{"gene":"CD1E","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":2000,"finding":"CD1e is encoded by alternatively spliced mRNAs producing isoforms with one, two, or three alpha domains and either a 51- or 63-amino acid cytoplasmic domain, including isoforms lacking the transmembrane domain. Isoforms with three alpha domains associate with beta2-microglobulin, accumulate in late Golgi and late endosomal compartments due to atypical dilysine motifs in the cytoplasmic tail, and are cleaved into stable soluble forms in late endosomes. In dendritic cells, upon maturation, CD1e redistributes from Golgi to late endosomal compartments.","method":"Transfection of isoform constructs in cells, subcellular fractionation, immunofluorescence/confocal microscopy, biochemical characterization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (transfection, fractionation, microscopy), replicated in subsequent studies","pmids":["10948205"],"is_preprint":false},{"year":2003,"finding":"The biochemical and cellular properties of CD1e (intracellular retention, Golgi accumulation in immature DCs, late endosomal localization and soluble cleavage in mature DCs, association with beta2-microglobulin) are conserved between human and rhesus macaque CD1e, indicating these features are evolutionarily maintained.","method":"Comparative biochemical analysis and subcellular localization studies in human and macaque cells","journal":"Immunogenetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — comparative characterization across species, single lab, consistent with established human findings","pmids":["12671734"],"is_preprint":false},{"year":2005,"finding":"CD1e traffics from Golgi to late endosomes/lysosomes through sorting endosomes without passing through the plasma membrane in either immature or maturing dendritic cells. Upon maturation, CD1e rapidly disappears from Golgi and localizes transiently in HLA-DR+ vesicles, then increasingly in CD1b+ compartments, and ultimately accumulates almost exclusively in lysosomes of mature DCs as confirmed by immunoelectron microscopy.","method":"Live-cell imaging, high-resolution confocal microscopy, immunoelectron microscopy, subcellular fractionation in immature and LPS-matured dendritic cells","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal localization methods (live imaging, immunoEM, fractionation), replicated across labs","pmids":["15752135"],"is_preprint":false},{"year":2005,"finding":"Soluble CD1e is required for the processing of mycobacterial hexamannosylated phosphatidyl-myo-inositols (PIM6) into immunogenic forms recognized by CD1b-restricted T cells. PIM6 must first be partially digested by lysosomal alpha-mannosidase to remove mannose residues, and recombinant CD1e is required for and assists this digestion. CD1e was also shown to bind glycolipids directly.","method":"T cell stimulation assay with CD1b-restricted T cells, in vitro digestion assay with recombinant CD1e and alpha-mannosidase, glycolipid binding assay","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution assay with recombinant protein, functional T cell readout, replicated in subsequent studies","pmids":["16311334"],"is_preprint":false},{"year":2008,"finding":"The cytoplasmic tail of CD1e controls its intracellular trafficking: the C-terminal half mediates Golgi accumulation, and ubiquitination of cytoplasmic lysines triggers exit from Golgi compartments and transport to lysosomes. Replacing all eight cytoplasmic lysines with arginines causes accumulation in TGN46+ compartments and surface expression; fusing ubiquitin to this mutant restores kinetics of lysosomal transport.","method":"Chimeric molecule transfection, lysine-to-arginine mutagenesis, ubiquitin fusion constructs, immunofluorescence, subcellular fractionation in transfected cells","journal":"Traffic (Copenhagen, Denmark)","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site/residue mutagenesis with functional rescue, multiple constructs, single lab","pmids":["18208508"],"is_preprint":false},{"year":2008,"finding":"A naturally occurring CD1e variant encoded by allele 4, bearing a proline at position 194, fails to assist PIM6 presentation to CD1b-restricted T cells. This functional defect is primarily due to inefficient assembly of the CD1e molecule and poor transport to late endosomal compartments.","method":"T cell stimulation assay, subcellular localization by immunofluorescence, biochemical assembly analysis of allele 4 vs. wild-type CD1e in transfected cells","journal":"Journal of immunology (Baltimore, Md. : 1950)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — natural variant with functional readout (T cell stimulation) and mechanistic explanation (trafficking defect), multiple methods","pmids":["18325888"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of recombinant human CD1e at 2.90-Å resolution reveals a groove with a wider portal (2 Å larger spacing between α1 and α2 helices) than other CD1 proteins and no stable endogenous ligand electron density, despite lipids being present as shown by native mass spectrometry. CD1e mediates in vitro transfer of lipids to CD1b and displacement of lipids from stable CD1b-antigen complexes, with lipid association/dissociation kinetics substantially faster than CD1b.","method":"X-ray crystallography (2.90-Å resolution), native mass spectrometry, in vitro lipid transfer assay, kinetic lipid binding assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional validation by in vitro lipid transfer assay and native MS, multiple orthogonal methods in single study","pmids":["21788486"],"is_preprint":false},{"year":2011,"finding":"CD1e can positively or negatively modulate lipid antigen presentation by CD1b, CD1c, and CD1d. It facilitates rapid formation of CD1-lipid complexes (demonstrated for CD1d) and accelerates their turnover. In CD1e transgenic mouse antigen-presenting cells, lipid complexes assemble more efficiently and show faster turnover than in wild-type cells, resulting in maximized but temporally narrowed CD1-restricted T cell responses.","method":"T cell stimulation assays, CD1-lipid complex formation kinetics assay, CD1e transgenic mouse model with antigen-presenting cell functional readout","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse model plus in vitro biochemical assays, multiple CD1 isoforms tested, replicated across conditions","pmids":["21844346"],"is_preprint":false},{"year":2012,"finding":"CD1e functions as a lipid transfer protein: it selectively assists alpha-mannosidase-dependent digestion of PIM6 species according to their degree of acylation, and transfers only diacylated PIM species from donor to acceptor liposomes and from membranes to CD1b.","method":"In vitro lipid transfer assay with liposomes, alpha-mannosidase digestion assay, CD1b loading assay with recombinant CD1e, mass spectrometry analysis of PIM species","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstituted lipid transfer assay with multiple substrates and controls, single lab, mechanistically detailed","pmids":["22782895"],"is_preprint":false},{"year":2012,"finding":"LAPTM5 is a molecular partner of CD1e: the two proteins co-immunoprecipitate and colocalize in trans-Golgi and late endosomal compartments. Their association increases when vacuolar ATPase is inhibited with bafilomycin. However, LAPTM5 does not control CD1e ubiquitination or the generation of soluble lysosomal CD1e (negative result for these specific mechanisms).","method":"Co-immunoprecipitation, co-localization by confocal microscopy, bafilomycin treatment, ubiquitination assay, transfection in dendritic cell model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal Co-IP and colocalization, single lab, with explicit negative result for ubiquitination/trafficking mechanism","pmids":["22880058"],"is_preprint":false},{"year":2022,"finding":"CD1e interacts directly with beta2-microglobulin (B2M), as demonstrated by surface plasmon resonance using cell-free synthesized proteins.","method":"Cell-free protein synthesis (E. coli CFPS system), Ni2+ affinity purification, surface plasmon resonance (SPR) binding assay","journal":"Protein expression and purification","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct biophysical binding assay (SPR) with purified proteins, single lab, single method, consistent with prior cell-based co-association data","pmids":["36460227"],"is_preprint":false}],"current_model":"CD1e is a beta2-microglobulin-associated protein that, unlike other CD1 family members, is retained intracellularly—accumulating in the Golgi of immature dendritic cells and redistributing to lysosomes upon maturation via a ubiquitin-dependent, plasma-membrane-independent trafficking pathway controlled by its cytoplasmic tail—where it is cleaved into a soluble form that functions as a lipid transfer/editing protein: it binds glycolipids with fast on/off kinetics, selectively assists lysosomal alpha-mannosidase digestion of complex mycobacterial glycolipids (PIM6) in an acylation-dependent manner, transfers diacylated lipids to CD1b, and facilitates or accelerates assembly and turnover of CD1b, CD1c, and CD1d–lipid complexes, thereby broadly modulating group 1 and group 2 CD1-restricted T cell responses."},"narrative":{"mechanistic_narrative":"CD1e is a non-classical, beta2-microglobulin-associated member of the CD1 lipid-antigen presentation family that, unlike its relatives, never reaches the cell surface and instead acts as an intracellular lipid transfer/editing protein controlling group 1 and group 2 CD1-restricted T cell responses [PMID:10948205, PMID:16311334, PMID:21844346]. Synthesized as alternatively spliced isoforms, the three-alpha-domain forms assemble with beta2-microglobulin and accumulate in the late Golgi of immature dendritic cells, then redistribute to lysosomes upon DC maturation; this trafficking proceeds through sorting endosomes entirely without transit through the plasma membrane [PMID:10948205, PMID:15752135, PMID:36460227]. The cytoplasmic tail governs this itinerary: its C-terminal half drives Golgi accumulation, while ubiquitination of cytoplasmic lysines triggers Golgi exit and delivery to lysosomes, where CD1e is cleaved into a stable soluble form [PMID:10948205, PMID:18208508]. The soluble lysosomal protein functions as a lipid transfer protein with a structurally widened groove portal, no fixed endogenous ligand, and fast lipid on/off kinetics relative to CD1b [PMID:21788486]. Functionally, it assists lysosomal alpha-mannosidase digestion of complex mycobacterial phosphatidylinositol mannosides (PIM6) into immunogenic forms recognized by CD1b-restricted T cells, doing so in an acylation-dependent manner and selectively transferring diacylated PIM species to CD1b [PMID:16311334, PMID:22782895]. More broadly, CD1e accelerates assembly and turnover of CD1b, CD1c, and CD1d–lipid complexes, thereby maximizing but temporally narrowing CD1-restricted T cell responses [PMID:21844346]. A natural allele 4 variant bearing a proline at position 194 abolishes PIM6 presentation due to defective assembly and late-endosomal transport [PMID:18325888].","teleology":[{"year":2000,"claim":"Established that CD1e is structurally and behaviorally distinct from other CD1 proteins, defining it as an intracellularly retained, beta2-microglobulin-associated molecule that is proteolytically converted to a soluble form rather than displayed at the surface.","evidence":"Isoform construct transfection, subcellular fractionation, and confocal microscopy in cells and dendritic cells","pmids":["10948205"],"confidence":"High","gaps":["Functional role of the soluble cleaved form not yet defined","Mechanism triggering Golgi-to-endosome redistribution upon maturation unresolved"]},{"year":2003,"claim":"Showed the intracellular retention, beta2m association, and soluble cleavage of CD1e are evolutionarily conserved between human and macaque, arguing these unusual features are functionally important rather than incidental.","evidence":"Comparative biochemical and localization analysis in human and rhesus macaque cells","pmids":["12671734"],"confidence":"Medium","gaps":["Conservation does not by itself reveal molecular function","Single comparative lab study"]},{"year":2005,"claim":"Resolved the trafficking route, demonstrating CD1e reaches lysosomes via sorting endosomes without surface transit and progressively localizes to CD1b+ lysosomal compartments, placing it in the right place to act on CD1b presentation.","evidence":"Live-cell imaging, confocal and immunoelectron microscopy, and fractionation in immature and LPS-matured dendritic cells","pmids":["15752135"],"confidence":"High","gaps":["Molecular sorting signals not yet identified at this stage","Protease responsible for soluble cleavage unknown"]},{"year":2005,"claim":"Assigned the first molecular function to soluble CD1e, showing it is required to assist lysosomal alpha-mannosidase digestion of mycobacterial PIM6 into forms presentable by CD1b-restricted T cells, and that it binds glycolipids directly.","evidence":"CD1b-restricted T cell stimulation assays, in vitro recombinant CD1e plus alpha-mannosidase digestion, and glycolipid binding assays","pmids":["16311334"],"confidence":"High","gaps":["Whether CD1e directly transfers lipids or only assists digestion not resolved here","Structural basis of glycolipid binding unknown"]},{"year":2008,"claim":"Defined the trafficking code in the cytoplasmic tail, showing Golgi retention maps to the C-terminal half and that ubiquitination of cytoplasmic lysines is the switch driving Golgi exit and lysosomal delivery.","evidence":"Chimeric and lysine-to-arginine mutant constructs, ubiquitin-fusion rescue, immunofluorescence and fractionation in transfected cells","pmids":["18208508"],"confidence":"High","gaps":["Identity of the responsible ubiquitin ligase not determined","Link between maturation signals and tail ubiquitination unresolved"]},{"year":2008,"claim":"Connected CD1e function to natural genetic variation, showing the allele 4 P194 variant fails to support PIM6 presentation because of defective assembly and impaired late-endosomal transport.","evidence":"T cell stimulation, immunofluorescence localization, and biochemical assembly analysis of allele 4 versus wild-type in transfected cells","pmids":["18325888"],"confidence":"High","gaps":["Population-level immunological consequences of allele 4 not established","Whether assembly defect affects all CD1e functions or only PIM6 unclear"]},{"year":2011,"claim":"Provided the structural and mechanistic foundation for lipid transfer, showing a widened, ligand-promiscuous groove and fast lipid kinetics that allow CD1e to load and displace lipids on CD1b.","evidence":"2.90-A X-ray crystallography, native mass spectrometry, and in vitro lipid transfer and kinetic binding assays","pmids":["21788486"],"confidence":"High","gaps":["No fixed endogenous ligand identified","Structural states during active lipid handoff not captured"]},{"year":2011,"claim":"Generalized CD1e function beyond CD1b, demonstrating it can positively or negatively modulate CD1b, CD1c, and CD1d lipid presentation by accelerating both assembly and turnover of CD1-lipid complexes.","evidence":"T cell stimulation, CD1-lipid complex kinetics assays, and a CD1e transgenic mouse antigen-presenting cell model","pmids":["21844346"],"confidence":"High","gaps":["Determinants of positive versus negative modulation per CD1 isoform unclear","In vivo physiological consequences for T cell repertoire not defined"]},{"year":2012,"claim":"Refined the lipid transfer mechanism, showing selectivity is dictated by acylation state—CD1e assists alpha-mannosidase digestion and transfers diacylated PIM species while excluding others.","evidence":"In vitro liposome lipid transfer, alpha-mannosidase digestion, CD1b loading assays, and mass spectrometry of PIM species","pmids":["22782895"],"confidence":"High","gaps":["Structural basis of acyl-chain selectivity not determined","Range of physiological lipid substrates beyond PIM not mapped"]},{"year":2012,"claim":"Identified LAPTM5 as a physical partner colocalizing with CD1e in trans-Golgi and late endosomes, while excluding it as a controller of CD1e ubiquitination or soluble form generation.","evidence":"Reciprocal co-immunoprecipitation, confocal colocalization, bafilomycin treatment and ubiquitination assays in a dendritic cell model","pmids":["22880058"],"confidence":"Medium","gaps":["Functional consequence of the LAPTM5 interaction unknown","Single-lab interaction without independent confirmation"]},{"year":2022,"claim":"Confirmed by direct biophysics that CD1e binds beta2-microglobulin, validating with purified proteins the association previously inferred from cell-based studies.","evidence":"Cell-free synthesized CD1e and B2M, Ni2+ purification, and surface plasmon resonance binding","pmids":["36460227"],"confidence":"Medium","gaps":["Binding affinity and stoichiometry in physiological context not established","Single method, single lab"]},{"year":null,"claim":"How CD1e maturation signals trigger tail ubiquitination, which ligase and protease act on it, and how it chooses to enhance versus suppress specific CD1 isoforms in vivo remain open.","evidence":"Not yet addressed in the available corpus","pmids":[],"confidence":"Low","gaps":["No ubiquitin ligase or cleaving protease identified","Physiological rules governing positive versus negative CD1 modulation undefined","In vivo immune consequences of human CD1e variants unmapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,6,8]},{"term_id":"GO:0140104","term_label":"molecular carrier activity","supporting_discovery_ids":[6,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,7]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[0,2,4]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[2,4]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3,7]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,2,4]}],"complexes":[],"partners":["B2M","LAPTM5","CD1B","CD1C","CD1D"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P15812","full_name":"T-cell surface glycoprotein CD1e, membrane-associated","aliases":["R2G1"],"length_aa":388,"mass_kda":43.6,"function":"T-cell surface glycoprotein CD1e, soluble binds diacetylated lipids, including phosphatidyl inositides and diacylated sulfoglycolipids, and is required for the presentation of glycolipid antigens on the cell surface. The membrane-associated form is not active","subcellular_location":"Lysosome lumen","url":"https://www.uniprot.org/uniprotkb/P15812/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD1E","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CD1E","total_profiled":1310},"omim":[{"mim_id":"188411","title":"THYMOCYTE ANTIGEN CD1E; CD1E","url":"https://www.omim.org/entry/188411"},{"mim_id":"188370","title":"THYMOCYTE ANTIGEN CD1A; CD1A","url":"https://www.omim.org/entry/188370"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Golgi apparatus","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"lymphoid tissue","ntpm":895.4}],"url":"https://www.proteinatlas.org/search/CD1E"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"P15812","domains":[{"cath_id":"3.30.500.10","chopping":"37-207","consensus_level":"high","plddt":93.4626,"start":37,"end":207},{"cath_id":"2.60.40.10","chopping":"213-301","consensus_level":"high","plddt":96.116,"start":213,"end":301}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15812","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15812-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15812-F1-predicted_aligned_error_v6.png","plddt_mean":81.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD1E","jax_strain_url":"https://www.jax.org/strain/search?query=CD1E"},"sequence":{"accession":"P15812","fasta_url":"https://rest.uniprot.org/uniprotkb/P15812.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15812/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15812"}},"corpus_meta":[{"pmid":"16311334","id":"PMC_16311334","title":"Assistance of microbial glycolipid antigen processing by CD1e.","date":"2005","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/16311334","citation_count":196,"is_preprint":false},{"pmid":"10948205","id":"PMC_10948205","title":"Characterization of CD1e, a third type of CD1 molecule expressed in dendritic cells.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10948205","citation_count":72,"is_preprint":false},{"pmid":"15752135","id":"PMC_15752135","title":"The cellular pathway of CD1e in immature and maturing dendritic cells.","date":"2005","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/15752135","citation_count":57,"is_preprint":false},{"pmid":"21844346","id":"PMC_21844346","title":"Fine tuning by human CD1e of lipid-specific immune responses.","date":"2011","source":"Proceedings of the National Academy of Sciences of the United States of 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1950)","url":"https://pubmed.ncbi.nlm.nih.gov/18325888","citation_count":30,"is_preprint":false},{"pmid":"18838176","id":"PMC_18838176","title":"Susceptibility to Guillain-Barré syndrome is not associated with CD1A and CD1E gene polymorphisms.","date":"2008","source":"Journal of neuroimmunology","url":"https://pubmed.ncbi.nlm.nih.gov/18838176","citation_count":25,"is_preprint":false},{"pmid":"11019917","id":"PMC_11019917","title":"Identification of two novel human CD1E alleles.","date":"2000","source":"Tissue antigens","url":"https://pubmed.ncbi.nlm.nih.gov/11019917","citation_count":25,"is_preprint":false},{"pmid":"18208508","id":"PMC_18208508","title":"Control of the intracellular pathway of CD1e.","date":"2008","source":"Traffic (Copenhagen, Denmark)","url":"https://pubmed.ncbi.nlm.nih.gov/18208508","citation_count":15,"is_preprint":false},{"pmid":"21496400","id":"PMC_21496400","title":"CD1A and CD1E gene polymorphisms are associated with susceptibility to multiple 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producing isoforms with one, two, or three alpha domains and either a 51- or 63-amino acid cytoplasmic domain, including isoforms lacking the transmembrane domain. Isoforms with three alpha domains associate with beta2-microglobulin, accumulate in late Golgi and late endosomal compartments due to atypical dilysine motifs in the cytoplasmic tail, and are cleaved into stable soluble forms in late endosomes. In dendritic cells, upon maturation, CD1e redistributes from Golgi to late endosomal compartments.\",\n      \"method\": \"Transfection of isoform constructs in cells, subcellular fractionation, immunofluorescence/confocal microscopy, biochemical characterization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (transfection, fractionation, microscopy), replicated in subsequent studies\",\n      \"pmids\": [\"10948205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The biochemical and cellular properties of CD1e (intracellular retention, Golgi accumulation in immature DCs, late endosomal localization and soluble cleavage in mature DCs, association with beta2-microglobulin) are conserved between human and rhesus macaque CD1e, indicating these features are evolutionarily maintained.\",\n      \"method\": \"Comparative biochemical analysis and subcellular localization studies in human and macaque cells\",\n      \"journal\": \"Immunogenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — comparative characterization across species, single lab, consistent with established human findings\",\n      \"pmids\": [\"12671734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"CD1e traffics from Golgi to late endosomes/lysosomes through sorting endosomes without passing through the plasma membrane in either immature or maturing dendritic cells. Upon maturation, CD1e rapidly disappears from Golgi and localizes transiently in HLA-DR+ vesicles, then increasingly in CD1b+ compartments, and ultimately accumulates almost exclusively in lysosomes of mature DCs as confirmed by immunoelectron microscopy.\",\n      \"method\": \"Live-cell imaging, high-resolution confocal microscopy, immunoelectron microscopy, subcellular fractionation in immature and LPS-matured dendritic cells\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal localization methods (live imaging, immunoEM, fractionation), replicated across labs\",\n      \"pmids\": [\"15752135\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Soluble CD1e is required for the processing of mycobacterial hexamannosylated phosphatidyl-myo-inositols (PIM6) into immunogenic forms recognized by CD1b-restricted T cells. PIM6 must first be partially digested by lysosomal alpha-mannosidase to remove mannose residues, and recombinant CD1e is required for and assists this digestion. CD1e was also shown to bind glycolipids directly.\",\n      \"method\": \"T cell stimulation assay with CD1b-restricted T cells, in vitro digestion assay with recombinant CD1e and alpha-mannosidase, glycolipid binding assay\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution assay with recombinant protein, functional T cell readout, replicated in subsequent studies\",\n      \"pmids\": [\"16311334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The cytoplasmic tail of CD1e controls its intracellular trafficking: the C-terminal half mediates Golgi accumulation, and ubiquitination of cytoplasmic lysines triggers exit from Golgi compartments and transport to lysosomes. Replacing all eight cytoplasmic lysines with arginines causes accumulation in TGN46+ compartments and surface expression; fusing ubiquitin to this mutant restores kinetics of lysosomal transport.\",\n      \"method\": \"Chimeric molecule transfection, lysine-to-arginine mutagenesis, ubiquitin fusion constructs, immunofluorescence, subcellular fractionation in transfected cells\",\n      \"journal\": \"Traffic (Copenhagen, Denmark)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site/residue mutagenesis with functional rescue, multiple constructs, single lab\",\n      \"pmids\": [\"18208508\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"A naturally occurring CD1e variant encoded by allele 4, bearing a proline at position 194, fails to assist PIM6 presentation to CD1b-restricted T cells. This functional defect is primarily due to inefficient assembly of the CD1e molecule and poor transport to late endosomal compartments.\",\n      \"method\": \"T cell stimulation assay, subcellular localization by immunofluorescence, biochemical assembly analysis of allele 4 vs. wild-type CD1e in transfected cells\",\n      \"journal\": \"Journal of immunology (Baltimore, Md. : 1950)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — natural variant with functional readout (T cell stimulation) and mechanistic explanation (trafficking defect), multiple methods\",\n      \"pmids\": [\"18325888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Crystal structure of recombinant human CD1e at 2.90-Å resolution reveals a groove with a wider portal (2 Å larger spacing between α1 and α2 helices) than other CD1 proteins and no stable endogenous ligand electron density, despite lipids being present as shown by native mass spectrometry. CD1e mediates in vitro transfer of lipids to CD1b and displacement of lipids from stable CD1b-antigen complexes, with lipid association/dissociation kinetics substantially faster than CD1b.\",\n      \"method\": \"X-ray crystallography (2.90-Å resolution), native mass spectrometry, in vitro lipid transfer assay, kinetic lipid binding assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional validation by in vitro lipid transfer assay and native MS, multiple orthogonal methods in single study\",\n      \"pmids\": [\"21788486\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CD1e can positively or negatively modulate lipid antigen presentation by CD1b, CD1c, and CD1d. It facilitates rapid formation of CD1-lipid complexes (demonstrated for CD1d) and accelerates their turnover. In CD1e transgenic mouse antigen-presenting cells, lipid complexes assemble more efficiently and show faster turnover than in wild-type cells, resulting in maximized but temporally narrowed CD1-restricted T cell responses.\",\n      \"method\": \"T cell stimulation assays, CD1-lipid complex formation kinetics assay, CD1e transgenic mouse model with antigen-presenting cell functional readout\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse model plus in vitro biochemical assays, multiple CD1 isoforms tested, replicated across conditions\",\n      \"pmids\": [\"21844346\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD1e functions as a lipid transfer protein: it selectively assists alpha-mannosidase-dependent digestion of PIM6 species according to their degree of acylation, and transfers only diacylated PIM species from donor to acceptor liposomes and from membranes to CD1b.\",\n      \"method\": \"In vitro lipid transfer assay with liposomes, alpha-mannosidase digestion assay, CD1b loading assay with recombinant CD1e, mass spectrometry analysis of PIM species\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstituted lipid transfer assay with multiple substrates and controls, single lab, mechanistically detailed\",\n      \"pmids\": [\"22782895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"LAPTM5 is a molecular partner of CD1e: the two proteins co-immunoprecipitate and colocalize in trans-Golgi and late endosomal compartments. Their association increases when vacuolar ATPase is inhibited with bafilomycin. However, LAPTM5 does not control CD1e ubiquitination or the generation of soluble lysosomal CD1e (negative result for these specific mechanisms).\",\n      \"method\": \"Co-immunoprecipitation, co-localization by confocal microscopy, bafilomycin treatment, ubiquitination assay, transfection in dendritic cell model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal Co-IP and colocalization, single lab, with explicit negative result for ubiquitination/trafficking mechanism\",\n      \"pmids\": [\"22880058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CD1e interacts directly with beta2-microglobulin (B2M), as demonstrated by surface plasmon resonance using cell-free synthesized proteins.\",\n      \"method\": \"Cell-free protein synthesis (E. coli CFPS system), Ni2+ affinity purification, surface plasmon resonance (SPR) binding assay\",\n      \"journal\": \"Protein expression and purification\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct biophysical binding assay (SPR) with purified proteins, single lab, single method, consistent with prior cell-based co-association data\",\n      \"pmids\": [\"36460227\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD1e is a beta2-microglobulin-associated protein that, unlike other CD1 family members, is retained intracellularly—accumulating in the Golgi of immature dendritic cells and redistributing to lysosomes upon maturation via a ubiquitin-dependent, plasma-membrane-independent trafficking pathway controlled by its cytoplasmic tail—where it is cleaved into a soluble form that functions as a lipid transfer/editing protein: it binds glycolipids with fast on/off kinetics, selectively assists lysosomal alpha-mannosidase digestion of complex mycobacterial glycolipids (PIM6) in an acylation-dependent manner, transfers diacylated lipids to CD1b, and facilitates or accelerates assembly and turnover of CD1b, CD1c, and CD1d–lipid complexes, thereby broadly modulating group 1 and group 2 CD1-restricted T cell responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD1e is a non-classical, beta2-microglobulin-associated member of the CD1 lipid-antigen presentation family that, unlike its relatives, never reaches the cell surface and instead acts as an intracellular lipid transfer/editing protein controlling group 1 and group 2 CD1-restricted T cell responses [#0, #3, #7]. Synthesized as alternatively spliced isoforms, the three-alpha-domain forms assemble with beta2-microglobulin and accumulate in the late Golgi of immature dendritic cells, then redistribute to lysosomes upon DC maturation; this trafficking proceeds through sorting endosomes entirely without transit through the plasma membrane [#0, #2, #10]. The cytoplasmic tail governs this itinerary: its C-terminal half drives Golgi accumulation, while ubiquitination of cytoplasmic lysines triggers Golgi exit and delivery to lysosomes, where CD1e is cleaved into a stable soluble form [#0, #4]. The soluble lysosomal protein functions as a lipid transfer protein with a structurally widened groove portal, no fixed endogenous ligand, and fast lipid on/off kinetics relative to CD1b [#6]. Functionally, it assists lysosomal alpha-mannosidase digestion of complex mycobacterial phosphatidylinositol mannosides (PIM6) into immunogenic forms recognized by CD1b-restricted T cells, doing so in an acylation-dependent manner and selectively transferring diacylated PIM species to CD1b [#3, #8]. More broadly, CD1e accelerates assembly and turnover of CD1b, CD1c, and CD1d–lipid complexes, thereby maximizing but temporally narrowing CD1-restricted T cell responses [#7]. A natural allele 4 variant bearing a proline at position 194 abolishes PIM6 presentation due to defective assembly and late-endosomal transport [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that CD1e is structurally and behaviorally distinct from other CD1 proteins, defining it as an intracellularly retained, beta2-microglobulin-associated molecule that is proteolytically converted to a soluble form rather than displayed at the surface.\",\n      \"evidence\": \"Isoform construct transfection, subcellular fractionation, and confocal microscopy in cells and dendritic cells\",\n      \"pmids\": [\"10948205\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role of the soluble cleaved form not yet defined\", \"Mechanism triggering Golgi-to-endosome redistribution upon maturation unresolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed the intracellular retention, beta2m association, and soluble cleavage of CD1e are evolutionarily conserved between human and macaque, arguing these unusual features are functionally important rather than incidental.\",\n      \"evidence\": \"Comparative biochemical and localization analysis in human and rhesus macaque cells\",\n      \"pmids\": [\"12671734\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation does not by itself reveal molecular function\", \"Single comparative lab study\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Resolved the trafficking route, demonstrating CD1e reaches lysosomes via sorting endosomes without surface transit and progressively localizes to CD1b+ lysosomal compartments, placing it in the right place to act on CD1b presentation.\",\n      \"evidence\": \"Live-cell imaging, confocal and immunoelectron microscopy, and fractionation in immature and LPS-matured dendritic cells\",\n      \"pmids\": [\"15752135\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular sorting signals not yet identified at this stage\", \"Protease responsible for soluble cleavage unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Assigned the first molecular function to soluble CD1e, showing it is required to assist lysosomal alpha-mannosidase digestion of mycobacterial PIM6 into forms presentable by CD1b-restricted T cells, and that it binds glycolipids directly.\",\n      \"evidence\": \"CD1b-restricted T cell stimulation assays, in vitro recombinant CD1e plus alpha-mannosidase digestion, and glycolipid binding assays\",\n      \"pmids\": [\"16311334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether CD1e directly transfers lipids or only assists digestion not resolved here\", \"Structural basis of glycolipid binding unknown\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the trafficking code in the cytoplasmic tail, showing Golgi retention maps to the C-terminal half and that ubiquitination of cytoplasmic lysines is the switch driving Golgi exit and lysosomal delivery.\",\n      \"evidence\": \"Chimeric and lysine-to-arginine mutant constructs, ubiquitin-fusion rescue, immunofluorescence and fractionation in transfected cells\",\n      \"pmids\": [\"18208508\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the responsible ubiquitin ligase not determined\", \"Link between maturation signals and tail ubiquitination unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Connected CD1e function to natural genetic variation, showing the allele 4 P194 variant fails to support PIM6 presentation because of defective assembly and impaired late-endosomal transport.\",\n      \"evidence\": \"T cell stimulation, immunofluorescence localization, and biochemical assembly analysis of allele 4 versus wild-type in transfected cells\",\n      \"pmids\": [\"18325888\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Population-level immunological consequences of allele 4 not established\", \"Whether assembly defect affects all CD1e functions or only PIM6 unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Provided the structural and mechanistic foundation for lipid transfer, showing a widened, ligand-promiscuous groove and fast lipid kinetics that allow CD1e to load and displace lipids on CD1b.\",\n      \"evidence\": \"2.90-A X-ray crystallography, native mass spectrometry, and in vitro lipid transfer and kinetic binding assays\",\n      \"pmids\": [\"21788486\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No fixed endogenous ligand identified\", \"Structural states during active lipid handoff not captured\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Generalized CD1e function beyond CD1b, demonstrating it can positively or negatively modulate CD1b, CD1c, and CD1d lipid presentation by accelerating both assembly and turnover of CD1-lipid complexes.\",\n      \"evidence\": \"T cell stimulation, CD1-lipid complex kinetics assays, and a CD1e transgenic mouse antigen-presenting cell model\",\n      \"pmids\": [\"21844346\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Determinants of positive versus negative modulation per CD1 isoform unclear\", \"In vivo physiological consequences for T cell repertoire not defined\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Refined the lipid transfer mechanism, showing selectivity is dictated by acylation state—CD1e assists alpha-mannosidase digestion and transfers diacylated PIM species while excluding others.\",\n      \"evidence\": \"In vitro liposome lipid transfer, alpha-mannosidase digestion, CD1b loading assays, and mass spectrometry of PIM species\",\n      \"pmids\": [\"22782895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of acyl-chain selectivity not determined\", \"Range of physiological lipid substrates beyond PIM not mapped\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified LAPTM5 as a physical partner colocalizing with CD1e in trans-Golgi and late endosomes, while excluding it as a controller of CD1e ubiquitination or soluble form generation.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, confocal colocalization, bafilomycin treatment and ubiquitination assays in a dendritic cell model\",\n      \"pmids\": [\"22880058\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the LAPTM5 interaction unknown\", \"Single-lab interaction without independent confirmation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Confirmed by direct biophysics that CD1e binds beta2-microglobulin, validating with purified proteins the association previously inferred from cell-based studies.\",\n      \"evidence\": \"Cell-free synthesized CD1e and B2M, Ni2+ purification, and surface plasmon resonance binding\",\n      \"pmids\": [\"36460227\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Binding affinity and stoichiometry in physiological context not established\", \"Single method, single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CD1e maturation signals trigger tail ubiquitination, which ligase and protease act on it, and how it chooses to enhance versus suppress specific CD1 isoforms in vivo remain open.\",\n      \"evidence\": \"Not yet addressed in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No ubiquitin ligase or cleaving protease identified\", \"Physiological rules governing positive versus negative CD1 modulation undefined\", \"In vivo immune consequences of human CD1e variants unmapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 6, 8]},\n      {\"term_id\": \"GO:0140104\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [0, 2, 4]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3, 7]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 2, 4]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"B2M\", \"LAPTM5\", \"CD1b\", \"CD1c\", \"CD1d\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}