{"gene":"SCARB2","run_date":"2026-06-10T07:46:29","timeline":{"discoveries":[{"year":2007,"finding":"LIMP-2 is a specific binding partner of β-glucocerebrosidase (GCase) and serves as the mannose-6-phosphate-independent lysosomal targeting receptor for GCase. The interaction involves a coiled-coil domain within the lumenal domain of LIMP-2. In LIMP-2-deficient mice, GCase is secreted rather than delivered to lysosomes, and reconstitution of LIMP-2 rescues lysosomal GCase levels and distribution.","method":"Affinity chromatography, LIMP-2-deficient mouse fibroblasts and macrophages, reconstitution experiments, subcellular fractionation","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — affinity chromatography identification, knockout mouse validation, reconstitution rescue, multiple orthogonal methods in a landmark study","pmids":["18022370"],"is_preprint":false},{"year":1998,"finding":"AP-3 selectively binds the cytoplasmic tail of LIMP-2 via a DEXXXLI dileucine-based motif, mediating sorting of LIMP-2 to lysosomes. AP-1 and AP-2 do not interact with this tail, establishing AP-3 as the specific adaptor for LIMP-2 lysosomal targeting.","method":"Surface plasmon resonance binding assay with recombinant AP complexes and cytoplasmic tail peptides","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with surface plasmon resonance, replicated finding across multiple adaptor complexes, mechanistically precise","pmids":["9482728"],"is_preprint":false},{"year":2003,"finding":"The [DE]XXXL[LI]-type dileucine signal in LIMP-2's cytoplasmic tail interacts specifically with the gamma-sigma1 subunits of AP-1 and delta-sigma3 subunits of AP-3, but not AP-2 or AP-4 hemicomplexes, defining the molecular basis of AP-3-mediated endosomal/lysosomal sorting.","method":"Yeast three-hybrid assay, in vitro binding to whole AP complexes","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — yeast three-hybrid plus in vitro binding, consistent with prior surface plasmon resonance data, two orthogonal methods","pmids":["14691137"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of LIMP-2 reveals a helical bundle where GCase binds and a large cavity/tunnel traversing the entire molecule, consistent with a lipid transport function. Mutagenesis of the tunnel in the SR-BI homologue indicates this cavity mediates cholesterol(ester) transfer from bound lipoproteins to the membrane.","method":"X-ray crystallography, homology modelling, site-directed mutagenesis of tunnel residues in SR-BI","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure determination combined with functional mutagenesis, high-impact structural study","pmids":["24162852"],"is_preprint":false},{"year":2009,"finding":"Disease-causing AMRF nonsense mutations in LIMP-2 (W146SfsX16, W178X) abolish GCase binding, while the Q288X truncation retains near-normal binding. The missense mutation H363N increases GCase binding affinity. A coiled-coil domain (residues 145–288) is essential for GCase binding; disruption of the helical/amphipathic coiled-coil structure abolishes this interaction.","method":"Co-immunoprecipitation, binding assays with mutant LIMP-2 constructs, synthetic peptide studies","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple AMRF disease mutations functionally characterized, coiled-coil domain mapped, multiple orthogonal approaches","pmids":["19933215"],"is_preprint":false},{"year":2012,"finding":"A single histidine residue in LIMP-2 (H363) functions as a pH sensor required for GCase binding at neutral pH and its release in late endosomal/lysosomal acidic compartments. Vacuolar H+-ATPase-mediated lumenal acidification triggers dissociation of the LIMP-2/GCase complex.","method":"Site-directed mutagenesis of H363, pharmacological inhibition of V-ATPase, co-immunoprecipitation at different pH values","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of single critical residue combined with pharmacological and biochemical validation, consistent with structural data","pmids":["22537104"],"is_preprint":false},{"year":2014,"finding":"Structural analysis of LIMP-2 reveals that GCase binding and pH-dependent release is governed by a histidine trigger, and that LIMP-2 carries P-Man9GlcNAc2 at N325 enabling it to bind the mannose-6-phosphate receptor (MPR) with affinity similar to the LIMP-2/GCase interaction; β-GCase and MPR binding sites are functionally separate, allowing formation of a stable ternary LIMP-2/GCase/MPR complex demonstrated in living cells by FLIM.","method":"X-ray crystallography, surface plasmon resonance, fluorescence lifetime imaging microscopy (FLIM) in living cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure, SPR binding, and FLIM in living cells, multiple orthogonal methods in one study","pmids":["25027712"],"is_preprint":false},{"year":2015,"finding":"LIMP-2 lysosomal sorting occurs via a mannose-6-phosphate-independent pathway: in fibroblasts lacking MPRs or GlcNAc-1-phosphotransferase (the M6P-forming enzyme), LIMP-2 still localizes to lysosomes, and lysosomal LIMP-2 levels are comparable in wild-type and phosphotransferase-defective mouse liver. The M6P modification on the LIMP-2 ectodomain is dispensable for its lysosomal targeting.","method":"Immunofluorescence in MPR-deficient and GlcNAc-1-phosphotransferase-defective fibroblasts, lysosome purification and immunoblot from mouse liver, heterologous expression of LIMP-2 luminal domain","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic knockout models (MPR-null, phosphotransferase-null), in vivo lysosome purification, consistent across cell and animal models","pmids":["26219725"],"is_preprint":false},{"year":2019,"finding":"LIMP-2 mediates lysosomal cholesterol export: the luminal cavity can bind and deliver exogenous cholesterol to the lysosomal membrane and subsequently to lipid droplets. LIMP-2 depletion alters SREBP-2-mediated cholesterol regulation and LDL-receptor levels, and LIMP-2 operates in parallel with NPC proteins for lysosomal cholesterol export.","method":"Molecular modeling, crosslinking studies, microscale thermophoresis, cell-based cholesterol transport assays, SREBP-2/LDL-receptor immunoblotting in LIMP-2 knockout cells","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — multiple orthogonal biochemical and cell-based methods in one study, structural cavity previously identified, single lab","pmids":["31387993"],"is_preprint":false},{"year":2000,"finding":"The dileucine sorting motif in LIMP-2's C-terminal tail requires an acidic glutamate (Glu) at position -4 upstream of the critical leucine for efficient intracellular sorting to lysosomes, but this residue is dispensable for surface internalization by endocytosis, demonstrating distinct structural requirements for intracellular sorting versus endocytosis.","method":"Site-directed mutagenesis of LIMP-2 cytoplasmic tail, subcellular localization by microscopy, endocytosis assays in transfected cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis with defined phenotypic readout, single lab, clear functional dissection","pmids":["10973972"],"is_preprint":false},{"year":1998,"finding":"SR-BII (an alternatively spliced isoform of the SCARB2/SR-BI gene with a distinct C-terminal cytoplasmic tail) is enriched in caveolae and mediates both selective cellular uptake of cholesteryl ether from HDL and HDL-dependent cholesterol efflux, but with ~4-fold lower efficiency than SR-BI.","method":"Subcellular fractionation of CHO transfectants, radiolabeled HDL cholesteryl ether uptake assay, cholesterol efflux assay, adenoviral overexpression in vivo","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional lipid transfer assays combined with subcellular fractionation and in vivo adenoviral experiments, multiple orthogonal methods","pmids":["9614139"],"is_preprint":false},{"year":2004,"finding":"SR-BII (the SCARB2 gene splice variant) is predominantly localized intracellularly (~80–90% intracellular vs ~70% surface for SR-BI) due to its distinct C-terminal cytoplasmic tail, and rapidly internalizes HDL via endocytosis, with internalized HDL co-localizing in the endosomal recycling compartment. Deletion of the SR-BI C-terminus does not affect its surface localization, confirming the SR-BII C-terminus confers intracellular targeting.","method":"Cell surface biotinylation, EGFP-tagged receptor imaging, pulse-chase HDL uptake experiments, subcellular co-localization with transferrin (endosomal recycling marker)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (biotinylation, live imaging, pulse-chase, co-localization) in one study, mechanistically defines C-tail function","pmids":["14726519"],"is_preprint":false},{"year":2005,"finding":"SR-BII mediates HDL endocytosis through a clathrin-dependent, caveolae-independent pathway. A dileucine motif at positions 492–493 in the SR-BII C-terminal cytoplasmic tail is required for HDL particle endocytosis; L492A substitution increases surface HDL binding and reduces endocytosis. Introduction of the SR-BII YTPLL motif into SR-BI converts it into an endocytic receptor.","method":"Site-directed mutagenesis of SR-BII tail residues, HDL endocytosis assays, clathrin/caveolin pathway inhibition, chimeric SR-BI/SR-BII constructs","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of specific residues with defined endocytosis readout, pathway dissection, gain-of-function chimera experiment","pmids":["16368683"],"is_preprint":false},{"year":2012,"finding":"SCARB2 functions as an uncoating receptor for EV71: after virus-SCARB2 complex internalization into endosomes, acidic pH (below 6.0) combined with SCARB2 triggers conversion of native EV71 virions into empty capsids lacking both genomic RNA and VP4. This uncoating does not occur with PSGL1 as receptor under any pH condition.","method":"Sucrose density gradient centrifugation analysis of viral uncoating, incubation of EV71 with L-SCARB2 cells or soluble SCARB2 at various pH values, immunofluorescence colocalization with endosomal markers","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct biochemical demonstration of uncoating with purified soluble SCARB2 and defined pH conditions, comparative experiment with PSGL1, multiple orthogonal readouts","pmids":["23302872"],"is_preprint":false},{"year":2014,"finding":"Crystal structures of SCARB2 under neutral and acidic conditions reveal a pH-dependent conformational change that opens a lipid-transfer tunnel, enabling expulsion of a hydrophobic pocket factor from EV71, a prerequisite for viral uncoating. The canyon region of EV71 VP1 mediates receptor interaction, with key residues identified.","method":"X-ray crystallography of SCARB2 at neutral and acidic pH, structural comparison, mutagenesis of virus-receptor contact residues","journal":"Protein & cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structures at two pH values combined with functional mutagenesis, direct mechanistic insight into conformational change","pmids":["24986489"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of the EV71-SCARB2 complex at 3.4 Å resolution shows SCARB2 binds EV71 on the southern rim of the canyon (not across the canyon as predicted). Helices α5 (152–163) and α7 (183–193) of SCARB2 and the VP1 GH and VP2 EF loops of EV71 dominate the interaction, suggesting an allosteric mechanism for low-pH uncoating.","method":"Cryo-electron microscopy of EV71-SCARB2 complex","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — high-resolution cryo-EM structure of the native virus-receptor complex, direct structural determination","pmids":["30531980"],"is_preprint":false},{"year":2011,"finding":"The region of human SCARB2 encompassing amino acids 142–204 is critical for EV71 virion binding and infection; chimeric SCARB2 constructs carrying this human region in a mouse Scarb2 backbone confer susceptibility to EV71, whereas those retaining the mouse sequence in this region do not support efficient viral binding.","method":"Human-mouse SCARB2 chimeric mutant expression in L929 cells, viral binding assays, infection assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — domain-swap chimera approach with binding and infection readouts, clear functional mapping of residues 142–204","pmids":["21389126"],"is_preprint":false},{"year":2012,"finding":"EV71 entry into cells expressing SCARB2 occurs via a clathrin-mediated, pH-dependent, cholesterol-sensitive endocytic pathway; siRNA knockdown of clathrin or dynamin blocks entry, whereas caveolin knockdown does not affect entry.","method":"siRNA knockdown of clathrin, dynamin, caveolin; chemical inhibitors of clathrin-mediated endocytosis and caveolae-mediated endocytosis; pH perturbation experiments; cholesterol depletion","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (siRNA) and pharmacological dissection of endocytic pathway, single lab, convergent results","pmids":["22272359"],"is_preprint":false},{"year":2015,"finding":"SCARB2 mediates endosomal translocation of TLR9 in plasmacytoid dendritic cells (pDCs): SCARB2 knockdown results in retention of TLR9 in the ER and impaired nuclear translocation of IRF7, leading to dramatically reduced CpG-induced type I IFN production. SCARB2 localizes to late endosomes/lysosomes in pDCs and is required for TLR7-ligand-induced IFN-I as well.","method":"siRNA knockdown of SCARB2 in pDC cell line GEN2.2, subcellular localization by immunofluorescence, TLR9/IRF7 localization by immunofluorescence, IFN-I ELISA","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple readouts (receptor localization, transcription factor translocation, cytokine secretion), single lab","pmids":["25862818"],"is_preprint":false},{"year":2014,"finding":"The GCase-binding sequence on GCase for LIMP-2 is an 11-amino acid stretch (DSPIIVDITKD); Asp399, Ile402, and Ile403 are particularly important. Alanine substitution at any of these residues decreases GCase binding to LIMP-2, alters pH-dependent binding, diminishes lysosomal trafficking of GCase, and increases GCase secretion. The EV71-binding site on LIMP-2/SCARB2 is distinct from the GCase-binding site.","method":"Deletion constructs, alanine-scanning mutagenesis, binding assays, co-localization, GCase secretion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic mutagenesis of multiple residues with binding, trafficking, and secretion readouts, mechanistically precise mapping","pmids":["25202012"],"is_preprint":false},{"year":2015,"finding":"In human fibroblasts and neuron-like cells, GCase lysosomal targeting is completely dependent on LIMP-2, whereas in blood (lymphocytes), GCase is partially targeted to lysosomes by a LIMP-2-independent mechanism. Recombinant human GCase (enzyme replacement therapy) is taken up by cells independently of LIMP-2 but its lysosomal trafficking requires LIMP-2.","method":"GCase activity and localization in AMRF patient fibroblasts, lymphocytes, and neuronal model; LIMP-2-deficient and -sufficient cell comparisons; recombinant GCase uptake/trafficking assay","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (patient cells) with multiple cell-type comparisons and enzyme replacement experiment, single lab","pmids":["26018676"],"is_preprint":false},{"year":2015,"finding":"LIMP-2 is a substrate of cathepsin-F: cathepsin-F mediates proteolytic cleavage of wild-type LIMP-2 in lysosomes in vitro and in vivo. Disease-causing cathepsin-F mutants (associated with type-B Kufs disease) fail to cleave LIMP-2.","method":"Heterologous expression of cathepsin-F variants, in vitro cleavage assay, purified lysosomes from mouse tissue, immunoblotting","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro cleavage assay, in vivo lysosomal evidence, disease-mutant comparison; single lab","pmids":["25576872"],"is_preprint":false},{"year":2010,"finding":"LIMP-2 controls late phagosomal trafficking and the innate immune response to Listeria monocytogenes in macrophages: LIMP-2-deficient mice show impaired phago-lysosome transformation, low listericidal activity, reduced acute-phase pro-inflammatory cytokines, and 25-fold increased susceptibility to Listeria. LIMP-2 transfection in CHO cells confirms its role in late endosomal/lysosomal fusion and activation of Rab5a.","method":"LIMP-2-deficient mouse macrophage functional assays, cytokine/chemokine measurement, phagolysosome biogenesis assay, CHO cell reconstitution with LIMP-2 transfection, Rab5a activation assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with multiple immune readouts and reconstitution in CHO cells, single lab","pmids":["21123180"],"is_preprint":false},{"year":2014,"finding":"LIMP-2 expression is critical for lysosomal GCase activity and α-synuclein clearance: LIMP-2-deficient mouse brains show reduced GCase activity, lipid storage, disturbed autophagy/lysosomal function, and α-synuclein accumulation causing dopaminergic neuron toxicity. Heterologous expression of LIMP-2 accelerates clearance of overexpressed α-synuclein by increasing lysosomal GCase activity.","method":"LIMP-2-deficient mouse brain analysis, GCase activity assay, autophagy markers, α-synuclein immunofluorescence/immunoblot, LIMP-2 overexpression rescue experiment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse with multiple mechanistic readouts plus gain-of-function rescue experiment, multiple orthogonal methods","pmids":["25316793"],"is_preprint":false},{"year":2011,"finding":"LIMP-2 deficiency causes a defect in proteolysis of reabsorbed proteins in renal proximal tubule cells: megalin/cubilin-dependent endocytosis is unaffected, but cathepsin B fails to co-localize with endosomal contents in Limp-2−/− mice, indicating that LIMP-2 is required for fusion of endosomes with lysosomes in the proximal tubule.","method":"Limp-2 knockout mice, in vivo fluorescent albumin uptake/tracking, cathepsin B co-localization by immunofluorescence, megalin/cubilin expression analysis","journal":"American journal of physiology. Renal physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with in vivo tracer experiment and mechanistic co-localization data, single lab","pmids":["21429972"],"is_preprint":false},{"year":2024,"finding":"GSH (glutathione) directly binds to SCARB2, interfering with the interaction between its N and C termini. This recruits mTORC1 to lysosomes through ARF1, leading to activation of mTOR signaling and promoting breast cancer progression.","method":"TME metabolomics, GCLC adipocyte-specific knockout mouse model, direct GSH-SCARB2 binding assay, mTORC1 lysosomal recruitment assay, ARF1 interaction studies","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding demonstrated, genetic mouse model, ARF1-mTOR pathway placement; single lab, relatively new finding","pmids":["39442522"],"is_preprint":false},{"year":2023,"finding":"SCARB2 promotes MYC acetylation by interfering with HDAC3-mediated deacetylation of MYC at lysine 148, thereby enhancing MYC transcriptional activity and hepatocellular carcinoma cancer stem cell properties. Knockout of Scarb2 in hepatocytes attenuates HCC initiation in MYC-driven and DEN-induced mouse models.","method":"CRISPR/Cas9 knockout library screen in HCC tumorspheres, Scarb2 hepatocyte-specific knockout HCC mouse models, co-immunoprecipitation of SCARB2/MYC/HDAC3, MYC acetylation assay at K148","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP of SCARB2/MYC/HDAC3 complex, in vivo mouse model, acetylation assay; single lab","pmids":["37739936"],"is_preprint":false},{"year":2024,"finding":"Cryo-EM structure of GCase in complex with LIMP-2 reveals that helix 5 and helix 7 of LIMP-2's ectodomain interact with a binding pocket on GCase via a mostly hydrophobic interface supported by one essential salt bridge. LIMP-2 overexpression increases lysosomal abundance and enzymatic activity of GCase, and acts as an allosteric activator; a peptide derived from the LIMP-2 single helix enhances lysosomal GCase activity in patient-derived fibroblasts.","method":"Cryo-electron microscopy with engineered LIMP-2 shuttle and pro-macrobodies, LIMP-2 overexpression in HEK293T cells, GCase activity assays in fibroblasts, co-purification of GCase-LIMP-2 complex","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with functional assays and peptide-based gain-of-function, multiple orthogonal methods","pmids":["40159502"],"is_preprint":false},{"year":2024,"finding":"LIMP-2 is present at ER-lysosome membrane contact sites through interaction with the endosomal protein STARD3 and ER-resident VAPB; STARD3 is required for the LIMP-2/VAPB interaction. This places LIMP-2 at organelle contact sites that may facilitate cholesterol transport from lysosomal to ER membrane.","method":"Proximity-based interaction screen (BioID), co-immunoprecipitation, immunofluorescence co-localization","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — BioID proximity proteomics validated by co-IP and imaging, STARD3 requirement established by dependency experiment; single lab","pmids":["39370902"],"is_preprint":false},{"year":2024,"finding":"Tetrandrine directly binds the LIMP-2 ectodomain (identified by clickable photoaffinity probe), inhibiting lysosomal cholesterol and sphingosine transport. LIMP-2 depletion or tetrandrine treatment inhibits NAADP-dependent calcium release via two-pore channels (TPCs); this is reversed by removing lysosomal cholesterol and sphingosine. Sphingosine triggers TPC-mediated lysosomal calcium release and restores this signaling in LIMP-2-deficient cells.","method":"Clickable photoaffinity probe for target identification, LIMP-2 knockdown, lysosomal calcium assays, sphingosine supplementation rescue, TPC functional assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — photoaffinity probe-based target identification validated by functional rescue experiments, defined mechanistic pathway; single lab","pmids":["40628771"],"is_preprint":false},{"year":2024,"finding":"SCARB2 deficiency in mice leads to gut dysbiosis and altered bile acid pool, causing hyperactivation of intestinal FXR, which impairs epithelium renewal and dietary lipid (including vitamin E) absorption. FXR inhibition or vitamin E supplementation ameliorates neuromotor impairment and neuropathy in Scarb2 knockout mice.","method":"Scarb2 knockout mouse model, gut microbiome analysis, bile acid profiling, FXR activity assay, vitamin E level measurement in patients, FXR inhibitor and vitamin E supplementation rescue experiments","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with multi-omic pathway analysis, pharmacological rescue, patient vitamin E measurement; single lab, novel gut axis mechanism","pmids":["38635907"],"is_preprint":false},{"year":2024,"finding":"EV-A71 does not encounter its uncoating receptor SCARB2 at the cell surface; SCARB2 is absent from the surface of RD and other susceptible cell lines and is concentrated in lysosomes/late endosomes. SCARB2 is dispensable for virus attachment but essential for infection, indicating that the critical SCARB2-EV-A71 interaction occurs intracellularly (in lysosomes) to trigger uncoating rather than at the plasma membrane.","method":"SCARB2 and PSGL-1 knockout cell lines, cell surface expression analysis, virus attachment assays, infection assays","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout experiments with attachment versus infection readouts, refines prior receptor localization model; single lab","pmids":["38359079"],"is_preprint":false},{"year":2003,"finding":"LIMP-2/LGP85-deficient mice exhibit peripheral demyelinating neuropathy associated with massive loss of peripheral myelin proteins and increased lysosomal protein activity, indicating a role for the lysosomal compartment in peripheral myelination; mice also show lysosome accumulation in ureteric epithelium with disturbed uroplakin surface expression, causing ureteropelvic junction obstruction.","method":"LIMP-2 knockout mouse phenotypic analysis: neuropathology, myelin protein immunoblotting, lysosomal enzyme activity assays, histology, immunofluorescence","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined cellular and molecular phenotypes, multiple organ pathology characterization; single lab","pmids":["12620969"],"is_preprint":false},{"year":2022,"finding":"SR-B2/LIMP-2 is present at the RPE cell surface (not exclusively intracellular), associates with lipid rafts, and participates in the control of photoreceptor outer segment (POS) phagocytosis speed in retinal pigment epithelial cells; siRNA inhibition of SR-B2/LIMP-2 alters POS internalization dynamics, similar to CD36.","method":"siRNA knockdown, immunoblotting, immunohistochemistry, lipid raft flotation gradients, phagocytosis assays in RPE cell lines and tissue","journal":"International journal of molecular sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — siRNA with phagocytosis assay but limited mechanistic detail in abstract, single lab","pmids":["35408805"],"is_preprint":false},{"year":2019,"finding":"In a human iPSC-derived cardiomyocyte model of Fabry disease, LIMP-2 accumulates relative to controls; overexpression of LIMP-2 directly induces secretion of cathepsin F and HSPA2/HSP70-2 and causes massive vacuole accumulation, suggesting LIMP-2 accumulation is causally linked to these downstream pathological events.","method":"iPSC-derived cardiomyocytes from Fabry disease patients, quantitative proteomics, LIMP-2 overexpression with cathepsin F/HSP70-2 secretion readout, genetic correction reversal","journal":"Stem cell reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — quantitative proteomics, gain-of-function overexpression with functional readout, genetic correction as control; single lab","pmids":["31378672"],"is_preprint":false},{"year":2022,"finding":"SCARB2 deficiency disrupts mTORC1-dependent mitochondrial oxidative phosphorylation (OXPHOS) in adipocytes: Scarb2 deficiency decreases the mTORC1/4E-BP1 pathway, leading to impaired mitochondrial respiration and enhanced glycolysis, resulting in reduced lipid storage in white adipose tissue.","method":"Adiponectin-Cre; Scarb2 conditional knockout mice, mTORC1/4E-BP1 pathway analysis by immunoblot, mitochondrial respiration (Seahorse), glycolysis assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional knockout mouse, mTOR pathway mechanistic analysis, mitochondrial function assays; single lab","pmids":["35955761"],"is_preprint":false}],"current_model":"SCARB2/LIMP-2 is an abundant lysosomal integral membrane protein with a large luminal domain containing a helical bundle that binds β-glucocerebrosidase via a coiled-coil domain, directing GCase to lysosomes independently of mannose-6-phosphate receptors through a pH-dependent mechanism (histidine trigger at H363); the protein also contains a hydrophobic tunnel that mediates transport of cholesterol and other lipids from the lysosomal lumen to the membrane (and onward to ER contact sites via STARD3-VAPB); its cytoplasmic dileucine (DEXXXLI) tail mediates selective binding to AP-3 (via gamma/delta-sigma subunits) for lysosomal sorting; the alternatively spliced SR-BII isoform differs only in its C-terminal cytoplasmic tail, which confers predominant intracellular localization and clathrin-dependent HDL endocytosis via a YTPLL dileucine motif; at the endosome/lysosome, SCARB2 functions as an uncoating receptor for EV71 and related enteroviruses by undergoing pH-dependent conformational change that opens its lipid-transfer tunnel to expel the viral pocket factor, facilitating genome release; SCARB2 additionally mediates TLR9 endosomal translocation and IRF7 nuclear translocation in plasmacytoid dendritic cells, contributes to macrophage phagolysosome maturation, and promotes MYC acetylation and mTORC1 lysosomal recruitment in cancer contexts."},"narrative":{"mechanistic_narrative":"SCARB2/LIMP-2 is an abundant lysosomal integral membrane protein that functions both as a dedicated trafficking receptor and as a lipid-transfer conduit at the lysosomal membrane [PMID:18022370, PMID:24162852]. Its large luminal domain binds β-glucocerebrosidase (GCase) through a helical bundle (helices 5 and 7) engaging a pocket on GCase, mapped to a coiled-coil region (residues 145–288) on LIMP-2 and an 11-residue stretch (D399/I402/I403) on GCase, and thereby delivers GCase to lysosomes independently of the mannose-6-phosphate pathway; loss of LIMP-2 redirects GCase to secretion [PMID:18022370, PMID:19933215, PMID:25202012, PMID:40159502, PMID:26219725]. This receptor function is pH-gated by a histidine trigger (H363): the complex assembles at neutral pH and dissociates upon V-ATPase-driven acidification in late endosomes/lysosomes [PMID:22537104, PMID:25027712]. LIMP-2 reaches lysosomes via a cytoplasmic [DE]XXXL[LI] dileucine signal that is selectively recognized by the AP-3 adaptor (and AP-1) through γ/δ–σ subunit interactions [PMID:9482728, PMID:14691137, PMID:10973972]. Beyond protein sorting, the molecule contains a hydrophobic tunnel that transfers cholesterol and other lipids from the lysosomal lumen to the membrane and onward toward the ER via contact sites involving STARD3 and VAPB, and it supports lysosomal sphingosine transport that gates two-pore-channel calcium release [PMID:24162852, PMID:31387993, PMID:39370902, PMID:40628771]. The same luminal architecture is exploited by enterovirus 71, for which SCARB2 acts as a low-pH uncoating receptor: an acid-induced conformational change opens the lipid tunnel to expel the viral pocket factor, an interaction that occurs intracellularly in lysosomes rather than at the cell surface [PMID:23302872, PMID:24986489, PMID:30531980, PMID:21389126, PMID:38359079]. Through its control of lysosomal GCase activity, LIMP-2 governs autophagic and lysosomal homeostasis, and its deficiency causes GCase loss, α-synuclein accumulation, and dopaminergic neurotoxicity; in humans, loss-of-function mutations cause action myoclonus–renal failure syndrome (AMRF) [PMID:19933215, PMID:25316793]. An alternatively spliced isoform (SR-BII) differs only in its C-terminal cytoplasmic tail, conferring predominant intracellular localization and clathrin-dependent HDL endocytosis via a YTPLL/dileucine motif [PMID:9614139, PMID:14726519, PMID:16368683]. LIMP-2 additionally functions in macrophage phagolysosome maturation and innate immunity, renal proximal-tubule endosome–lysosome fusion, TLR9/IRF7-driven type I interferon responses in plasmacytoid dendritic cells, and in cancer contexts where it promotes MYC acetylation and mTORC1 lysosomal recruitment [PMID:21123180, PMID:21429972, PMID:25862818, PMID:37739936, PMID:39442522].","teleology":[{"year":1998,"claim":"Established how LIMP-2 itself reaches lysosomes by identifying the adaptor that reads its cytoplasmic sorting tail, answering how the receptor is delivered to its compartment.","evidence":"Surface plasmon resonance binding of recombinant AP complexes to cytoplasmic tail peptides","pmids":["9482728"],"confidence":"High","gaps":["Did not resolve which AP subunits contact the motif","In vitro peptide binding without cellular trafficking validation"]},{"year":2003,"claim":"Defined the molecular basis of LIMP-2 sorting by mapping the dileucine motif to specific γ-σ1 (AP-1) and δ-σ3 (AP-3) hemicomplex subunits, refining adaptor specificity.","evidence":"Yeast three-hybrid plus in vitro binding to whole AP complexes","pmids":["14691137"],"confidence":"High","gaps":["Relative contribution of AP-1 vs AP-3 in vivo not resolved","Structural basis of subunit recognition not determined"]},{"year":2007,"claim":"Identified LIMP-2 as the long-sought mannose-6-phosphate-independent lysosomal targeting receptor for GCase, answering how this enzyme reaches lysosomes.","evidence":"Affinity chromatography, LIMP-2-deficient mouse cells, reconstitution rescue, subcellular fractionation","pmids":["18022370"],"confidence":"High","gaps":["Binding interface residues not yet mapped","pH-dependence of the interaction not defined"]},{"year":2009,"claim":"Linked human AMRF disease mutations to loss of GCase binding and mapped the binding determinant to a coiled-coil region, connecting molecular interaction to clinical phenotype.","evidence":"Co-immunoprecipitation and binding assays with AMRF mutant constructs and synthetic peptides","pmids":["19933215"],"confidence":"High","gaps":["Did not explain why H363N increases affinity","Functional consequence in patient tissues not addressed"]},{"year":2012,"claim":"Explained how the LIMP-2/GCase complex assembles and releases its cargo by defining H363 as a pH sensor controlled by lysosomal acidification.","evidence":"Site-directed mutagenesis of H363, V-ATPase inhibition, pH-dependent co-IP","pmids":["22537104"],"confidence":"High","gaps":["Structural mechanism of the histidine switch not directly visualized in this study","Whether other residues contribute to pH sensing unknown"]},{"year":2013,"claim":"Provided the structural framework for both functions by revealing a GCase-binding helical bundle and a tunnel traversing the molecule consistent with lipid transfer.","evidence":"X-ray crystallography, homology modelling, mutagenesis of tunnel residues in the SR-BI homologue","pmids":["24162852"],"confidence":"High","gaps":["Direct lipid transfer by LIMP-2 itself not demonstrated here","Cargo selectivity of the tunnel not defined"]},{"year":2014,"claim":"Resolved how a single receptor reconciles two sorting routes by showing LIMP-2 carries M6P at N325, binds MPR with separable affinity, and can form a ternary LIMP-2/GCase/MPR complex.","evidence":"X-ray crystallography, SPR, FLIM in living cells","pmids":["25027712"],"confidence":"High","gaps":["Physiological role of M6P-MPR binding remained uncertain (later shown dispensable)","Stoichiometry of the ternary complex in vivo unknown"]},{"year":2014,"claim":"Mapped the reciprocal GCase determinant for LIMP-2 binding and showed it is distinct from the EV71-binding site, establishing functional separation of cargo and pathogen interactions.","evidence":"Alanine-scanning mutagenesis, binding, co-localization, and GCase secretion assays","pmids":["25202012"],"confidence":"High","gaps":["Structure of the interface awaited later cryo-EM","Effect of disease-relevant GCase variants not tested"]},{"year":2015,"claim":"Demonstrated that LIMP-2 lysosomal targeting is genuinely M6P-independent, resolving whether the N325 modification is required for its own delivery.","evidence":"Immunofluorescence and lysosome purification in MPR-null and phosphotransferase-defective cells and mouse liver","pmids":["26219725"],"confidence":"High","gaps":["The functional purpose of the M6P modification on LIMP-2 remains unexplained","Tail-dependent (AP-3) versus luminal contributions not jointly quantified"]},{"year":2014,"claim":"Connected LIMP-2 to neurodegeneration by showing its loss reduces lysosomal GCase activity, impairs autophagy, and drives α-synuclein accumulation and dopaminergic toxicity.","evidence":"LIMP-2-deficient mouse brain analysis with GCase activity, autophagy markers, and α-synuclein rescue by overexpression","pmids":["25316793"],"confidence":"High","gaps":["Direct relevance to human Parkinson's disease not established","Whether lipid transport defects contribute independently unknown"]},{"year":2024,"claim":"Visualized the GCase-LIMP-2 interface at near-atomic resolution and demonstrated LIMP-2 acts as an allosteric GCase activator, enabling peptide-based enhancement of lysosomal GCase activity.","evidence":"Cryo-EM with engineered shuttle, overexpression, GCase activity assays in patient fibroblasts","pmids":["40159502"],"confidence":"High","gaps":["Therapeutic durability of the activating peptide not established","Allosteric mechanism in the acidic lysosomal environment not fully resolved"]},{"year":1998,"claim":"Characterized the SR-BII splice isoform, showing its distinct C-tail supports HDL cholesteryl ester uptake and efflux, distinguishing it functionally from SR-BI.","evidence":"Subcellular fractionation, radiolabeled HDL uptake and efflux assays, in vivo adenoviral expression","pmids":["9614139"],"confidence":"High","gaps":["Mechanistic basis of the lower efficiency not defined","Relationship to lysosomal LIMP-2 function not addressed"]},{"year":2005,"claim":"Defined how the SR-BII tail confers endocytic behavior by identifying a dileucine/YTPLL motif required for clathrin-dependent HDL internalization, and converted SR-BI into an endocytic receptor by motif transplantation.","evidence":"Mutagenesis, HDL endocytosis assays, pathway inhibition, chimeric constructs","pmids":["16368683","14726519"],"confidence":"High","gaps":["Physiological significance of SR-BII endocytosis in vivo unclear","Adaptor reading the YTPLL motif not identified"]},{"year":2012,"claim":"Established SCARB2 as a low-pH uncoating receptor for EV71, showing that acidic endosomal conditions plus SCARB2 convert virions to empty capsids, defining the genome-release step.","evidence":"Density gradient uncoating analysis with soluble SCARB2 at defined pH, comparison with PSGL1","pmids":["23302872"],"confidence":"High","gaps":["Structural mechanism of uncoating not yet visualized","Receptor surface vs intracellular site of action not resolved here"]},{"year":2018,"claim":"Resolved the structural mechanism of EV71 uncoating by combining acidic/neutral SCARB2 crystal structures with the cryo-EM virus-receptor complex, showing pH-driven tunnel opening expels the pocket factor.","evidence":"X-ray crystallography at two pH values and cryo-EM of the EV71-SCARB2 complex with mutagenesis","pmids":["24986489","30531980","21389126"],"confidence":"High","gaps":["Dynamics of the conformational transition not captured in real time","How endosomal lipids participate in pocket-factor expulsion unknown"]},{"year":2024,"claim":"Refined the entry model by showing SCARB2 is absent from the cell surface and that the critical EV-A71 interaction occurs intracellularly in lysosomes, dispensable for attachment but essential for infection.","evidence":"SCARB2 and PSGL-1 knockout cell lines with surface expression, attachment, and infection assays","pmids":["38359079","22272359"],"confidence":"Medium","gaps":["Single lab","Initial attachment receptor in surface-SCARB2-negative cells not fully defined"]},{"year":2019,"claim":"Demonstrated that LIMP-2 directly mediates lysosomal cholesterol export to membrane and lipid droplets and influences SREBP-2/LDLR regulation, operating in parallel with NPC proteins.","evidence":"Molecular modeling, crosslinking, microscale thermophoresis, cholesterol transport assays, and SREBP-2/LDLR immunoblot in knockout cells","pmids":["31387993"],"confidence":"High","gaps":["Quantitative contribution relative to NPC pathway unclear","Directionality and regulation of the tunnel not fully defined"]},{"year":2024,"claim":"Placed LIMP-2 at ER-lysosome contact sites via STARD3-dependent VAPB interaction, providing a route for lysosome-to-ER cholesterol handoff.","evidence":"BioID proximity screen, co-IP, and immunofluorescence co-localization","pmids":["39370902"],"confidence":"Medium","gaps":["Single lab","Direct cholesterol flux across the contact site not measured","STARD3/VAPB interaction stoichiometry undefined"]},{"year":2024,"claim":"Linked LIMP-2 lipid transport to lysosomal signaling by showing it supplies cholesterol/sphingosine that enable NAADP/TPC-mediated calcium release, druggable by tetrandrine.","evidence":"Photoaffinity target identification, knockdown, lysosomal calcium assays, sphingosine rescue, TPC functional assays","pmids":["40628771"],"confidence":"Medium","gaps":["Single lab","Whether LIMP-2 directly transports sphingosine or acts indirectly not fully resolved"]},{"year":2010,"claim":"Showed LIMP-2 controls late phagosome maturation and innate defense, linking the lysosomal protein to Listeria immunity and Rab5a activation.","evidence":"LIMP-2-deficient mouse macrophages, cytokine assays, phagolysosome biogenesis, CHO reconstitution, Rab5a activation","pmids":["21123180"],"confidence":"Medium","gaps":["Single lab","Molecular link between LIMP-2 and Rab5a activation undefined"]},{"year":2011,"claim":"Demonstrated a tissue-specific requirement for LIMP-2 in renal proximal-tubule endosome-lysosome fusion, downstream of intact megalin/cubilin endocytosis.","evidence":"Limp-2 knockout mice, in vivo albumin tracking, cathepsin B co-localization","pmids":["21429972"],"confidence":"Medium","gaps":["Single lab","Mechanism by which LIMP-2 promotes fusion not defined"]},{"year":2015,"claim":"Identified a role for SCARB2 in innate antiviral signaling by showing it is required for TLR9 endosomal translocation and IRF7-driven type I interferon in plasmacytoid dendritic cells.","evidence":"siRNA knockdown in GEN2.2 pDCs with receptor/transcription-factor localization and IFN-I ELISA","pmids":["25862818"],"confidence":"Medium","gaps":["Single lab, siRNA only","Direct molecular interaction with TLR9 not shown"]},{"year":2024,"claim":"Connected SCARB2 to oncogenic mTORC1 signaling by showing GSH binding disrupts its N/C-terminal interaction and recruits mTORC1 to lysosomes via ARF1 in breast cancer.","evidence":"TME metabolomics, GCLC knockout mouse, GSH-SCARB2 binding, mTORC1 recruitment, ARF1 interaction studies","pmids":["39442522","35955761"],"confidence":"Medium","gaps":["Single lab","Structural basis of GSH-induced conformational change undefined","Generality across cancer types unknown"]},{"year":2023,"claim":"Revealed a nuclear-adjacent function in cancer by showing SCARB2 protects MYC from HDAC3-mediated deacetylation at K148, enhancing MYC activity and HCC stemness.","evidence":"CRISPR screen, hepatocyte-specific Scarb2 knockout HCC models, SCARB2/MYC/HDAC3 co-IP, K148 acetylation assay","pmids":["37739936"],"confidence":"Medium","gaps":["Single lab","How a lysosomal protein engages MYC/HDAC3 spatially not explained"]},{"year":null,"claim":"It remains unresolved how LIMP-2's canonical lysosomal lipid/protein-transport functions mechanistically connect to its reported nuclear/transcriptional (MYC) and signaling (mTORC1, TLR9) roles, and whether these reflect distinct subcellular pools or moonlighting activities.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying structural or trafficking model bridging lysosomal and signaling/transcriptional roles","Subcellular pool responsible for cancer-associated functions not defined","Most signaling roles rest on single-lab knockdown/knockout studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,8,29]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[8,28,29]},{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[13,14,15,16,31]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,27]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[5,14]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[5,25]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[0,7,18,31]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[11,13,31]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[10,33]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[28]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[8,10,30,35]},{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,1,7,19]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[11,12,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,23,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[18,22]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[25,29,35]}],"complexes":["LIMP-2/GCase complex","LIMP-2/GCase/MPR ternary complex","ER-lysosome contact site (LIMP-2/STARD3/VAPB)"],"partners":["GBA (GCASE)","AP-3","AP-1","STARD3","VAPB","MYC","HDAC3","ARF1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q14108","full_name":"Lysosome membrane protein 2","aliases":["85 kDa lysosomal membrane sialoglycoprotein","LGP85","CD36 antigen-like 2","Lysosome membrane protein II","LIMP II","Scavenger receptor class B member 2"],"length_aa":478,"mass_kda":54.3,"function":"Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting (Microbial infection) Acts as a receptor for enterovirus 71","subcellular_location":"Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q14108/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SCARB2","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"LAMP1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/SCARB2","total_profiled":1310},"omim":[{"mim_id":"610788","title":"SOLUTE CARRIER FAMILY 35 (3-PRIME-PHOSPHOADENOSINE 5-PRIME-PHOSPHOSULFATE TRANSPORTER), MEMBER B2; SLC35B2","url":"https://www.omim.org/entry/610788"},{"mim_id":"606463","title":"GLUCOSIDASE, BETA, ACID; GBA","url":"https://www.omim.org/entry/606463"},{"mim_id":"606374","title":"BETA-1,3-GLUCURONYLTRANSFERASE 3; B3GAT3","url":"https://www.omim.org/entry/606374"},{"mim_id":"602257","title":"SCAVENGER RECEPTOR CLASS B, MEMBER 2; SCARB2","url":"https://www.omim.org/entry/602257"},{"mim_id":"254900","title":"EPILEPSY, PROGRESSIVE MYOCLONIC, 4, WITH OR WITHOUT RENAL FAILURE; EPM4","url":"https://www.omim.org/entry/254900"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SCARB2"},"hgnc":{"alias_symbol":["HLGP85","LIMPII","SR-BII","LIMP-2"],"prev_symbol":["CD36L2"]},"alphafold":{"accession":"Q14108","domains":[{"cath_id":"-","chopping":"59-417","consensus_level":"medium","plddt":95.9951,"start":59,"end":417}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14108","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q14108-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q14108-F1-predicted_aligned_error_v6.png","plddt_mean":92.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SCARB2","jax_strain_url":"https://www.jax.org/strain/search?query=SCARB2"},"sequence":{"accession":"Q14108","fasta_url":"https://rest.uniprot.org/uniprotkb/Q14108.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q14108/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q14108"}},"corpus_meta":[{"pmid":"18022370","id":"PMC_18022370","title":"LIMP-2 is a receptor for lysosomal mannose-6-phosphate-independent targeting of beta-glucocerebrosidase.","date":"2007","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/18022370","citation_count":436,"is_preprint":false},{"pmid":"9482728","id":"PMC_9482728","title":"A di-leucine-based motif in the cytoplasmic tail of LIMP-II and tyrosinase mediates selective binding of AP-3.","date":"1998","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/9482728","citation_count":254,"is_preprint":false},{"pmid":"24162852","id":"PMC_24162852","title":"Structure of LIMP-2 provides functional insights with implications for SR-BI and CD36.","date":"2013","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/24162852","citation_count":245,"is_preprint":false},{"pmid":"7689561","id":"PMC_7689561","title":"Identification, primary structure, and distribution of CLA-1, a novel member of the CD36/LIMPII gene family.","date":"1993","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7689561","citation_count":220,"is_preprint":false},{"pmid":"9614139","id":"PMC_9614139","title":"SR-BII, an isoform of the scavenger receptor BI containing an alternate cytoplasmic tail, mediates lipid transfer between high density lipoprotein and cells.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9614139","citation_count":196,"is_preprint":false},{"pmid":"14691137","id":"PMC_14691137","title":"Recognition of dileucine-based sorting signals from HIV-1 Nef and LIMP-II by the AP-1 gamma-sigma1 and AP-3 delta-sigma3 hemicomplexes.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14691137","citation_count":193,"is_preprint":false},{"pmid":"18308289","id":"PMC_18308289","title":"Array-based gene discovery with three unrelated subjects shows SCARB2/LIMP-2 deficiency causes myoclonus epilepsy and glomerulosclerosis.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18308289","citation_count":188,"is_preprint":false},{"pmid":"15576377","id":"PMC_15576377","title":"Serum amyloid A binding to CLA-1 (CD36 and LIMPII analogous-1) mediates serum amyloid A protein-induced activation of ERK1/2 and p38 mitogen-activated protein kinases.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15576377","citation_count":152,"is_preprint":false},{"pmid":"22438546","id":"PMC_22438546","title":"Human SCARB2-dependent infection by coxsackievirus A7, A14, and A16 and enterovirus 71.","date":"2012","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/22438546","citation_count":139,"is_preprint":false},{"pmid":"31387993","id":"PMC_31387993","title":"Lysosomal integral membrane protein-2 (LIMP-2/SCARB2) is involved in lysosomal cholesterol export.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31387993","citation_count":127,"is_preprint":false},{"pmid":"23302872","id":"PMC_23302872","title":"Functional comparison of SCARB2 and PSGL1 as receptors for enterovirus 71.","date":"2013","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/23302872","citation_count":108,"is_preprint":false},{"pmid":"24986489","id":"PMC_24986489","title":"Molecular mechanism of SCARB2-mediated attachment and uncoating of EV71.","date":"2014","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/24986489","citation_count":107,"is_preprint":false},{"pmid":"7539776","id":"PMC_7539776","title":"The CD36, CLA-1 (CD36L1), and LIMPII (CD36L2) gene family: cellular distribution, chromosomal location, and genetic evolution.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7539776","citation_count":102,"is_preprint":false},{"pmid":"25316793","id":"PMC_25316793","title":"LIMP-2 expression is critical for β-glucocerebrosidase activity and α-synuclein clearance.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25316793","citation_count":102,"is_preprint":false},{"pmid":"30531980","id":"PMC_30531980","title":"Unexpected mode of engagement between enterovirus 71 and its receptor SCARB2.","date":"2018","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30531980","citation_count":97,"is_preprint":false},{"pmid":"12620969","id":"PMC_12620969","title":"LIMP-2/LGP85 deficiency causes ureteric pelvic junction obstruction, deafness and peripheral neuropathy in mice.","date":"2003","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12620969","citation_count":94,"is_preprint":false},{"pmid":"23451246","id":"PMC_23451246","title":"Human SCARB2 transgenic mice as an infectious animal model for enterovirus 71.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23451246","citation_count":91,"is_preprint":false},{"pmid":"26094596","id":"PMC_26094596","title":"Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson's disease cells.","date":"2015","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/26094596","citation_count":87,"is_preprint":false},{"pmid":"14726519","id":"PMC_14726519","title":"High density lipoprotein uptake by scavenger receptor SR-BII.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14726519","citation_count":83,"is_preprint":false},{"pmid":"25027712","id":"PMC_25027712","title":"Lysosome sorting of β-glucocerebrosidase by LIMP-2 is targeted by the mannose 6-phosphate receptor.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/25027712","citation_count":83,"is_preprint":false},{"pmid":"21389126","id":"PMC_21389126","title":"Identification of a human SCARB2 region that is important for enterovirus 71 binding and infection.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21389126","citation_count":80,"is_preprint":false},{"pmid":"19933215","id":"PMC_19933215","title":"Disease-causing mutations within the lysosomal integral membrane protein type 2 (LIMP-2) reveal the nature of binding to its ligand beta-glucocerebrosidase.","date":"2009","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19933215","citation_count":78,"is_preprint":false},{"pmid":"18424452","id":"PMC_18424452","title":"A nonsense mutation in the LIMP-2 gene associated with progressive myoclonic epilepsy and nephrotic syndrome.","date":"2008","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18424452","citation_count":76,"is_preprint":false},{"pmid":"10973972","id":"PMC_10973972","title":"Distinct reading of different structural determinants modulates the dileucine-mediated transport steps of the lysosomal membrane protein LIMPII and the insulin-sensitive glucose transporter GLUT4.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10973972","citation_count":71,"is_preprint":false},{"pmid":"19847901","id":"PMC_19847901","title":"SCARB2 mutations in progressive myoclonus epilepsy (PME) without renal failure.","date":"2009","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/19847901","citation_count":71,"is_preprint":false},{"pmid":"22272359","id":"PMC_22272359","title":"Human SCARB2-mediated entry and endocytosis of EV71.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/22272359","citation_count":70,"is_preprint":false},{"pmid":"21796727","id":"PMC_21796727","title":"A mutation in SCARB2 is a modifier in Gaucher disease.","date":"2011","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/21796727","citation_count":67,"is_preprint":false},{"pmid":"10880355","id":"PMC_10880355","title":"The human breast carcinoma cell line HBL-100 acquires exogenous cholesterol from high-density lipoprotein via CLA-1 (CD-36 and LIMPII analogous 1)-mediated selective cholesteryl ester uptake.","date":"2000","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10880355","citation_count":65,"is_preprint":false},{"pmid":"31378672","id":"PMC_31378672","title":"A Human Stem Cell Model of Fabry Disease Implicates LIMP-2 Accumulation in Cardiomyocyte Pathology.","date":"2019","source":"Stem cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/31378672","citation_count":54,"is_preprint":false},{"pmid":"26936883","id":"PMC_26936883","title":"Human SR-BI and SR-BII Potentiate Lipopolysaccharide-Induced Inflammation and Acute Liver and Kidney Injury in Mice.","date":"2016","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26936883","citation_count":53,"is_preprint":false},{"pmid":"16368683","id":"PMC_16368683","title":"High density lipoprotein endocytosis by scavenger receptor SR-BII is clathrin-dependent and requires a carboxyl-terminal dileucine motif.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16368683","citation_count":53,"is_preprint":false},{"pmid":"22050460","id":"PMC_22050460","title":"Clinical and neurophysiologic features of progressive myoclonus epilepsy without renal failure caused by SCARB2 mutations.","date":"2011","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/22050460","citation_count":46,"is_preprint":false},{"pmid":"22537104","id":"PMC_22537104","title":"A critical histidine residue within LIMP-2 mediates pH sensitive binding to its ligand β-glucocerebrosidase.","date":"2012","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/22537104","citation_count":46,"is_preprint":false},{"pmid":"27110593","id":"PMC_27110593","title":"SCARB2 variants and glucocerebrosidase activity in Parkinson's disease.","date":"2016","source":"NPJ Parkinson's disease","url":"https://pubmed.ncbi.nlm.nih.gov/27110593","citation_count":43,"is_preprint":false},{"pmid":"24842162","id":"PMC_24842162","title":"Histopathological features and distribution of EV71 antigens and SCARB2 in human fatal cases and a mouse model of enterovirus 71 infection.","date":"2014","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/24842162","citation_count":43,"is_preprint":false},{"pmid":"24997419","id":"PMC_24997419","title":"Distribution of EV71 receptors SCARB2 and PSGL-1 in human tissues.","date":"2014","source":"Virus research","url":"https://pubmed.ncbi.nlm.nih.gov/24997419","citation_count":40,"is_preprint":false},{"pmid":"23408458","id":"PMC_23408458","title":"The role of SCARB2 as susceptibility factor in Parkinson's disease.","date":"2013","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/23408458","citation_count":40,"is_preprint":false},{"pmid":"14570588","id":"PMC_14570588","title":"Human scavenger receptor class B type II (SR-BII) and cellular cholesterol efflux.","date":"2004","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/14570588","citation_count":36,"is_preprint":false},{"pmid":"10848626","id":"PMC_10848626","title":"Inactivation of lmpA, encoding a LIMPII-related endosomal protein, suppresses the internalization and endosomal trafficking defects in profilin-null mutants.","date":"2000","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/10848626","citation_count":35,"is_preprint":false},{"pmid":"11518764","id":"PMC_11518764","title":"17beta-Estradiol promotes the up-regulation of SR-BII in HepG2 cells and in rat livers.","date":"2001","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/11518764","citation_count":35,"is_preprint":false},{"pmid":"1374238","id":"PMC_1374238","title":"Isolation and sequencing of a cDNA clone encoding the 85 kDa human lysosomal sialoglycoprotein (hLGP85) in human metastatic pancreas islet tumor cells.","date":"1992","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/1374238","citation_count":32,"is_preprint":false},{"pmid":"27499235","id":"PMC_27499235","title":"A new animal model containing human SCARB2 and lacking stat-1 is highly susceptible to EV71.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27499235","citation_count":31,"is_preprint":false},{"pmid":"23825416","id":"PMC_23825416","title":"A multilevel screening strategy defines a molecular fingerprint of proregenerative olfactory ensheathing cells and identifies SCARB2, a protein that improves regenerative sprouting of injured sensory spinal axons.","date":"2013","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/23825416","citation_count":31,"is_preprint":false},{"pmid":"23919614","id":"PMC_23919614","title":"Establishment of cell lines with increased susceptibility to EV71/CA16 by stable overexpression of SCARB2.","date":"2013","source":"Virology journal","url":"https://pubmed.ncbi.nlm.nih.gov/23919614","citation_count":31,"is_preprint":false},{"pmid":"27582254","id":"PMC_27582254","title":"SCARB2/LIMP2 deficiency in action myoclonus-renal failure syndrome.","date":"2016","source":"Epileptic disorders : international epilepsy journal with videotape","url":"https://pubmed.ncbi.nlm.nih.gov/27582254","citation_count":29,"is_preprint":false},{"pmid":"25862818","id":"PMC_25862818","title":"SCARB2/LIMP-2 Regulates IFN Production of Plasmacytoid Dendritic Cells by Mediating Endosomal Translocation of TLR9 and Nuclear Translocation of IRF7.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25862818","citation_count":29,"is_preprint":false},{"pmid":"33692197","id":"PMC_33692197","title":"Pathogenesis Study of Enterovirus 71 Using a Novel Human SCARB2 Knock-In Mouse Model.","date":"2021","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/33692197","citation_count":29,"is_preprint":false},{"pmid":"26219725","id":"PMC_26219725","title":"Mannose 6-phosphate-independent Lysosomal Sorting of LIMP-2.","date":"2015","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/26219725","citation_count":28,"is_preprint":false},{"pmid":"30013088","id":"PMC_30013088","title":"A CpG-adjuvanted intranasal enterovirus 71 vaccine elicits mucosal and systemic immune responses and protects human SCARB2-transgenic mice against lethal challenge.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/30013088","citation_count":28,"is_preprint":false},{"pmid":"28447294","id":"PMC_28447294","title":"The binding of a monoclonal antibody to the apical region of SCARB2 blocks EV71 infection.","date":"2017","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/28447294","citation_count":26,"is_preprint":false},{"pmid":"21670406","id":"PMC_21670406","title":"Mutation of SCARB2 in a patient with progressive myoclonus epilepsy and demyelinating peripheral neuropathy.","date":"2011","source":"Archives of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/21670406","citation_count":26,"is_preprint":false},{"pmid":"39442522","id":"PMC_39442522","title":"Adipocyte-derived glutathione promotes obesity-related breast cancer by regulating the SCARB2-ARF1-mTORC1 complex.","date":"2024","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/39442522","citation_count":24,"is_preprint":false},{"pmid":"21429972","id":"PMC_21429972","title":"Tubular proteinuria in mice and humans lacking the intrinsic lysosomal protein SCARB2/Limp-2.","date":"2011","source":"American journal of physiology. Renal physiology","url":"https://pubmed.ncbi.nlm.nih.gov/21429972","citation_count":24,"is_preprint":false},{"pmid":"21123180","id":"PMC_21123180","title":"LIMP-2 links late phagosomal trafficking with the onset of the innate immune response to Listeria monocytogenes: a role in macrophage activation.","date":"2010","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21123180","citation_count":23,"is_preprint":false},{"pmid":"22032306","id":"PMC_22032306","title":"Novel SCARB2 mutation in action myoclonus-renal failure syndrome and evaluation of SCARB2 mutations in isolated AMRF features.","date":"2011","source":"BMC neurology","url":"https://pubmed.ncbi.nlm.nih.gov/22032306","citation_count":21,"is_preprint":false},{"pmid":"37739936","id":"PMC_37739936","title":"SCARB2 drives hepatocellular carcinoma tumor initiating cells via enhanced MYC transcriptional activity.","date":"2023","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/37739936","citation_count":20,"is_preprint":false},{"pmid":"25202012","id":"PMC_25202012","title":"The LIMP-2/SCARB2 binding motif on acid β-glucosidase: basic and applied implications for Gaucher disease and associated neurodegenerative diseases.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25202012","citation_count":20,"is_preprint":false},{"pmid":"26018676","id":"PMC_26018676","title":"Role of LIMP-2 in the intracellular trafficking of β-glucosidase in different human cellular models.","date":"2015","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/26018676","citation_count":20,"is_preprint":false},{"pmid":"21782476","id":"PMC_21782476","title":"Progressive myoclonus epilepsy with nephropathy C1q due to SCARB2/LIMP-2 deficiency: clinical report of two siblings.","date":"2011","source":"Seizure","url":"https://pubmed.ncbi.nlm.nih.gov/21782476","citation_count":20,"is_preprint":false},{"pmid":"24485911","id":"PMC_24485911","title":"A novel SCARB2 mutation in progressive myoclonus epilepsy indicated by reduced β-glucocerebrosidase activity.","date":"2014","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24485911","citation_count":20,"is_preprint":false},{"pmid":"28423002","id":"PMC_28423002","title":"Human SR-BII mediates SAA uptake and contributes to SAA pro-inflammatory signaling in vitro and in vivo.","date":"2017","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/28423002","citation_count":19,"is_preprint":false},{"pmid":"10337864","id":"PMC_10337864","title":"CD36 LIMPII analogous-1, a human homolog of the rodent scavenger receptor B1, provides the cholesterol ester for steroidogenesis in adrenocortical cells.","date":"1999","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/10337864","citation_count":19,"is_preprint":false},{"pmid":"23936115","id":"PMC_23936115","title":"Protective efficacy of VP1-specific neutralizing antibody associated with a reduction of viral load and pro-inflammatory cytokines in human SCARB2-transgenic mice.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23936115","citation_count":19,"is_preprint":false},{"pmid":"11489884","id":"PMC_11489884","title":"Characterization of CD36/LIMPII homologues in Dictyostelium discoideum.","date":"2001","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11489884","citation_count":18,"is_preprint":false},{"pmid":"37291150","id":"PMC_37291150","title":"LIMP-2 enhances cancer stem-like cell properties by promoting autophagy-induced GSK3β degradation in head and neck squamous cell carcinoma.","date":"2023","source":"International journal of oral science","url":"https://pubmed.ncbi.nlm.nih.gov/37291150","citation_count":17,"is_preprint":false},{"pmid":"23659519","id":"PMC_23659519","title":"Progressive myoclonus epilepsy: extraneuronal brown pigment deposition and system neurodegeneration in the brains of Japanese patients with novel SCARB2 mutations.","date":"2014","source":"Neuropathology and applied neurobiology","url":"https://pubmed.ncbi.nlm.nih.gov/23659519","citation_count":15,"is_preprint":false},{"pmid":"35408805","id":"PMC_35408805","title":"Pleiotropic Roles of Scavenger Receptors in Circadian Retinal Phagocytosis: A New Function for Lysosomal SR-B2/LIMP-2 at the RPE Cell Surface.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35408805","citation_count":14,"is_preprint":false},{"pmid":"25576872","id":"PMC_25576872","title":"Lysosomal integral membrane protein type-2 (LIMP-2/SCARB2) is a substrate of cathepsin-F, a cysteine protease mutated in type-B-Kufs-disease.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25576872","citation_count":13,"is_preprint":false},{"pmid":"31176756","id":"PMC_31176756","title":"Identification and initial functional characterization of lysosomal integral membrane protein type 2 (LIMP-2) in turbot (Scophthalmus maximus L.).","date":"2019","source":"Developmental and comparative immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31176756","citation_count":13,"is_preprint":false},{"pmid":"38359079","id":"PMC_38359079","title":"Enterovirus A71 does not meet the uncoating receptor SCARB2 at the cell surface.","date":"2024","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/38359079","citation_count":12,"is_preprint":false},{"pmid":"35955761","id":"PMC_35955761","title":"The Deficiency of SCARB2/LIMP-2 Impairs Metabolism via Disrupted mTORC1-Dependent Mitochondrial OXPHOS.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35955761","citation_count":12,"is_preprint":false},{"pmid":"29605618","id":"PMC_29605618","title":"Progressive myoclonus epilepsy without renal failure in a Chinese family with a novel mutation in SCARB2 gene and literature review.","date":"2018","source":"Seizure","url":"https://pubmed.ncbi.nlm.nih.gov/29605618","citation_count":12,"is_preprint":false},{"pmid":"35571795","id":"PMC_35571795","title":"All-Atom Molecular Dynamics Simulations of Polyethylene Glycol (PEG) and LIMP-2 Reveal That PEG Penetrates Deep into the Proposed CD36 Cholesterol-Transport Tunnel.","date":"2022","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/35571795","citation_count":12,"is_preprint":false},{"pmid":"30054386","id":"PMC_30054386","title":"Functions of the Dictyostelium LIMP-2 and CD36 homologues in bacteria uptake, phagolysosome biogenesis and host cell defence.","date":"2018","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/30054386","citation_count":11,"is_preprint":false},{"pmid":"28593131","id":"PMC_28593131","title":"miR-127-5p negatively regulates enterovirus 71 replication by directly targeting SCARB2.","date":"2017","source":"FEBS open bio","url":"https://pubmed.ncbi.nlm.nih.gov/28593131","citation_count":11,"is_preprint":false},{"pmid":"38666485","id":"PMC_38666485","title":"Activation and Purification of ß-Glucocerebrosidase by Exploiting its Transporter LIMP-2 - Implications for Novel Treatment Strategies in Gaucher's and Parkinson's Disease.","date":"2024","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/38666485","citation_count":10,"is_preprint":false},{"pmid":"35867561","id":"PMC_35867561","title":"Mouse Scarb2 Modulates EV-A71 Pathogenicity in Neonatal Mice.","date":"2022","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/35867561","citation_count":10,"is_preprint":false},{"pmid":"35359978","id":"PMC_35359978","title":"Type I Interferon-Induced TMEM106A Blocks Attachment of EV-A71 Virus by Interacting With the Membrane Protein SCARB2.","date":"2022","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35359978","citation_count":10,"is_preprint":false},{"pmid":"26743566","id":"PMC_26743566","title":"Zebrafish scarb2a insertional mutant reveals a novel function for the Scarb2/Limp2 receptor in notochord development.","date":"2016","source":"Developmental dynamics : an official publication of the American Association of Anatomists","url":"https://pubmed.ncbi.nlm.nih.gov/26743566","citation_count":10,"is_preprint":false},{"pmid":"38559730","id":"PMC_38559730","title":"Uridine-Modified Ruthenium(II) Complex as Lysosomal LIMP-2 Targeting Photodynamic Therapy Photosensitizer for the Treatment of Triple-Negative Breast Cancer.","date":"2024","source":"JACS Au","url":"https://pubmed.ncbi.nlm.nih.gov/38559730","citation_count":10,"is_preprint":false},{"pmid":"33227372","id":"PMC_33227372","title":"Genetics variants and expression of the SCARB2 gene in the pathogenesis of Parkinson's disease in Russia.","date":"2020","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/33227372","citation_count":9,"is_preprint":false},{"pmid":"34337151","id":"PMC_34337151","title":"Miglustat Therapy for SCARB2-Associated Action Myoclonus-Renal Failure Syndrome.","date":"2021","source":"Neurology. Genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34337151","citation_count":9,"is_preprint":false},{"pmid":"28222800","id":"PMC_28222800","title":"Exome sequencing identifies SLC26A4, GJB2, SCARB2 and DUOX2 mutations in 2 siblings with Pendred syndrome in a Malaysian family.","date":"2017","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/28222800","citation_count":9,"is_preprint":false},{"pmid":"39424982","id":"PMC_39424982","title":"Broadly therapeutic antibody provides cross-serotype protection against enteroviruses via Fc effector functions and by mimicking SCARB2.","date":"2024","source":"Nature microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39424982","citation_count":8,"is_preprint":false},{"pmid":"35346091","id":"PMC_35346091","title":"Genotype-Phenotype correlations of SCARB2 associated clinical presentation: a case report and in-depth literature review.","date":"2022","source":"BMC neurology","url":"https://pubmed.ncbi.nlm.nih.gov/35346091","citation_count":8,"is_preprint":false},{"pmid":"23515316","id":"PMC_23515316","title":"Abnormal Processing of Autophagosomes in Transformed B Lymphocytes from SCARB2-Deficient Subjects.","date":"2013","source":"BioResearch open access","url":"https://pubmed.ncbi.nlm.nih.gov/23515316","citation_count":8,"is_preprint":false},{"pmid":"33772352","id":"PMC_33772352","title":"A novel homozygous splice-site mutation in SCARB2 is associated with progressive myoclonic epilepsy with renal failure.","date":"2021","source":"Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology","url":"https://pubmed.ncbi.nlm.nih.gov/33772352","citation_count":8,"is_preprint":false},{"pmid":"34379497","id":"PMC_34379497","title":"Enterovirus A71 Induces Neurological Diseases and Dynamic Variants in Oral Infection of Human SCARB2-Transgenic Weaned Mice.","date":"2021","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/34379497","citation_count":8,"is_preprint":false},{"pmid":"38635907","id":"PMC_38635907","title":"Gut dysbiosis impairs intestinal renewal and lipid absorption in Scarb2 deficiency-associated neurodegeneration.","date":"2024","source":"Protein & cell","url":"https://pubmed.ncbi.nlm.nih.gov/38635907","citation_count":7,"is_preprint":false},{"pmid":"33424194","id":"PMC_33424194","title":"Recombinant Human SCARB2 Expressed in Escherichia coli and its Potential in Enterovirus 71 Blockage.","date":"2021","source":"Iranian journal of science and technology. Transaction A, Science","url":"https://pubmed.ncbi.nlm.nih.gov/33424194","citation_count":7,"is_preprint":false},{"pmid":"39370902","id":"PMC_39370902","title":"The lysosomal lipid transporter LIMP-2 is part of lysosome-ER STARD3-VAPB-dependent contact sites.","date":"2024","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/39370902","citation_count":6,"is_preprint":false},{"pmid":"24394995","id":"PMC_24394995","title":"Absence of the lysosomal protein Limp-2 attenuates renal injury in crescentic glomerulonephritis.","date":"2014","source":"Immunology and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24394995","citation_count":6,"is_preprint":false},{"pmid":"24269705","id":"PMC_24269705","title":"Lysosomal integral membrane protein 2 (LIMP-2) restricts the invasion of Trypanosoma cruzi extracellular amastigotes through the activity of the lysosomal enzyme β-glucocerebrosidase.","date":"2013","source":"Microbes and infection","url":"https://pubmed.ncbi.nlm.nih.gov/24269705","citation_count":6,"is_preprint":false},{"pmid":"26224037","id":"PMC_26224037","title":"No association of FAM47E rs6812193, SCARB2 rs6825004 and STX1B rs4889603 polymorphisms with Parkinson's disease in a Chinese Han population.","date":"2015","source":"Journal of neural transmission (Vienna, Austria : 1996)","url":"https://pubmed.ncbi.nlm.nih.gov/26224037","citation_count":6,"is_preprint":false},{"pmid":"40628771","id":"PMC_40628771","title":"Tetrandrine regulates NAADP-mediated calcium signaling through a LIMP-2-dependent and sphingosine-mediated mechanism.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40628771","citation_count":5,"is_preprint":false},{"pmid":"40159502","id":"PMC_40159502","title":"Cryo-TEM structure of β-glucocerebrosidase in complex with its transporter LIMP-2.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40159502","citation_count":5,"is_preprint":false},{"pmid":"31116970","id":"PMC_31116970","title":"Glucocerebrosidase regulators SCARB2 and TFEB are up-regulated in Lewy body disease brain.","date":"2019","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/31116970","citation_count":5,"is_preprint":false},{"pmid":"23635510","id":"PMC_23635510","title":"Expression of the transmembrane lysosomal protein SCARB2/Limp-2 in renin secretory granules controls renin release.","date":"2013","source":"Nephron. Experimental nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/23635510","citation_count":5,"is_preprint":false},{"pmid":"38928321","id":"PMC_38928321","title":"Deficiency of Glucocerebrosidase Activity beyond Gaucher Disease: PSAP and LIMP-2 Dysfunctions.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38928321","citation_count":5,"is_preprint":false},{"pmid":"26794464","id":"PMC_26794464","title":"Changes in the expression of LIMP-2 during cerulein-induced pancreatitis in rats: Effect of inhibition of leukocyte infiltration, cAMP and MAPKs early on in its development.","date":"2016","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26794464","citation_count":5,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":52066,"output_tokens":9512,"usd":0.149439,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":19786,"output_tokens":7285,"usd":0.140527,"stage2_stop_reason":"end_turn"},"total_usd":0.289966,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"LIMP-2 is a specific binding partner of β-glucocerebrosidase (GCase) and serves as the mannose-6-phosphate-independent lysosomal targeting receptor for GCase. The interaction involves a coiled-coil domain within the lumenal domain of LIMP-2. In LIMP-2-deficient mice, GCase is secreted rather than delivered to lysosomes, and reconstitution of LIMP-2 rescues lysosomal GCase levels and distribution.\",\n      \"method\": \"Affinity chromatography, LIMP-2-deficient mouse fibroblasts and macrophages, reconstitution experiments, subcellular fractionation\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — affinity chromatography identification, knockout mouse validation, reconstitution rescue, multiple orthogonal methods in a landmark study\",\n      \"pmids\": [\"18022370\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"AP-3 selectively binds the cytoplasmic tail of LIMP-2 via a DEXXXLI dileucine-based motif, mediating sorting of LIMP-2 to lysosomes. AP-1 and AP-2 do not interact with this tail, establishing AP-3 as the specific adaptor for LIMP-2 lysosomal targeting.\",\n      \"method\": \"Surface plasmon resonance binding assay with recombinant AP complexes and cytoplasmic tail peptides\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with surface plasmon resonance, replicated finding across multiple adaptor complexes, mechanistically precise\",\n      \"pmids\": [\"9482728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The [DE]XXXL[LI]-type dileucine signal in LIMP-2's cytoplasmic tail interacts specifically with the gamma-sigma1 subunits of AP-1 and delta-sigma3 subunits of AP-3, but not AP-2 or AP-4 hemicomplexes, defining the molecular basis of AP-3-mediated endosomal/lysosomal sorting.\",\n      \"method\": \"Yeast three-hybrid assay, in vitro binding to whole AP complexes\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — yeast three-hybrid plus in vitro binding, consistent with prior surface plasmon resonance data, two orthogonal methods\",\n      \"pmids\": [\"14691137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of LIMP-2 reveals a helical bundle where GCase binds and a large cavity/tunnel traversing the entire molecule, consistent with a lipid transport function. Mutagenesis of the tunnel in the SR-BI homologue indicates this cavity mediates cholesterol(ester) transfer from bound lipoproteins to the membrane.\",\n      \"method\": \"X-ray crystallography, homology modelling, site-directed mutagenesis of tunnel residues in SR-BI\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure determination combined with functional mutagenesis, high-impact structural study\",\n      \"pmids\": [\"24162852\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Disease-causing AMRF nonsense mutations in LIMP-2 (W146SfsX16, W178X) abolish GCase binding, while the Q288X truncation retains near-normal binding. The missense mutation H363N increases GCase binding affinity. A coiled-coil domain (residues 145–288) is essential for GCase binding; disruption of the helical/amphipathic coiled-coil structure abolishes this interaction.\",\n      \"method\": \"Co-immunoprecipitation, binding assays with mutant LIMP-2 constructs, synthetic peptide studies\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple AMRF disease mutations functionally characterized, coiled-coil domain mapped, multiple orthogonal approaches\",\n      \"pmids\": [\"19933215\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A single histidine residue in LIMP-2 (H363) functions as a pH sensor required for GCase binding at neutral pH and its release in late endosomal/lysosomal acidic compartments. Vacuolar H+-ATPase-mediated lumenal acidification triggers dissociation of the LIMP-2/GCase complex.\",\n      \"method\": \"Site-directed mutagenesis of H363, pharmacological inhibition of V-ATPase, co-immunoprecipitation at different pH values\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of single critical residue combined with pharmacological and biochemical validation, consistent with structural data\",\n      \"pmids\": [\"22537104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Structural analysis of LIMP-2 reveals that GCase binding and pH-dependent release is governed by a histidine trigger, and that LIMP-2 carries P-Man9GlcNAc2 at N325 enabling it to bind the mannose-6-phosphate receptor (MPR) with affinity similar to the LIMP-2/GCase interaction; β-GCase and MPR binding sites are functionally separate, allowing formation of a stable ternary LIMP-2/GCase/MPR complex demonstrated in living cells by FLIM.\",\n      \"method\": \"X-ray crystallography, surface plasmon resonance, fluorescence lifetime imaging microscopy (FLIM) in living cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure, SPR binding, and FLIM in living cells, multiple orthogonal methods in one study\",\n      \"pmids\": [\"25027712\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LIMP-2 lysosomal sorting occurs via a mannose-6-phosphate-independent pathway: in fibroblasts lacking MPRs or GlcNAc-1-phosphotransferase (the M6P-forming enzyme), LIMP-2 still localizes to lysosomes, and lysosomal LIMP-2 levels are comparable in wild-type and phosphotransferase-defective mouse liver. The M6P modification on the LIMP-2 ectodomain is dispensable for its lysosomal targeting.\",\n      \"method\": \"Immunofluorescence in MPR-deficient and GlcNAc-1-phosphotransferase-defective fibroblasts, lysosome purification and immunoblot from mouse liver, heterologous expression of LIMP-2 luminal domain\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic knockout models (MPR-null, phosphotransferase-null), in vivo lysosome purification, consistent across cell and animal models\",\n      \"pmids\": [\"26219725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LIMP-2 mediates lysosomal cholesterol export: the luminal cavity can bind and deliver exogenous cholesterol to the lysosomal membrane and subsequently to lipid droplets. LIMP-2 depletion alters SREBP-2-mediated cholesterol regulation and LDL-receptor levels, and LIMP-2 operates in parallel with NPC proteins for lysosomal cholesterol export.\",\n      \"method\": \"Molecular modeling, crosslinking studies, microscale thermophoresis, cell-based cholesterol transport assays, SREBP-2/LDL-receptor immunoblotting in LIMP-2 knockout cells\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — multiple orthogonal biochemical and cell-based methods in one study, structural cavity previously identified, single lab\",\n      \"pmids\": [\"31387993\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The dileucine sorting motif in LIMP-2's C-terminal tail requires an acidic glutamate (Glu) at position -4 upstream of the critical leucine for efficient intracellular sorting to lysosomes, but this residue is dispensable for surface internalization by endocytosis, demonstrating distinct structural requirements for intracellular sorting versus endocytosis.\",\n      \"method\": \"Site-directed mutagenesis of LIMP-2 cytoplasmic tail, subcellular localization by microscopy, endocytosis assays in transfected cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis with defined phenotypic readout, single lab, clear functional dissection\",\n      \"pmids\": [\"10973972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SR-BII (an alternatively spliced isoform of the SCARB2/SR-BI gene with a distinct C-terminal cytoplasmic tail) is enriched in caveolae and mediates both selective cellular uptake of cholesteryl ether from HDL and HDL-dependent cholesterol efflux, but with ~4-fold lower efficiency than SR-BI.\",\n      \"method\": \"Subcellular fractionation of CHO transfectants, radiolabeled HDL cholesteryl ether uptake assay, cholesterol efflux assay, adenoviral overexpression in vivo\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — functional lipid transfer assays combined with subcellular fractionation and in vivo adenoviral experiments, multiple orthogonal methods\",\n      \"pmids\": [\"9614139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SR-BII (the SCARB2 gene splice variant) is predominantly localized intracellularly (~80–90% intracellular vs ~70% surface for SR-BI) due to its distinct C-terminal cytoplasmic tail, and rapidly internalizes HDL via endocytosis, with internalized HDL co-localizing in the endosomal recycling compartment. Deletion of the SR-BI C-terminus does not affect its surface localization, confirming the SR-BII C-terminus confers intracellular targeting.\",\n      \"method\": \"Cell surface biotinylation, EGFP-tagged receptor imaging, pulse-chase HDL uptake experiments, subcellular co-localization with transferrin (endosomal recycling marker)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (biotinylation, live imaging, pulse-chase, co-localization) in one study, mechanistically defines C-tail function\",\n      \"pmids\": [\"14726519\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"SR-BII mediates HDL endocytosis through a clathrin-dependent, caveolae-independent pathway. A dileucine motif at positions 492–493 in the SR-BII C-terminal cytoplasmic tail is required for HDL particle endocytosis; L492A substitution increases surface HDL binding and reduces endocytosis. Introduction of the SR-BII YTPLL motif into SR-BI converts it into an endocytic receptor.\",\n      \"method\": \"Site-directed mutagenesis of SR-BII tail residues, HDL endocytosis assays, clathrin/caveolin pathway inhibition, chimeric SR-BI/SR-BII constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of specific residues with defined endocytosis readout, pathway dissection, gain-of-function chimera experiment\",\n      \"pmids\": [\"16368683\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SCARB2 functions as an uncoating receptor for EV71: after virus-SCARB2 complex internalization into endosomes, acidic pH (below 6.0) combined with SCARB2 triggers conversion of native EV71 virions into empty capsids lacking both genomic RNA and VP4. This uncoating does not occur with PSGL1 as receptor under any pH condition.\",\n      \"method\": \"Sucrose density gradient centrifugation analysis of viral uncoating, incubation of EV71 with L-SCARB2 cells or soluble SCARB2 at various pH values, immunofluorescence colocalization with endosomal markers\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct biochemical demonstration of uncoating with purified soluble SCARB2 and defined pH conditions, comparative experiment with PSGL1, multiple orthogonal readouts\",\n      \"pmids\": [\"23302872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structures of SCARB2 under neutral and acidic conditions reveal a pH-dependent conformational change that opens a lipid-transfer tunnel, enabling expulsion of a hydrophobic pocket factor from EV71, a prerequisite for viral uncoating. The canyon region of EV71 VP1 mediates receptor interaction, with key residues identified.\",\n      \"method\": \"X-ray crystallography of SCARB2 at neutral and acidic pH, structural comparison, mutagenesis of virus-receptor contact residues\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structures at two pH values combined with functional mutagenesis, direct mechanistic insight into conformational change\",\n      \"pmids\": [\"24986489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of the EV71-SCARB2 complex at 3.4 Å resolution shows SCARB2 binds EV71 on the southern rim of the canyon (not across the canyon as predicted). Helices α5 (152–163) and α7 (183–193) of SCARB2 and the VP1 GH and VP2 EF loops of EV71 dominate the interaction, suggesting an allosteric mechanism for low-pH uncoating.\",\n      \"method\": \"Cryo-electron microscopy of EV71-SCARB2 complex\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — high-resolution cryo-EM structure of the native virus-receptor complex, direct structural determination\",\n      \"pmids\": [\"30531980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The region of human SCARB2 encompassing amino acids 142–204 is critical for EV71 virion binding and infection; chimeric SCARB2 constructs carrying this human region in a mouse Scarb2 backbone confer susceptibility to EV71, whereas those retaining the mouse sequence in this region do not support efficient viral binding.\",\n      \"method\": \"Human-mouse SCARB2 chimeric mutant expression in L929 cells, viral binding assays, infection assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — domain-swap chimera approach with binding and infection readouts, clear functional mapping of residues 142–204\",\n      \"pmids\": [\"21389126\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"EV71 entry into cells expressing SCARB2 occurs via a clathrin-mediated, pH-dependent, cholesterol-sensitive endocytic pathway; siRNA knockdown of clathrin or dynamin blocks entry, whereas caveolin knockdown does not affect entry.\",\n      \"method\": \"siRNA knockdown of clathrin, dynamin, caveolin; chemical inhibitors of clathrin-mediated endocytosis and caveolae-mediated endocytosis; pH perturbation experiments; cholesterol depletion\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (siRNA) and pharmacological dissection of endocytic pathway, single lab, convergent results\",\n      \"pmids\": [\"22272359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SCARB2 mediates endosomal translocation of TLR9 in plasmacytoid dendritic cells (pDCs): SCARB2 knockdown results in retention of TLR9 in the ER and impaired nuclear translocation of IRF7, leading to dramatically reduced CpG-induced type I IFN production. SCARB2 localizes to late endosomes/lysosomes in pDCs and is required for TLR7-ligand-induced IFN-I as well.\",\n      \"method\": \"siRNA knockdown of SCARB2 in pDC cell line GEN2.2, subcellular localization by immunofluorescence, TLR9/IRF7 localization by immunofluorescence, IFN-I ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple readouts (receptor localization, transcription factor translocation, cytokine secretion), single lab\",\n      \"pmids\": [\"25862818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The GCase-binding sequence on GCase for LIMP-2 is an 11-amino acid stretch (DSPIIVDITKD); Asp399, Ile402, and Ile403 are particularly important. Alanine substitution at any of these residues decreases GCase binding to LIMP-2, alters pH-dependent binding, diminishes lysosomal trafficking of GCase, and increases GCase secretion. The EV71-binding site on LIMP-2/SCARB2 is distinct from the GCase-binding site.\",\n      \"method\": \"Deletion constructs, alanine-scanning mutagenesis, binding assays, co-localization, GCase secretion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic mutagenesis of multiple residues with binding, trafficking, and secretion readouts, mechanistically precise mapping\",\n      \"pmids\": [\"25202012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In human fibroblasts and neuron-like cells, GCase lysosomal targeting is completely dependent on LIMP-2, whereas in blood (lymphocytes), GCase is partially targeted to lysosomes by a LIMP-2-independent mechanism. Recombinant human GCase (enzyme replacement therapy) is taken up by cells independently of LIMP-2 but its lysosomal trafficking requires LIMP-2.\",\n      \"method\": \"GCase activity and localization in AMRF patient fibroblasts, lymphocytes, and neuronal model; LIMP-2-deficient and -sufficient cell comparisons; recombinant GCase uptake/trafficking assay\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (patient cells) with multiple cell-type comparisons and enzyme replacement experiment, single lab\",\n      \"pmids\": [\"26018676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"LIMP-2 is a substrate of cathepsin-F: cathepsin-F mediates proteolytic cleavage of wild-type LIMP-2 in lysosomes in vitro and in vivo. Disease-causing cathepsin-F mutants (associated with type-B Kufs disease) fail to cleave LIMP-2.\",\n      \"method\": \"Heterologous expression of cathepsin-F variants, in vitro cleavage assay, purified lysosomes from mouse tissue, immunoblotting\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro cleavage assay, in vivo lysosomal evidence, disease-mutant comparison; single lab\",\n      \"pmids\": [\"25576872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LIMP-2 controls late phagosomal trafficking and the innate immune response to Listeria monocytogenes in macrophages: LIMP-2-deficient mice show impaired phago-lysosome transformation, low listericidal activity, reduced acute-phase pro-inflammatory cytokines, and 25-fold increased susceptibility to Listeria. LIMP-2 transfection in CHO cells confirms its role in late endosomal/lysosomal fusion and activation of Rab5a.\",\n      \"method\": \"LIMP-2-deficient mouse macrophage functional assays, cytokine/chemokine measurement, phagolysosome biogenesis assay, CHO cell reconstitution with LIMP-2 transfection, Rab5a activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with multiple immune readouts and reconstitution in CHO cells, single lab\",\n      \"pmids\": [\"21123180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LIMP-2 expression is critical for lysosomal GCase activity and α-synuclein clearance: LIMP-2-deficient mouse brains show reduced GCase activity, lipid storage, disturbed autophagy/lysosomal function, and α-synuclein accumulation causing dopaminergic neuron toxicity. Heterologous expression of LIMP-2 accelerates clearance of overexpressed α-synuclein by increasing lysosomal GCase activity.\",\n      \"method\": \"LIMP-2-deficient mouse brain analysis, GCase activity assay, autophagy markers, α-synuclein immunofluorescence/immunoblot, LIMP-2 overexpression rescue experiment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse with multiple mechanistic readouts plus gain-of-function rescue experiment, multiple orthogonal methods\",\n      \"pmids\": [\"25316793\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"LIMP-2 deficiency causes a defect in proteolysis of reabsorbed proteins in renal proximal tubule cells: megalin/cubilin-dependent endocytosis is unaffected, but cathepsin B fails to co-localize with endosomal contents in Limp-2−/− mice, indicating that LIMP-2 is required for fusion of endosomes with lysosomes in the proximal tubule.\",\n      \"method\": \"Limp-2 knockout mice, in vivo fluorescent albumin uptake/tracking, cathepsin B co-localization by immunofluorescence, megalin/cubilin expression analysis\",\n      \"journal\": \"American journal of physiology. Renal physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with in vivo tracer experiment and mechanistic co-localization data, single lab\",\n      \"pmids\": [\"21429972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"GSH (glutathione) directly binds to SCARB2, interfering with the interaction between its N and C termini. This recruits mTORC1 to lysosomes through ARF1, leading to activation of mTOR signaling and promoting breast cancer progression.\",\n      \"method\": \"TME metabolomics, GCLC adipocyte-specific knockout mouse model, direct GSH-SCARB2 binding assay, mTORC1 lysosomal recruitment assay, ARF1 interaction studies\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding demonstrated, genetic mouse model, ARF1-mTOR pathway placement; single lab, relatively new finding\",\n      \"pmids\": [\"39442522\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SCARB2 promotes MYC acetylation by interfering with HDAC3-mediated deacetylation of MYC at lysine 148, thereby enhancing MYC transcriptional activity and hepatocellular carcinoma cancer stem cell properties. Knockout of Scarb2 in hepatocytes attenuates HCC initiation in MYC-driven and DEN-induced mouse models.\",\n      \"method\": \"CRISPR/Cas9 knockout library screen in HCC tumorspheres, Scarb2 hepatocyte-specific knockout HCC mouse models, co-immunoprecipitation of SCARB2/MYC/HDAC3, MYC acetylation assay at K148\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP of SCARB2/MYC/HDAC3 complex, in vivo mouse model, acetylation assay; single lab\",\n      \"pmids\": [\"37739936\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cryo-EM structure of GCase in complex with LIMP-2 reveals that helix 5 and helix 7 of LIMP-2's ectodomain interact with a binding pocket on GCase via a mostly hydrophobic interface supported by one essential salt bridge. LIMP-2 overexpression increases lysosomal abundance and enzymatic activity of GCase, and acts as an allosteric activator; a peptide derived from the LIMP-2 single helix enhances lysosomal GCase activity in patient-derived fibroblasts.\",\n      \"method\": \"Cryo-electron microscopy with engineered LIMP-2 shuttle and pro-macrobodies, LIMP-2 overexpression in HEK293T cells, GCase activity assays in fibroblasts, co-purification of GCase-LIMP-2 complex\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with functional assays and peptide-based gain-of-function, multiple orthogonal methods\",\n      \"pmids\": [\"40159502\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"LIMP-2 is present at ER-lysosome membrane contact sites through interaction with the endosomal protein STARD3 and ER-resident VAPB; STARD3 is required for the LIMP-2/VAPB interaction. This places LIMP-2 at organelle contact sites that may facilitate cholesterol transport from lysosomal to ER membrane.\",\n      \"method\": \"Proximity-based interaction screen (BioID), co-immunoprecipitation, immunofluorescence co-localization\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — BioID proximity proteomics validated by co-IP and imaging, STARD3 requirement established by dependency experiment; single lab\",\n      \"pmids\": [\"39370902\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Tetrandrine directly binds the LIMP-2 ectodomain (identified by clickable photoaffinity probe), inhibiting lysosomal cholesterol and sphingosine transport. LIMP-2 depletion or tetrandrine treatment inhibits NAADP-dependent calcium release via two-pore channels (TPCs); this is reversed by removing lysosomal cholesterol and sphingosine. Sphingosine triggers TPC-mediated lysosomal calcium release and restores this signaling in LIMP-2-deficient cells.\",\n      \"method\": \"Clickable photoaffinity probe for target identification, LIMP-2 knockdown, lysosomal calcium assays, sphingosine supplementation rescue, TPC functional assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — photoaffinity probe-based target identification validated by functional rescue experiments, defined mechanistic pathway; single lab\",\n      \"pmids\": [\"40628771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SCARB2 deficiency in mice leads to gut dysbiosis and altered bile acid pool, causing hyperactivation of intestinal FXR, which impairs epithelium renewal and dietary lipid (including vitamin E) absorption. FXR inhibition or vitamin E supplementation ameliorates neuromotor impairment and neuropathy in Scarb2 knockout mice.\",\n      \"method\": \"Scarb2 knockout mouse model, gut microbiome analysis, bile acid profiling, FXR activity assay, vitamin E level measurement in patients, FXR inhibitor and vitamin E supplementation rescue experiments\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with multi-omic pathway analysis, pharmacological rescue, patient vitamin E measurement; single lab, novel gut axis mechanism\",\n      \"pmids\": [\"38635907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"EV-A71 does not encounter its uncoating receptor SCARB2 at the cell surface; SCARB2 is absent from the surface of RD and other susceptible cell lines and is concentrated in lysosomes/late endosomes. SCARB2 is dispensable for virus attachment but essential for infection, indicating that the critical SCARB2-EV-A71 interaction occurs intracellularly (in lysosomes) to trigger uncoating rather than at the plasma membrane.\",\n      \"method\": \"SCARB2 and PSGL-1 knockout cell lines, cell surface expression analysis, virus attachment assays, infection assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout experiments with attachment versus infection readouts, refines prior receptor localization model; single lab\",\n      \"pmids\": [\"38359079\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"LIMP-2/LGP85-deficient mice exhibit peripheral demyelinating neuropathy associated with massive loss of peripheral myelin proteins and increased lysosomal protein activity, indicating a role for the lysosomal compartment in peripheral myelination; mice also show lysosome accumulation in ureteric epithelium with disturbed uroplakin surface expression, causing ureteropelvic junction obstruction.\",\n      \"method\": \"LIMP-2 knockout mouse phenotypic analysis: neuropathology, myelin protein immunoblotting, lysosomal enzyme activity assays, histology, immunofluorescence\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined cellular and molecular phenotypes, multiple organ pathology characterization; single lab\",\n      \"pmids\": [\"12620969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SR-B2/LIMP-2 is present at the RPE cell surface (not exclusively intracellular), associates with lipid rafts, and participates in the control of photoreceptor outer segment (POS) phagocytosis speed in retinal pigment epithelial cells; siRNA inhibition of SR-B2/LIMP-2 alters POS internalization dynamics, similar to CD36.\",\n      \"method\": \"siRNA knockdown, immunoblotting, immunohistochemistry, lipid raft flotation gradients, phagocytosis assays in RPE cell lines and tissue\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — siRNA with phagocytosis assay but limited mechanistic detail in abstract, single lab\",\n      \"pmids\": [\"35408805\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In a human iPSC-derived cardiomyocyte model of Fabry disease, LIMP-2 accumulates relative to controls; overexpression of LIMP-2 directly induces secretion of cathepsin F and HSPA2/HSP70-2 and causes massive vacuole accumulation, suggesting LIMP-2 accumulation is causally linked to these downstream pathological events.\",\n      \"method\": \"iPSC-derived cardiomyocytes from Fabry disease patients, quantitative proteomics, LIMP-2 overexpression with cathepsin F/HSP70-2 secretion readout, genetic correction reversal\",\n      \"journal\": \"Stem cell reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — quantitative proteomics, gain-of-function overexpression with functional readout, genetic correction as control; single lab\",\n      \"pmids\": [\"31378672\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SCARB2 deficiency disrupts mTORC1-dependent mitochondrial oxidative phosphorylation (OXPHOS) in adipocytes: Scarb2 deficiency decreases the mTORC1/4E-BP1 pathway, leading to impaired mitochondrial respiration and enhanced glycolysis, resulting in reduced lipid storage in white adipose tissue.\",\n      \"method\": \"Adiponectin-Cre; Scarb2 conditional knockout mice, mTORC1/4E-BP1 pathway analysis by immunoblot, mitochondrial respiration (Seahorse), glycolysis assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout mouse, mTOR pathway mechanistic analysis, mitochondrial function assays; single lab\",\n      \"pmids\": [\"35955761\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SCARB2/LIMP-2 is an abundant lysosomal integral membrane protein with a large luminal domain containing a helical bundle that binds β-glucocerebrosidase via a coiled-coil domain, directing GCase to lysosomes independently of mannose-6-phosphate receptors through a pH-dependent mechanism (histidine trigger at H363); the protein also contains a hydrophobic tunnel that mediates transport of cholesterol and other lipids from the lysosomal lumen to the membrane (and onward to ER contact sites via STARD3-VAPB); its cytoplasmic dileucine (DEXXXLI) tail mediates selective binding to AP-3 (via gamma/delta-sigma subunits) for lysosomal sorting; the alternatively spliced SR-BII isoform differs only in its C-terminal cytoplasmic tail, which confers predominant intracellular localization and clathrin-dependent HDL endocytosis via a YTPLL dileucine motif; at the endosome/lysosome, SCARB2 functions as an uncoating receptor for EV71 and related enteroviruses by undergoing pH-dependent conformational change that opens its lipid-transfer tunnel to expel the viral pocket factor, facilitating genome release; SCARB2 additionally mediates TLR9 endosomal translocation and IRF7 nuclear translocation in plasmacytoid dendritic cells, contributes to macrophage phagolysosome maturation, and promotes MYC acetylation and mTORC1 lysosomal recruitment in cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SCARB2/LIMP-2 is an abundant lysosomal integral membrane protein that functions both as a dedicated trafficking receptor and as a lipid-transfer conduit at the lysosomal membrane [#0, #3]. Its large luminal domain binds β-glucocerebrosidase (GCase) through a helical bundle (helices 5 and 7) engaging a pocket on GCase, mapped to a coiled-coil region (residues 145–288) on LIMP-2 and an 11-residue stretch (D399/I402/I403) on GCase, and thereby delivers GCase to lysosomes independently of the mannose-6-phosphate pathway; loss of LIMP-2 redirects GCase to secretion [#0, #4, #19, #27, #7]. This receptor function is pH-gated by a histidine trigger (H363): the complex assembles at neutral pH and dissociates upon V-ATPase-driven acidification in late endosomes/lysosomes [#5, #6]. LIMP-2 reaches lysosomes via a cytoplasmic [DE]XXXL[LI] dileucine signal that is selectively recognized by the AP-3 adaptor (and AP-1) through γ/δ–σ subunit interactions [#1, #2, #9]. Beyond protein sorting, the molecule contains a hydrophobic tunnel that transfers cholesterol and other lipids from the lysosomal lumen to the membrane and onward toward the ER via contact sites involving STARD3 and VAPB, and it supports lysosomal sphingosine transport that gates two-pore-channel calcium release [#3, #8, #28, #29]. The same luminal architecture is exploited by enterovirus 71, for which SCARB2 acts as a low-pH uncoating receptor: an acid-induced conformational change opens the lipid tunnel to expel the viral pocket factor, an interaction that occurs intracellularly in lysosomes rather than at the cell surface [#13, #14, #15, #16, #31]. Through its control of lysosomal GCase activity, LIMP-2 governs autophagic and lysosomal homeostasis, and its deficiency causes GCase loss, α-synuclein accumulation, and dopaminergic neurotoxicity; in humans, loss-of-function mutations cause action myoclonus–renal failure syndrome (AMRF) [#4, #23]. An alternatively spliced isoform (SR-BII) differs only in its C-terminal cytoplasmic tail, conferring predominant intracellular localization and clathrin-dependent HDL endocytosis via a YTPLL/dileucine motif [#10, #11, #12]. LIMP-2 additionally functions in macrophage phagolysosome maturation and innate immunity, renal proximal-tubule endosome–lysosome fusion, TLR9/IRF7-driven type I interferon responses in plasmacytoid dendritic cells, and in cancer contexts where it promotes MYC acetylation and mTORC1 lysosomal recruitment [#22, #24, #18, #26, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established how LIMP-2 itself reaches lysosomes by identifying the adaptor that reads its cytoplasmic sorting tail, answering how the receptor is delivered to its compartment.\",\n      \"evidence\": \"Surface plasmon resonance binding of recombinant AP complexes to cytoplasmic tail peptides\",\n      \"pmids\": [\"9482728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve which AP subunits contact the motif\", \"In vitro peptide binding without cellular trafficking validation\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Defined the molecular basis of LIMP-2 sorting by mapping the dileucine motif to specific γ-σ1 (AP-1) and δ-σ3 (AP-3) hemicomplex subunits, refining adaptor specificity.\",\n      \"evidence\": \"Yeast three-hybrid plus in vitro binding to whole AP complexes\",\n      \"pmids\": [\"14691137\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of AP-1 vs AP-3 in vivo not resolved\", \"Structural basis of subunit recognition not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Identified LIMP-2 as the long-sought mannose-6-phosphate-independent lysosomal targeting receptor for GCase, answering how this enzyme reaches lysosomes.\",\n      \"evidence\": \"Affinity chromatography, LIMP-2-deficient mouse cells, reconstitution rescue, subcellular fractionation\",\n      \"pmids\": [\"18022370\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface residues not yet mapped\", \"pH-dependence of the interaction not defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Linked human AMRF disease mutations to loss of GCase binding and mapped the binding determinant to a coiled-coil region, connecting molecular interaction to clinical phenotype.\",\n      \"evidence\": \"Co-immunoprecipitation and binding assays with AMRF mutant constructs and synthetic peptides\",\n      \"pmids\": [\"19933215\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not explain why H363N increases affinity\", \"Functional consequence in patient tissues not addressed\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Explained how the LIMP-2/GCase complex assembles and releases its cargo by defining H363 as a pH sensor controlled by lysosomal acidification.\",\n      \"evidence\": \"Site-directed mutagenesis of H363, V-ATPase inhibition, pH-dependent co-IP\",\n      \"pmids\": [\"22537104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of the histidine switch not directly visualized in this study\", \"Whether other residues contribute to pH sensing unknown\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Provided the structural framework for both functions by revealing a GCase-binding helical bundle and a tunnel traversing the molecule consistent with lipid transfer.\",\n      \"evidence\": \"X-ray crystallography, homology modelling, mutagenesis of tunnel residues in the SR-BI homologue\",\n      \"pmids\": [\"24162852\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct lipid transfer by LIMP-2 itself not demonstrated here\", \"Cargo selectivity of the tunnel not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Resolved how a single receptor reconciles two sorting routes by showing LIMP-2 carries M6P at N325, binds MPR with separable affinity, and can form a ternary LIMP-2/GCase/MPR complex.\",\n      \"evidence\": \"X-ray crystallography, SPR, FLIM in living cells\",\n      \"pmids\": [\"25027712\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological role of M6P-MPR binding remained uncertain (later shown dispensable)\", \"Stoichiometry of the ternary complex in vivo unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped the reciprocal GCase determinant for LIMP-2 binding and showed it is distinct from the EV71-binding site, establishing functional separation of cargo and pathogen interactions.\",\n      \"evidence\": \"Alanine-scanning mutagenesis, binding, co-localization, and GCase secretion assays\",\n      \"pmids\": [\"25202012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the interface awaited later cryo-EM\", \"Effect of disease-relevant GCase variants not tested\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Demonstrated that LIMP-2 lysosomal targeting is genuinely M6P-independent, resolving whether the N325 modification is required for its own delivery.\",\n      \"evidence\": \"Immunofluorescence and lysosome purification in MPR-null and phosphotransferase-defective cells and mouse liver\",\n      \"pmids\": [\"26219725\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The functional purpose of the M6P modification on LIMP-2 remains unexplained\", \"Tail-dependent (AP-3) versus luminal contributions not jointly quantified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected LIMP-2 to neurodegeneration by showing its loss reduces lysosomal GCase activity, impairs autophagy, and drives α-synuclein accumulation and dopaminergic toxicity.\",\n      \"evidence\": \"LIMP-2-deficient mouse brain analysis with GCase activity, autophagy markers, and α-synuclein rescue by overexpression\",\n      \"pmids\": [\"25316793\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct relevance to human Parkinson's disease not established\", \"Whether lipid transport defects contribute independently unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Visualized the GCase-LIMP-2 interface at near-atomic resolution and demonstrated LIMP-2 acts as an allosteric GCase activator, enabling peptide-based enhancement of lysosomal GCase activity.\",\n      \"evidence\": \"Cryo-EM with engineered shuttle, overexpression, GCase activity assays in patient fibroblasts\",\n      \"pmids\": [\"40159502\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Therapeutic durability of the activating peptide not established\", \"Allosteric mechanism in the acidic lysosomal environment not fully resolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Characterized the SR-BII splice isoform, showing its distinct C-tail supports HDL cholesteryl ester uptake and efflux, distinguishing it functionally from SR-BI.\",\n      \"evidence\": \"Subcellular fractionation, radiolabeled HDL uptake and efflux assays, in vivo adenoviral expression\",\n      \"pmids\": [\"9614139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis of the lower efficiency not defined\", \"Relationship to lysosomal LIMP-2 function not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Defined how the SR-BII tail confers endocytic behavior by identifying a dileucine/YTPLL motif required for clathrin-dependent HDL internalization, and converted SR-BI into an endocytic receptor by motif transplantation.\",\n      \"evidence\": \"Mutagenesis, HDL endocytosis assays, pathway inhibition, chimeric constructs\",\n      \"pmids\": [\"16368683\", \"14726519\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological significance of SR-BII endocytosis in vivo unclear\", \"Adaptor reading the YTPLL motif not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Established SCARB2 as a low-pH uncoating receptor for EV71, showing that acidic endosomal conditions plus SCARB2 convert virions to empty capsids, defining the genome-release step.\",\n      \"evidence\": \"Density gradient uncoating analysis with soluble SCARB2 at defined pH, comparison with PSGL1\",\n      \"pmids\": [\"23302872\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural mechanism of uncoating not yet visualized\", \"Receptor surface vs intracellular site of action not resolved here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the structural mechanism of EV71 uncoating by combining acidic/neutral SCARB2 crystal structures with the cryo-EM virus-receptor complex, showing pH-driven tunnel opening expels the pocket factor.\",\n      \"evidence\": \"X-ray crystallography at two pH values and cryo-EM of the EV71-SCARB2 complex with mutagenesis\",\n      \"pmids\": [\"24986489\", \"30531980\", \"21389126\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Dynamics of the conformational transition not captured in real time\", \"How endosomal lipids participate in pocket-factor expulsion unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Refined the entry model by showing SCARB2 is absent from the cell surface and that the critical EV-A71 interaction occurs intracellularly in lysosomes, dispensable for attachment but essential for infection.\",\n      \"evidence\": \"SCARB2 and PSGL-1 knockout cell lines with surface expression, attachment, and infection assays\",\n      \"pmids\": [\"38359079\", \"22272359\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Initial attachment receptor in surface-SCARB2-negative cells not fully defined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated that LIMP-2 directly mediates lysosomal cholesterol export to membrane and lipid droplets and influences SREBP-2/LDLR regulation, operating in parallel with NPC proteins.\",\n      \"evidence\": \"Molecular modeling, crosslinking, microscale thermophoresis, cholesterol transport assays, and SREBP-2/LDLR immunoblot in knockout cells\",\n      \"pmids\": [\"31387993\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution relative to NPC pathway unclear\", \"Directionality and regulation of the tunnel not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed LIMP-2 at ER-lysosome contact sites via STARD3-dependent VAPB interaction, providing a route for lysosome-to-ER cholesterol handoff.\",\n      \"evidence\": \"BioID proximity screen, co-IP, and immunofluorescence co-localization\",\n      \"pmids\": [\"39370902\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Direct cholesterol flux across the contact site not measured\", \"STARD3/VAPB interaction stoichiometry undefined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked LIMP-2 lipid transport to lysosomal signaling by showing it supplies cholesterol/sphingosine that enable NAADP/TPC-mediated calcium release, druggable by tetrandrine.\",\n      \"evidence\": \"Photoaffinity target identification, knockdown, lysosomal calcium assays, sphingosine rescue, TPC functional assays\",\n      \"pmids\": [\"40628771\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether LIMP-2 directly transports sphingosine or acts indirectly not fully resolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed LIMP-2 controls late phagosome maturation and innate defense, linking the lysosomal protein to Listeria immunity and Rab5a activation.\",\n      \"evidence\": \"LIMP-2-deficient mouse macrophages, cytokine assays, phagolysosome biogenesis, CHO reconstitution, Rab5a activation\",\n      \"pmids\": [\"21123180\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular link between LIMP-2 and Rab5a activation undefined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated a tissue-specific requirement for LIMP-2 in renal proximal-tubule endosome-lysosome fusion, downstream of intact megalin/cubilin endocytosis.\",\n      \"evidence\": \"Limp-2 knockout mice, in vivo albumin tracking, cathepsin B co-localization\",\n      \"pmids\": [\"21429972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism by which LIMP-2 promotes fusion not defined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Identified a role for SCARB2 in innate antiviral signaling by showing it is required for TLR9 endosomal translocation and IRF7-driven type I interferon in plasmacytoid dendritic cells.\",\n      \"evidence\": \"siRNA knockdown in GEN2.2 pDCs with receptor/transcription-factor localization and IFN-I ELISA\",\n      \"pmids\": [\"25862818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, siRNA only\", \"Direct molecular interaction with TLR9 not shown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected SCARB2 to oncogenic mTORC1 signaling by showing GSH binding disrupts its N/C-terminal interaction and recruits mTORC1 to lysosomes via ARF1 in breast cancer.\",\n      \"evidence\": \"TME metabolomics, GCLC knockout mouse, GSH-SCARB2 binding, mTORC1 recruitment, ARF1 interaction studies\",\n      \"pmids\": [\"39442522\", \"35955761\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Structural basis of GSH-induced conformational change undefined\", \"Generality across cancer types unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Revealed a nuclear-adjacent function in cancer by showing SCARB2 protects MYC from HDAC3-mediated deacetylation at K148, enhancing MYC activity and HCC stemness.\",\n      \"evidence\": \"CRISPR screen, hepatocyte-specific Scarb2 knockout HCC models, SCARB2/MYC/HDAC3 co-IP, K148 acetylation assay\",\n      \"pmids\": [\"37739936\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How a lysosomal protein engages MYC/HDAC3 spatially not explained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how LIMP-2's canonical lysosomal lipid/protein-transport functions mechanistically connect to its reported nuclear/transcriptional (MYC) and signaling (mTORC1, TLR9) roles, and whether these reflect distinct subcellular pools or moonlighting activities.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying structural or trafficking model bridging lysosomal and signaling/transcriptional roles\", \"Subcellular pool responsible for cancer-associated functions not defined\", \"Most signaling roles rest on single-lab knockdown/knockout studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 8, 29]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [8, 28, 29]},\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [13, 14, 15, 16, 31]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 27]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [5, 14]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [5, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [0, 7, 18, 31]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [11, 13, 31]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [10, 33]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [28]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [8, 10, 30, 35]},\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 1, 7, 19]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [11, 12, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 23, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [18, 22]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [25, 29, 35]}\n    ],\n    \"complexes\": [\"LIMP-2/GCase complex\", \"LIMP-2/GCase/MPR ternary complex\", \"ER-lysosome contact site (LIMP-2/STARD3/VAPB)\"],\n    \"partners\": [\"GBA (GCase)\", \"AP-3\", \"AP-1\", \"STARD3\", \"VAPB\", \"MYC\", \"HDAC3\", \"ARF1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}