increased |
| GO:0016242 negative regulation of macroautophagy | IMP PMID:17468177 Autophagy in Niemann-Pick C disease is dependent upon Beclin... | KEEP AS NON CORE | Summary: IMP negative regulation of macroautophagy in Npc1-deficient cells. Reason: A genuine genetic result kept as non-core: NPC1-deficient mouse and human fibroblasts show elevated Beclin-1 and LC3-II and increased long-lived protein degradation, and the effect depends on Beclin-1, so wild-type NPC1 restrains macroautophagy. The link runs through the lipid trafficking defect rather than through an autophagy activity of NPC1 itself, which is why this is peripheral to the core cholesterol-transfer function. Supporting Evidence: PMID:17468177 like npc1(-/-) mice fibroblasts, showed increased PMID:17468177 associated with increased expression of Beclin-1 |
| GO:0022008 neurogenesis | IMP PMID:21697390 Unesterified cholesterol accumulation in late endosomes/lyso... | MARK AS OVER ANNOTATED | Summary: IMP neurogenesis from the neurodegeneration/cyclodextrin rescue study. Reason: The phenotype in that study is progressive neurodegeneration in an adult animal - Purkinje-cell loss prevented by driving cholesterol out of the late endosomal/lysosomal compartment - not a defect in generating neurons. NPC1 performs no step of neurogenesis; the term looks like a mis-selection for neurodegeneration and is flagged upstream. Supporting Evidence: PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration PMID:21697390 a compound known to prevent this C accumulation |
| GO:0030299 intestinal cholesterol absorption | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: IBA intestinal cholesterol absorption from the PANTHER NPC1/NPC1L1 node. Reason: Intestinal cholesterol absorption is the defining function of the NPC1L1 branch of this family (UniProtKB:Q9UHC9 is in the WITH/FROM), where the protein sits in the apical enterocyte membrane and is the ezetimibe target. Mouse NPC1 acts in the lysosomal membrane of cells generally; enterocyte sterol uptake is affected by Npc1 mutation only through the same lysosomal export defect seen elsewhere. The term is therefore a paralog-scoped over-annotation rather than a false claim about the tissue. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: WRONG ORTHOLOG OR PARALOG ROLE CONFLATION Sources checked: PANTHER:PTN000083973 · PTN000083973 SOURCE WEAK OR INFERRED The node spans NPC1 and NPC1L1; intestinal cholesterol absorption is an NPC1L1-branch role placed at a node that also covers NPC1. Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane PMID:21289032 processing and export of sterol |
| GO:0030301 cholesterol transport | IEA GO_REF:0000120 | MODIFY | Summary: Combined automatic methods (including an ARBA rule) assert cholesterol transport. Reason: Correct but less specific than the evidence supports: the transport NPC1 performs is intracellular, out of the lysosome, and the gene already carries GO:0032367 intracellular cholesterol transport (a descendant of GO:0030301) and GO:0090120. Refine the generic cholesterol transport rows to the intracellular child. Proposed replacements: intracellular cholesterol transport Supporting Evidence: PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol PMID:21289032 processing and export of sterol |
| GO:0030301 cholesterol transport | IMP PMID:21697390 Unesterified cholesterol accumulation in late endosomes/lyso... | MODIFY | Summary: IMP cholesterol transport from the neurodegeneration/cyclodextrin study in npc1-/- mice. Reason: Correct but less specific than the evidence supports: the transport NPC1 performs is intracellular, out of the lysosome, and the gene already carries GO:0032367 intracellular cholesterol transport (a descendant of GO:0030301) and GO:0090120. Refine the generic cholesterol transport rows to the intracellular child. Proposed replacements: intracellular cholesterol transport Supporting Evidence: PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration PMID:21697390 a compound known to prevent this C accumulation |
| GO:0030301 cholesterol transport | ISO GO_REF:0000119 | MODIFY | Summary: Mouse-human ortholog transfer of cholesterol transport. Reason: Correct but less specific than the evidence supports: the transport NPC1 performs is intracellular, out of the lysosome, and the gene already carries GO:0032367 intracellular cholesterol transport (a descendant of GO:0030301) and GO:0090120. Refine the generic cholesterol transport rows to the intracellular child. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 cholesterol transport is well established; only the granularity is refined, and the human entry itself carries the intracellular child. Proposed replacements: intracellular cholesterol transport Supporting Evidence: PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol PMID:21289032 processing and export of sterol |
| GO:0030301 cholesterol transport | ISS GO_REF:0000024 | MODIFY | Summary: Curator sequence-similarity transfer of cholesterol transport from human NPC1. Reason: Correct but less specific than the evidence supports: the transport NPC1 performs is intracellular, out of the lysosome, and the gene already carries GO:0032367 intracellular cholesterol transport (a descendant of GO:0030301) and GO:0090120. Refine the generic cholesterol transport rows to the intracellular child. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Same human source; the claim transfers, the granularity is refined. Proposed replacements: intracellular cholesterol transport Supporting Evidence: PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol PMID:21289032 processing and export of sterol |
| GO:0031579 membrane raft organization | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of human membrane raft organization. Reason: The human source annotation comes from a study of annexin A6 behaviour in detergent-resistant microdomains isolated from NPC1-mutant fibroblasts: NPC cells contain more late endosomal/lysosomal microdomains and AnxA6 redistributes into them. That is the cholesterol- and sphingolipid-storage phenotype acting on membrane order, not NPC1 organizing rafts. Membrane composition does depend on NPC1 cholesterol export, so the term is an over-reading rather than a falsehood. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS SOURCE BUT NOT TARGET Human NPC1 GO:0031579 IMP (PMID:23360953) scores microdomain content and AnxA6 partitioning in NPC1-mutant fibroblasts - a storage phenotype, not an organizing activity. Supporting Evidence: PMID:23360953 the cholesterol-interacting protein, AnxA6, which participates in the transport PMID:15078881 accumulating GSL is part of a mislocalized membrane |
| GO:0031579 membrane raft organization | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Mouse-human ortholog transfer of human membrane raft organization. Reason: The human source annotation comes from a study of annexin A6 behaviour in detergent-resistant microdomains isolated from NPC1-mutant fibroblasts: NPC cells contain more late endosomal/lysosomal microdomains and AnxA6 redistributes into them. That is the cholesterol- and sphingolipid-storage phenotype acting on membrane order, not NPC1 organizing rafts. Membrane composition does depend on NPC1 cholesterol export, so the term is an over-reading rather than a falsehood. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS SOURCE BUT NOT TARGET Same human IMP source; the phenotype-for-activity reading transfers with it. Supporting Evidence: PMID:23360953 the cholesterol-interacting protein, AnxA6, which participates in the transport PMID:15078881 accumulating GSL is part of a mislocalized membrane |
| GO:0031902 late endosome membrane | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automatic methods (UniProt SL-0151 late endosome membrane) place NPC1 in the late endosome membrane. Reason: Core location alongside the lysosomal membrane: NPC1 resides in the limiting membrane of late endosomes and lysosomes, which is where LDL-derived cholesterol is handed over by NPC2. Curated UniProt subcellular location states late endosome membrane directly. Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Late endosome membrane file:mouse/Npc1/Npc1-uniprot.txt Multi-pass membrane protein |
| GO:0031902 late endosome membrane | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse-human ortholog transfer of late endosome membrane localization. Reason: Core location alongside the lysosomal membrane: NPC1 resides in the limiting membrane of late endosomes and lysosomes, which is where LDL-derived cholesterol is handed over by NPC2. Curated UniProt subcellular location states late endosome membrane directly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 late endosome membrane localization is experimentally established and matches the curated mouse subcellular location. Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Late endosome membrane |
| GO:0031902 late endosome membrane | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of late endosome membrane localization. Reason: Core location alongside the lysosomal membrane: NPC1 resides in the limiting membrane of late endosomes and lysosomes, which is where LDL-derived cholesterol is handed over by NPC2. Curated UniProt subcellular location states late endosome membrane directly. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Same human source, by sequence-similarity transfer; consistent with the curated mouse location. Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Late endosome membrane |
| GO:0031982 vesicle | IDA PMID:10787428 Localization of the murine Niemann-Pick C1 protein to two di... | KEEP AS NON CORE | Summary: IDA vesicle: murine NPC1 occupies a distinctive cholesterol- and caveolin-1-containing vesicular compartment with extensive internal membranes. Reason: This is an honest record of what the imaging showed - a vesicular compartment that did not coincide with the standard organelle markers - and vesicle is not an ancestor of lysosome, so it is not entailed by the lysosomal terms and cannot be marked too general. It is also not where the cholesterol hand-off has been localized, so it is kept as a non-core location. Supporting Evidence: PMID:10787428 vesicular compartment enriched with cholesterol and containing caveolin-1 PMID:10787428 do not colocalize with major |
| GO:0032365 intracellular lipid transport | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfer of human intracellular lipid transport. Reason: True but less specific than the evidence supports: the lipid NPC1 moves is cholesterol, and GO:0032367 intracellular cholesterol transport (a descendant of GO:0032365) is already asserted for this gene. Refine to the cholesterol-specific child. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 intracellular lipid transport is sound; only the granularity is refined. Proposed replacements: intracellular cholesterol transport Supporting Evidence: PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol PMID:21289032 processing and export of sterol |
| GO:0032365 intracellular lipid transport | ISO GO_REF:0000119 | MODIFY | Summary: Mouse-human ortholog transfer of intracellular lipid transport. Reason: True but less specific than the evidence supports: the lipid NPC1 moves is cholesterol, and GO:0032367 intracellular cholesterol transport (a descendant of GO:0032365) is already asserted for this gene. Refine to the cholesterol-specific child. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Same human source; claim transfers, granularity refined. Proposed replacements: intracellular cholesterol transport Supporting Evidence: PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol PMID:21289032 processing and export of sterol |
| GO:0032365 intracellular lipid transport | ISS GO_REF:0000024 | MODIFY | Summary: Curator sequence-similarity transfer of intracellular lipid transport. Reason: True but less specific than the evidence supports: the lipid NPC1 moves is cholesterol, and GO:0032367 intracellular cholesterol transport (a descendant of GO:0032365) is already asserted for this gene. Refine to the cholesterol-specific child. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Same human source, by sequence similarity; granularity refined. Proposed replacements: intracellular cholesterol transport Supporting Evidence: PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol PMID:21289032 processing and export of sterol |
| GO:0032367 intracellular cholesterol transport | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of intracellular cholesterol transport. Reason: Core biological process. NPC1 receives cholesterol from NPC2 in the lysosomal lumen and delivers it into the limiting membrane for distribution to the ER and plasma membrane; mouse knock-in of a binding-dead N-terminal domain blocks this step and reproduces the null phenotype. Supporting Evidence: PMID:21896731 the cholesterol binding site in the N-terminal domain of NPC1 is PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol PMID:21289032 processing and export of sterol |
| GO:0032367 intracellular cholesterol transport | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse-human ortholog transfer of intracellular cholesterol transport. Reason: Core biological process. NPC1 receives cholesterol from NPC2 in the lysosomal lumen and delivers it into the limiting membrane for distribution to the ER and plasma membrane; mouse knock-in of a binding-dead N-terminal domain blocks this step and reproduces the null phenotype. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 intracellular cholesterol transport is established by multiple IMP/IDA rows; mouse knock-in and pathway-dissection data give the target its own grounding. Supporting Evidence: PMID:21896731 the cholesterol binding site in the N-terminal domain of NPC1 is PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol |
| GO:0032367 intracellular cholesterol transport | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of intracellular cholesterol transport. Reason: Core biological process. NPC1 receives cholesterol from NPC2 in the lysosomal lumen and delivers it into the limiting membrane for distribution to the ER and plasma membrane; mouse knock-in of a binding-dead N-terminal domain blocks this step and reproduces the null phenotype. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Same human source, by sequence similarity; the mouse protein has direct evidence for the same process. Supporting Evidence: PMID:21896731 the cholesterol binding site in the N-terminal domain of NPC1 is PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol |
| GO:0033344 cholesterol efflux | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of human cholesterol efflux. Reason: Cholesterol efflux is the transfer of cellular cholesterol to an extracellular acceptor, executed by the ABC transporters; NPC1 supplies the substrate pool by releasing cholesterol from lysosomes, so the gene is required for efflux without performing the efflux step itself. Kept as a non-core process term rather than treated as a core function. Supporting Evidence: PMID:21289032 processing and export of sterol PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol |
| GO:0033344 cholesterol efflux | IMP PMID:17148552 Different cellular traffic of LDL-cholesterol and acetylated... | KEEP AS NON CORE | Summary: IMP cholesterol efflux from the macrophage LDL/AcLDL reverse cholesterol transport study. Reason: Cholesterol efflux is the transfer of cellular cholesterol to an extracellular acceptor, executed by the ABC transporters; NPC1 supplies the substrate pool by releasing cholesterol from lysosomes, so the gene is required for efflux without performing the efflux step itself. Kept as a non-core process term rather than treated as a core function. That study separates LDL- and AcLDL-derived cholesterol into distinct endosomal routes and different efflux acceptors, consistent with NPC1 acting on the lysosomal leg of the pathway. Supporting Evidence: PMID:17148552 mediators of diffusional PMID:21289032 processing and export of sterol |
| GO:0033344 cholesterol efflux | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Mouse-human ortholog transfer of cholesterol efflux. Reason: Cholesterol efflux is the transfer of cellular cholesterol to an extracellular acceptor, executed by the ABC transporters; NPC1 supplies the substrate pool by releasing cholesterol from lysosomes, so the gene is required for efflux without performing the efflux step itself. Kept as a non-core process term rather than treated as a core function. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 cholesterol efflux annotation rests on direct assays; the role is upstream of the efflux step in both species, hence non-core. Supporting Evidence: PMID:21289032 processing and export of sterol |
| GO:0042632 cholesterol homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: IBA cholesterol homeostasis from the PANTHER NPC1 family node, seeded by mouse, worm, zebrafish and human members. Reason: Core biological process, and the one the gene was discovered through: loss of NPC1 in mouse expands the whole-animal sterol pool and sequesters unesterified cholesterol in late endosomes/lysosomes, and restoring export (cyclodextrin) normalizes the sterol-regulated gene programme. Cholesterol homeostasis is the systemic consequence of the transfer activity NPC1 performs. The node placement is sound: cholesterol (or sterol) homeostasis is shared across the clade, and mouse Npc1 appearing in the WITH/FROM reflects its own experimental grounding, which is expected rather than circular. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000083973 · PTN000083973 SUPPORTS TRANSFER Node seeded by experimentally characterized NPC1-family members including mouse Npc1 itself; sterol homeostasis is the ancestral role. Supporting Evidence: PMID:21896731 the cholesterol binding site in the N-terminal domain of NPC1 is PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration |
| GO:0042632 cholesterol homeostasis | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of cholesterol homeostasis. Reason: Core biological process, and the one the gene was discovered through: loss of NPC1 in mouse expands the whole-animal sterol pool and sequesters unesterified cholesterol in late endosomes/lysosomes, and restoring export (cyclodextrin) normalizes the sterol-regulated gene programme. Cholesterol homeostasis is the systemic consequence of the transfer activity NPC1 performs. Supporting Evidence: PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration PMID:21289032 processing and export of sterol |
| GO:0042632 cholesterol homeostasis | IMP PMID:21896731 Amino acid substitution in NPC1 that abolishes cholesterol b... | ACCEPT | Summary: IMP cholesterol homeostasis: Npc1 P202A/F203A knock-in mice reproduce complete NPC1 deficiency with lysosomal cholesterol accumulation. Reason: Core biological process, and the one the gene was discovered through: loss of NPC1 in mouse expands the whole-animal sterol pool and sequesters unesterified cholesterol in late endosomes/lysosomes, and restoring export (cyclodextrin) normalizes the sterol-regulated gene programme. Cholesterol homeostasis is the systemic consequence of the transfer activity NPC1 performs. This row is the strongest mouse evidence for the term, since it ties the systemic phenotype to the cholesterol-binding site rather than to loss of the protein. Supporting Evidence: PMID:21896731 reproduce the phenotype of complete NPC1 deficiency when knocked into the mouse PMID:21896731 npc1(pf/pf) mice accumulated excess cholesterol in lysosomes PMID:21896731 the cholesterol binding site in the N-terminal domain of NPC1 is |
| GO:0042632 cholesterol homeostasis | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse-human ortholog transfer of cholesterol homeostasis. Reason: Core biological process, and the one the gene was discovered through: loss of NPC1 in mouse expands the whole-animal sterol pool and sequesters unesterified cholesterol in late endosomes/lysosomes, and restoring export (cyclodextrin) normalizes the sterol-regulated gene programme. Cholesterol homeostasis is the systemic consequence of the transfer activity NPC1 performs. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 cholesterol homeostasis is established experimentally; mouse Npc1 has its own IMP row for the same term. Supporting Evidence: PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration |
| GO:0042632 cholesterol homeostasis | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of cholesterol homeostasis from human NPC1. Reason: Core biological process, and the one the gene was discovered through: loss of NPC1 in mouse expands the whole-animal sterol pool and sequesters unesterified cholesterol in late endosomes/lysosomes, and restoring export (cyclodextrin) normalizes the sterol-regulated gene programme. Cholesterol homeostasis is the systemic consequence of the transfer activity NPC1 performs. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Same human source, by sequence similarity; redundant with, and consistent with, the mouse IMP row. Supporting Evidence: PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration |
| GO:0042632 cholesterol homeostasis | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of cholesterol homeostasis from UniProtKB:Q7TMD4. Reason: Core biological process, and the one the gene was discovered through: loss of NPC1 in mouse expands the whole-animal sterol pool and sequesters unesterified cholesterol in late endosomes/lysosomes, and restoring export (cyclodextrin) normalizes the sterol-regulated gene programme. Cholesterol homeostasis is the systemic consequence of the transfer activity NPC1 performs. The donor is an unreviewed UniProt entry for the same mouse gene, so this row adds nothing beyond the other rows for the term; the claim itself is correct and directly supported in mouse. Propagation Review Root cause: EVIDENCE CIRCULAR OR REDUNDANT Sources checked: UniProtKB:Q7TMD4 · Npc1 CIRCULAR OR REDUNDANT Q7TMD4 is a second, unreviewed UniProt entry for the same mouse Npc1 gene, so a sequence-similarity transfer from it to O35604 adds no independent support; the target already has direct IMP evidence. Supporting Evidence: PMID:21896731 reproduce the phenotype of complete NPC1 deficiency when knocked into the mouse PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration |
| GO:0045121 membrane raft | IDA PMID:10787428 Localization of the murine Niemann-Pick C1 protein to two di... | KEEP AS NON CORE | Summary: IDA membrane raft: a fraction of murine NPC1 cosediments with caveolin-1 in detergent-resistant rafts. Reason: A real biochemical observation in mouse liver membranes and fibroblasts, but the cholesterol hand-off from NPC2 occurs in the acidic lysosomal lumen, so raft association is a peripheral localization rather than the site of the core activity. Supporting Evidence: PMID:10787428 a fraction of NPC1 cosediments with caveolin-1 in rafts PMID:10787428 vesicular compartment enriched with cholesterol and containing caveolin-1 |
| GO:0046686 response to cadmium ion | IEA GO_REF:0000107 | UNDECIDED | Summary: Ensembl Compara transfer of a rat response to cadmium ion annotation. Reason: This claim reaches mouse only through rat Npc1 (RGD:628693), and the underlying rat annotation has no reference we can inspect: no PMID is carried in the GOA row and the rat source record gives no experimental statement for it. Response-to-chemical terms of this kind are frequently based on expression changes after exposure, which would not establish participation. The function is not independently established for mouse NPC1, so the row is left undecided rather than accepted or dismissed. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:G3V7K5 · Npc1 UNRESOLVED Rat Npc1 (G3V7K5/RGD:628693) is the proximate source; the supporting reference for the rat annotation could not be recovered from the GOA row or the rat entry, so the basis of the claim cannot be judged. |
| GO:0046686 response to cadmium ion | ISO GO_REF:0000096 | UNDECIDED | Summary: Mouse-rat ortholog transfer of the rat response to cadmium ion annotation. Reason: This claim reaches mouse only through rat Npc1 (RGD:628693), and the underlying rat annotation has no reference we can inspect: no PMID is carried in the GOA row and the rat source record gives no experimental statement for it. Response-to-chemical terms of this kind are frequently based on expression changes after exposure, which would not establish participation. The function is not independently established for mouse NPC1, so the row is left undecided rather than accepted or dismissed. Propagation Review Root cause: UNRESOLVED Sources checked: RGD:628693 · Npc1 UNRESOLVED Same rat source annotation; its underlying reference is not recoverable here, so the transfer cannot be assessed. |
| GO:0046718 symbiont entry into host cell | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of symbiont entry into host cell. Reason: A well-documented host-factor role: NPC1 is the intracellular receptor for the primed Ebola virus glycoprotein, cells and mice lacking or reduced for NPC1 resist filovirus infection, and the requirement is independent of NPC1 cholesterol transport activity (the transport-dead P692S protein still supports entry). Real, but a function the virus exploits rather than the core cellular activity of the gene, so it is kept as non-core. Supporting Evidence: PMID:21866101 Thus, EboV entry is strictly dependent on NPC1 expression but not NPC1-dependent cholesterol transport activity |
| GO:0046718 symbiont entry into host cell | IMP PMID:21866101 Small molecule inhibitors reveal Niemann-Pick C1 is essentia... | KEEP AS NON CORE | Summary: IMP symbiont entry into host cell: small-molecule and genetic disruption of NPC1 blocks Ebola virus infection, including in mouse embryonic fibroblasts. Reason: A well-documented host-factor role: NPC1 is the intracellular receptor for the primed Ebola virus glycoprotein, cells and mice lacking or reduced for NPC1 resist filovirus infection, and the requirement is independent of NPC1 cholesterol transport activity (the transport-dead P692S protein still supports entry). Real, but a function the virus exploits rather than the core cellular activity of the gene, so it is kept as non-core. Supporting Evidence: PMID:21866101 Thus, EboV entry is strictly dependent on NPC1 expression but not NPC1-dependent cholesterol transport activity |
| GO:0046718 symbiont entry into host cell | IMP PMID:21866103 Ebola virus entry requires the cholesterol transporter Niema... | KEEP AS NON CORE | Summary: IMP symbiont entry into host cell: Ebola virus entry requires NPC1; Npc1+/- mice were used in filovirus challenge experiments. Reason: A well-documented host-factor role: NPC1 is the intracellular receptor for the primed Ebola virus glycoprotein, cells and mice lacking or reduced for NPC1 resist filovirus infection, and the requirement is independent of NPC1 cholesterol transport activity (the transport-dead P692S protein still supports entry). Real, but a function the virus exploits rather than the core cellular activity of the gene, so it is kept as non-core. Supporting Evidence: PMID:21866103 BALB/c NPC1+/− mice and BALB/c NPC1 +/+ mice (5 to 8 week old) PMID:21866101 Thus, EboV entry is strictly dependent on NPC1 expression but not NPC1-dependent cholesterol transport activity |
| GO:0046718 symbiont entry into host cell | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Mouse-human ortholog transfer of symbiont entry into host cell. Reason: A well-documented host-factor role: NPC1 is the intracellular receptor for the primed Ebola virus glycoprotein, cells and mice lacking or reduced for NPC1 resist filovirus infection, and the requirement is independent of NPC1 cholesterol transport activity (the transport-dead P692S protein still supports entry). Real, but a function the virus exploits rather than the core cellular activity of the gene, so it is kept as non-core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 is the established filovirus entry receptor; mouse Npc1 carries its own IMP rows for the same term. Supporting Evidence: PMID:21866101 Thus, EboV entry is strictly dependent on NPC1 expression but not NPC1-dependent cholesterol transport activity |
| GO:0048471 perinuclear region of cytoplasm | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl Compara transfer of human perinuclear region of cytoplasm. Reason: NPC1-positive late endosomes/lysosomes cluster in the perinuclear region, and the human source annotation records exactly that imaging observation. It describes where the NPC1 compartment sits in the cell rather than a distinct site of action, so it is kept as a non-core location. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 perinuclear signal is directly observed; the same compartment distribution is expected in mouse. Non-core in both. Supporting Evidence: PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to file:mouse/Npc1/Npc1-uniprot.txt Late endosome membrane |
| GO:0048471 perinuclear region of cytoplasm | ISO GO_REF:0000119 | KEEP AS NON CORE | Summary: Mouse-human ortholog transfer of human perinuclear region of cytoplasm. Reason: NPC1-positive late endosomes/lysosomes cluster in the perinuclear region, and the human source annotation records exactly that imaging observation. It describes where the NPC1 compartment sits in the cell rather than a distinct site of action, so it is kept as a non-core location. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 perinuclear signal is directly observed; the same compartment distribution is expected in mouse. Non-core in both. Supporting Evidence: PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to file:mouse/Npc1/Npc1-uniprot.txt Late endosome membrane |
| GO:0048471 perinuclear region of cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Curator sequence-similarity transfer of human perinuclear region of cytoplasm. Reason: NPC1-positive late endosomes/lysosomes cluster in the perinuclear region, and the human source annotation records exactly that imaging observation. It describes where the NPC1 compartment sits in the cell rather than a distinct site of action, so it is kept as a non-core location. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 perinuclear signal is directly observed; the same compartment distribution is expected in mouse. Non-core in both. Supporting Evidence: PMID:12554680 colocalized with Rab7-positive late endosomes whereas NPC1-C113R localized to file:mouse/Npc1/Npc1-uniprot.txt Late endosome membrane |
| GO:0071383 cellular response to steroid hormone stimulus | IDA PMID:10787428 Localization of the murine Niemann-Pick C1 protein to two di... | MARK AS OVER ANNOTATED | Summary: IDA cellular response to steroid hormone stimulus: progesterone treatment increases NPC1 colocalization with LAMP1-positive compartments. Reason: Progesterone is used here as a pharmacological blocker of lysosomal cholesterol egress (alongside chloroquine), at concentrations far above hormonal signalling, and the readout is redistribution of NPC1 in a cholesterol-trafficking block. Reading that as a cellular response to a steroid hormone over-interprets the experiment, though NPC1 does respond to the sterol status the drug imposes. Supporting Evidence: PMID:10787428 can be further enhanced by treating fibroblasts with progesterone or PMID:10787428 colocalization of NPC1 with LAMP1-containing compartments |
| GO:0071404 cellular response to low-density lipoprotein particle stimulus | IDA PMID:10787428 Localization of the murine Niemann-Pick C1 protein to two di... | KEEP AS NON CORE | Summary: IDA cellular response to low-density lipoprotein particle stimulus: LDL loading increases NPC1 colocalization with LAMP1-containing compartments. Reason: A genuine, mechanistically sensible response: LDL delivery to lysosomes is the physiological input to the NPC1 pathway, and NPC1 redistributes towards LAMP1-positive compartments when cells are LDL-loaded. It describes regulation of the protein distribution rather than the transfer activity itself, so it is kept as non-core. Supporting Evidence: PMID:10787428 Incubation of fibroblasts with low density lipoprotein (LDL) increases PMID:10787428 colocalization of NPC1 with LAMP1-containing compartments PMID:21289032 endosomal/lysosomal (E/L) compartment by the sequential action of lysosomal acid |
| GO:0090120 lysosome to ER cholesterol transport | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of lysosome to ER cholesterol transport. Reason: Core process. After receiving cholesterol from NPC2, NPC1 delivers it towards the endoplasmic reticulum, tethering lysosome-ER membrane contact sites and handing sterol to GRAMD1B; this is the specific transport step the gene performs, and the destination-specific term is the right level for it. Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Mediates cholesterol transfer from lysosomes to endoplasmic reticulum by tethering PMID:18772377 NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid |
| GO:0090120 lysosome to ER cholesterol transport | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse-human ortholog transfer of lysosome to ER cholesterol transport. Reason: Core process. After receiving cholesterol from NPC2, NPC1 delivers it towards the endoplasmic reticulum, tethering lysosome-ER membrane contact sites and handing sterol to GRAMD1B; this is the specific transport step the gene performs, and the destination-specific term is the right level for it. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 lysosome-to-ER cholesterol transport rests on direct bidirectional transfer assays (PMID:18772377) and contact-site work; the mechanism is conserved and curated for the mouse entry. Supporting Evidence: file:mouse/Npc1/Npc1-uniprot.txt Mediates cholesterol transfer from lysosomes to endoplasmic reticulum by tethering PMID:18772377 NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid |
| GO:0090150 establishment of protein localization to membrane | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl Compara transfer of human establishment of protein localization to membrane. Reason: The human source annotation comes from the annexin A6 microdomain study, where AnxA6 translocates into detergent-resistant microdomains of NPC1-mutant cells when calcium rises. That is a lipid-composition consequence of cholesterol storage acting on another protein distribution; NPC1 performs no step of establishing protein localization to a membrane. Because membrane cholesterol does depend on NPC1, the term is an over-reading rather than a flat falsehood. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION SOURCE EVIDENCE WEAK Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS SOURCE BUT NOT TARGET Human NPC1 GO:0090150 IDA (PMID:23360953) records AnxA6 redistribution in NPC1-mutant fibroblast microdomains, a downstream effect of lipid storage. Supporting Evidence: PMID:23360953 the cholesterol-interacting protein, AnxA6, which participates in the transport |
| GO:0090150 establishment of protein localization to membrane | ISO GO_REF:0000119 | MARK AS OVER ANNOTATED | Summary: Mouse-human ortholog transfer of establishment of protein localization to membrane. Reason: The human source annotation comes from the annexin A6 microdomain study, where AnxA6 translocates into detergent-resistant microdomains of NPC1-mutant cells when calcium rises. That is a lipid-composition consequence of cholesterol storage acting on another protein distribution; NPC1 performs no step of establishing protein localization to a membrane. Because membrane cholesterol does depend on NPC1, the term is an over-reading rather than a flat falsehood. Propagation Review Root cause: SOURCE WEAK OR INFERRED Failure modes: ROLE CONFLATION Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS SOURCE BUT NOT TARGET Same human source row; the reading transfers with it. Supporting Evidence: PMID:23360953 the cholesterol-interacting protein, AnxA6, which participates in the transport |
| GO:0098574 cytoplasmic side of lysosomal membrane | IEA GO_REF:0000107 | MODIFY | Summary: Ensembl Compara transfer of human is_active_in cytoplasmic side of lysosomal membrane. Reason: Over-specific and on the wrong face of the membrane. NPC1 is a 13-transmembrane protein whose cholesterol-receiving machinery - the N-terminal domain, the middle lumenal domain that binds NPC2, and the C-terminal lumenal domain that orients the NTD - is lumenal, and the sterol-sensing domain sits within the bilayer. The claim that the activity occurs on the cytoplasmic side of the membrane does not follow from the structural work the source rests on. Generalize to the lysosomal membrane, where the protein and its activity reside. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH GRANULARITY MISMATCH Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS SOURCE BUT NOT TARGET The human source (IDA, PMID:28784760) is the NPC1 crystal structure defining the lumenal NTD-CTD interface; it does not place the activity on the cytoplasmic face. Proposed replacements: lysosomal membrane Supporting Evidence: PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol PMID:28784760 function to keep the NTD in the proper file:mouse/Npc1/Npc1-uniprot.txt Multi-pass membrane protein file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0098574 cytoplasmic side of lysosomal membrane | ISO GO_REF:0000119 | MODIFY | Summary: Mouse-human ortholog transfer of is_active_in cytoplasmic side of lysosomal membrane. Reason: Over-specific and on the wrong face of the membrane. NPC1 is a 13-transmembrane protein whose cholesterol-receiving machinery - the N-terminal domain, the middle lumenal domain that binds NPC2, and the C-terminal lumenal domain that orients the NTD - is lumenal, and the sterol-sensing domain sits within the bilayer. The claim that the activity occurs on the cytoplasmic side of the membrane does not follow from the structural work the source rests on. Generalize to the lysosomal membrane, where the protein and its activity reside. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS SOURCE BUT NOT TARGET Same human structural source; the side-of-membrane claim is not what it shows. Proposed replacements: lysosomal membrane Supporting Evidence: PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol PMID:28784760 function to keep the NTD in the proper file:mouse/Npc1/Npc1-uniprot.txt Lysosome membrane |
| GO:0120020 cholesterol transfer activity | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of cholesterol transfer activity. Reason: Core molecular function. NPC1 accepts cholesterol from NPC2 at its middle lumenal domain, holds it in the N-terminal domain pocket and moves it into the lysosomal membrane; purified NPC1 NTD exchanges cholesterol with lipid bilayers in an NPC2-dependent manner, the NPC1-MLD/NPC2 structure reveals a continuous transfer tunnel, and knock-in of a binding-dead pocket in mouse abolishes the activity in vivo. Supporting Evidence: PMID:18772377 NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol PMID:21896731 the cholesterol binding site in the N-terminal domain of NPC1 is |
| GO:0120020 cholesterol transfer activity | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse-human ortholog transfer of cholesterol transfer activity. Reason: Core molecular function. NPC1 accepts cholesterol from NPC2 at its middle lumenal domain, holds it in the N-terminal domain pocket and moves it into the lysosomal membrane; purified NPC1 NTD exchanges cholesterol with lipid bilayers in an NPC2-dependent manner, the NPC1-MLD/NPC2 structure reveals a continuous transfer tunnel, and knock-in of a binding-dead pocket in mouse abolishes the activity in vivo. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 cholesterol transfer activity is directly demonstrated (PMID:18772377, PMID:27551080); the mouse MLD was assayed in the same structural work and the mouse knock-in confirms the activity in vivo. Supporting Evidence: PMID:18772377 NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid PMID:27551080 second (middle), lumenally oriented domain (MLD) and transfers cholesterol |
| GO:0120020 cholesterol transfer activity | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of cholesterol transfer activity. Reason: Core molecular function. NPC1 accepts cholesterol from NPC2 at its middle lumenal domain, holds it in the N-terminal domain pocket and moves it into the lysosomal membrane; purified NPC1 NTD exchanges cholesterol with lipid bilayers in an NPC2-dependent manner, the NPC1-MLD/NPC2 structure reveals a continuous transfer tunnel, and knock-in of a binding-dead pocket in mouse abolishes the activity in vivo. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Same human source, by sequence similarity; the mouse protein has its own structural and genetic grounding for the activity. Supporting Evidence: PMID:18772377 NPC2 facilitates bidirectional transfer of cholesterol between NPC1 and lipid PMID:21896731 the cholesterol binding site in the N-terminal domain of NPC1 is |
| GO:1904036 negative regulation of epithelial cell apoptotic process | IEA GO_REF:0000107 | UNDECIDED | Summary: Ensembl Compara transfer of a rat negative regulation of epithelial cell apoptotic process annotation. Reason: As with the cadmium row, this claim reaches mouse only via rat Npc1 (RGD:628693) and the rat annotation reference cannot be recovered here, so there is nothing to inspect. Nor is a role in restraining epithelial apoptosis independently established for mouse NPC1: Npc1-null mice show neuronal and hepatic cell death, which if anything runs the other way. Left undecided rather than judged. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:G3V7K5 · Npc1 UNRESOLVED Rat Npc1 is the proximate source; its supporting reference is not recoverable from the GOA row or the rat entry. |
| GO:1904036 negative regulation of epithelial cell apoptotic process | ISO GO_REF:0000096 | UNDECIDED | Summary: Mouse-rat ortholog transfer of the rat negative regulation of epithelial cell apoptotic process annotation. Reason: As with the cadmium row, this claim reaches mouse only via rat Npc1 (RGD:628693) and the rat annotation reference cannot be recovered here, so there is nothing to inspect. Nor is a role in restraining epithelial apoptosis independently established for mouse NPC1: Npc1-null mice show neuronal and hepatic cell death, which if anything runs the other way. Left undecided rather than judged. Propagation Review Root cause: UNRESOLVED Sources checked: RGD:628693 · Npc1 UNRESOLVED Same rat source annotation; basis not recoverable. |
| GO:1904262 negative regulation of TORC1 signaling | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl Compara transfer of negative regulation of TORC1 signaling. Reason: A second, mechanistically distinct activity of NPC1 that the evidence supports directly: NPC1 binds SLC38A9 at the lysosomal surface and, through its sterol transport function, keeps lysosomal cholesterol from driving mTORC1 recruitment and activation. The curated mouse record carries the interaction and its consequence, and the regulation is exerted by NPC1 own transport activity rather than by a downstream phenotype, so the term is accepted. Supporting Evidence: PMID:28336668 binds to SLC38A9 and inhibits mTORC1 signaling through its sterol PMID:28336668 NPC1 associates with the mTORC1 scaffolding complex and translates cholesterol depletion into mTORC1 inhibition file:mouse/Npc1/Npc1-uniprot.txt Interacts with SLC38A9; this interaction inhibits |
| GO:1904262 negative regulation of TORC1 signaling | ISO GO_REF:0000119 | ACCEPT | Summary: Mouse-human ortholog transfer of negative regulation of TORC1 signaling. Reason: A second, mechanistically distinct activity of NPC1 that the evidence supports directly: NPC1 binds SLC38A9 at the lysosomal surface and, through its sterol transport function, keeps lysosomal cholesterol from driving mTORC1 recruitment and activation. The curated mouse record carries the interaction and its consequence, and the regulation is exerted by NPC1 own transport activity rather than by a downstream phenotype, so the term is accepted. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Human NPC1 GO:1904262 rests on direct assays of the SLC38A9-NPC1 complex and mTORC1 output (PMID:28336668); the interaction and its inhibitory consequence are curated for the mouse entry by similarity. Supporting Evidence: PMID:28336668 binds to SLC38A9 and inhibits mTORC1 signaling through its sterol file:mouse/Npc1/Npc1-uniprot.txt Interacts with SLC38A9; this interaction inhibits |
| GO:1904262 negative regulation of TORC1 signaling | ISS GO_REF:0000024 | ACCEPT | Summary: Curator sequence-similarity transfer of negative regulation of TORC1 signaling. Reason: A second, mechanistically distinct activity of NPC1 that the evidence supports directly: NPC1 binds SLC38A9 at the lysosomal surface and, through its sterol transport function, keeps lysosomal cholesterol from driving mTORC1 recruitment and activation. The curated mouse record carries the interaction and its consequence, and the regulation is exerted by NPC1 own transport activity rather than by a downstream phenotype, so the term is accepted. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:O15118 · NPC1 SUPPORTS TRANSFER Same human source, by sequence similarity; mechanism (sterol transport plus SLC38A9 binding) is conserved and curated for mouse. Supporting Evidence: PMID:28336668 binds to SLC38A9 and inhibits mTORC1 signaling through its sterol file:mouse/Npc1/Npc1-uniprot.txt Interacts with SLC38A9; this interaction inhibits |
| GO:2000900 cyclodextrin metabolic process | IMP PMID:21697390 Unesterified cholesterol accumulation in late endosomes/lyso... | MARK AS OVER ANNOTATED | Summary: IMP cyclodextrin metabolic process from the HP-beta-cyclodextrin rescue experiment in npc1-/- mice. Reason: Hydroxypropyl-beta-cyclodextrin is the therapeutic agent in that study, not a metabolite of NPC1: it was infused into the CNS, diffused through the brain and was excreted with a 6.5 h half-life while rescuing cholesterol sequestration. NPC1 neither synthesizes nor degrades cyclodextrin; the annotation records the experimental intervention. The row is an experimental one whose full text we could not read, so it is marked over-annotated and the term is flagged upstream rather than removed. Supporting Evidence: PMID:21697390 a compound known to prevent this C accumulation PMID:21697390 Inactivation of NPC1 leads to lysosomal C sequestration |
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Download this section (compressed HTML)Q: Should GO annotate a substrate of glycosylation to GO:0009101 glycoprotein biosynthetic process? The human NPC1 row (IDA, PMID:10821832) treats NPC1 own N-glycosylation, used as a topological reporter, as participation in the pathway, and it propagates to mouse by IEA and ISO.
Suggested experts: GO editorial office, UniProt curators
Q: Would a GO-CAM model of lysosomal cholesterol egress capture the NPC2-to-NPC1 hand-off better than the present pair of independent cholesterol transfer activity annotations - i.e. NPC2 cholesterol transfer activity with has input cholesterol providing input to NPC1 transfer activity at the lysosomal membrane?
Suggested experts: GO-CAM curators
Q: Is the is_active_in GO:0098574 cytoplasmic side of lysosomal membrane annotation intended to mark where cholesterol leaves NPC1, or is it a mis-selection? NPC1 cholesterol-receiving domains (NTD, MLD, CTD) are all lumenal.
Suggested experts: UniProt curators, NPC1 structural biologists
Q: Can the rat-sourced annotations propagated to mouse Npc1 (GO:0046686 response to cadmium ion, GO:1904036 negative regulation of epithelial cell apoptotic process, both from RGD:628693) be traced to a reference? Neither row carries a PMID that we could recover.
Suggested experts: RGD curators
Experiment: Reconstitute purified full-length mouse NPC1 into asymmetric liposomes with leaflet-specific sterol sensors (e.g. a lumenal and a cytosolic-side fluorescent sterol-binding probe) and follow NPC2-dependent cholesterol arrival in each leaflet, with the binding-dead P202A/F203A protein as the negative control. This would settle which face the transfer terminates on, and hence whether a side-of-membrane cellular-component term is warranted.
Hypothesis: Cholesterol leaving NPC1 enters the cytosolic leaflet of the lysosomal limiting membrane before being picked up by cytosolic-facing acceptors such as GRAMD1B.
Type: in vitro reconstitution
Experiment: Compare autophagic flux in Npc1-/- mouse embryonic fibroblasts, in Npc1 P202A/F203A knock-in cells (protein present, transport dead) and in wild-type cells acutely loaded with cholesterol by U18666A, before and after cyclodextrin-mediated cholesterol removal. If flux tracks cholesterol load rather than NPC1 presence, GO:0016242 should remain non-core and the regulatory reading is a phenotype.
Hypothesis: The elevated macroautophagy of Npc1-null cells is a consequence of lysosomal cholesterol storage rather than of losing an NPC1 activity that restrains autophagy.
Type: cell biology / genetic epistasis
Experiment: Measure chloroquine pharmacokinetics and lysosomal accumulation in liver and brain of Npc1+/- and Npc1 P202A/F203A knock-in mice versus wild type, to test whether the knockdown phenotype reported in rat hepatoma cells reflects a transport-dependent role of NPC1.
Hypothesis: Mouse NPC1 contributes to clearance of lysosomotropic xenobiotics (e.g. chloroquine) in vivo, not only in cultured hepatoma cells.
Type: in vivo pharmacology
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