{"gene":"CD46","run_date":"2026-06-09T22:57:17","timeline":{"discoveries":[{"year":1993,"finding":"CD46 (membrane cofactor protein) functions as the cellular receptor for measles virus (Edmonston strain): hamster cells expressing human CD46 gained the ability to bind measles virus, form syncytia, and produce viral proteins; polyclonal antisera against CD46 blocked virus binding and infection.","method":"Somatic cell hybrid mapping, transfection of CD46 cDNA into non-permissive hamster cells, virus binding and infection assays, antibody inhibition","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in heterologous cells with multiple orthogonal assays (binding, syncytia, viral protein production, antibody block), independently replicated in a second paper (PMID:8371352)","pmids":["8402913","8371352"],"is_preprint":false},{"year":1991,"finding":"CD46 acts as a cofactor for the serine protease factor I to mediate proteolytic cleavage (inactivation) of complement components C3b and C4b deposited on host cells, thereby protecting cells from complement-mediated lysis.","method":"Biochemical purification, functional cofactor activity assays with factor I and C3b/C4b substrates","journal":"Annual review of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzymatic cofactor activity established by direct in vitro biochemical assay, replicated across multiple studies in the corpus","pmids":["1910685"],"is_preprint":false},{"year":1995,"finding":"The measles virus receptor determinant on CD46 maps to SCR1 and SCR2 (short consensus repeat domains 1 and 2) of the extracellular region; monoclonal antibodies against SCR1 or SCR2 blocked MV infection, whereas the C3b/C4b binding site maps to SCR3 and SCR4, demonstrating that the MV and complement binding sites are distinct.","method":"Chimeric CD46/DAF mutants, SCR domain truncations and swaps, GPI-anchored CD46 ectodomain constructs, monoclonal antibody blocking, cell infection assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — structure-function mutagenesis with multiple chimeras and domain swaps, confirmed by antibody competition, single lab with multiple orthogonal methods","pmids":["7534417"],"is_preprint":false},{"year":1999,"finding":"CD46 serves as a cellular receptor for human herpesvirus 6 (HHV-6, both subgroups A and B): HHV-6 infection downregulates surface CD46; anti-CD46 monoclonal antibody and soluble CD46 inhibit cell fusion and entry; non-human cells became susceptible to HHV-6 upon expression of recombinant human CD46.","method":"Flow cytometry for CD46 downregulation, neutralization with anti-CD46 mAb and soluble CD46, transfection of CD46 into non-permissive cells, infection and fusion assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in heterologous cells plus multiple inhibition approaches (antibody, soluble receptor), single rigorous paper with orthogonal methods","pmids":["10619434"],"is_preprint":false},{"year":1997,"finding":"CD46 is a pilus receptor for pathogenic Neisseria (N. gonorrhoeae and N. meningitidis): purified pili bound a 55-60 kDa doublet consistent with CD46; anti-CD46 antibodies blocked bacterial attachment; piliated gonococci bound CHO cells transfected with CD46 cDNA but not non-transfected cells; recombinant CD46 protein directly bound piliated Neisseria and inhibited attachment.","method":"SDS-PAGE binding assays, antibody blocking, transfection of CD46 cDNA into CHO cells, direct binding with recombinant CD46, competition inhibition","journal":"Molecular microbiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in heterologous CHO cells plus direct protein-protein interaction with recombinant CD46, multiple orthogonal methods in one study","pmids":["9379894"],"is_preprint":false},{"year":2003,"finding":"Adenovirus type 11 (species B) uses CD46 as a primary cellular attachment receptor: Ad11 bound CD46-transfected CHO cells ~10× more than CAR- or CD55-transfected cells; CD46 cDNA transfection rendered non-permissive CHO cells permissive to Ad11 infection; soluble Ad11 fiber knob and anti-CD46 antibodies inhibited Ad11 binding and infection.","method":"Transfection of CD46 cDNA into CHO cells, virus binding assays, soluble fiber knob competition, antibody inhibition of binding and infection","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in heterologous cells with multiple orthogonal inhibition experiments, single rigorous paper","pmids":["12915534"],"is_preprint":false},{"year":2003,"finding":"Co-engagement of CD3 and CD46 on human CD4+ T cells in the presence of IL-2 induces a T regulatory 1 (Tr1) cytokine phenotype, with strong IL-10 production, suppression of bystander T cells, and acquisition of a memory phenotype.","method":"CD3/CD46 co-stimulation of primary human CD4+ T cells, cytokine measurement (IL-10, IFN-γ), bystander suppression assays, phenotypic characterization","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean primary human cell KD/stimulation with defined cytokine phenotype, replicated in multiple subsequent studies, original paper in Nature with comprehensive assays","pmids":["12540904"],"is_preprint":false},{"year":1992,"finding":"CD46 protein isoform expression is controlled by alternative splicing: differential splicing of 5 exons (including STP-rich exons 7, 8, 9 and cytoplasmic tail exons 13/14) generates at least 14 mRNA variants in a tissue-specific, allele-specific, and malignancy-related manner; cytoplasmic tail CYT-1 (exon 13) or CYT-2 (exon 14) arise from mutually exclusive splicing.","method":"RT-PCR, Northern blotting, SDS-PAGE/Western blotting of tissue-specific isoforms, allelic analysis","journal":"European journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal RNA and protein methods across many tissues, replicated in subsequent studies (PMID:7692239)","pmids":["1601037","7692239"],"is_preprint":false},{"year":2009,"finding":"Engagement of CD46 (specifically the CD46-Cyt-1 isoform) induces autophagy through its interaction with the scaffold protein GOPC, which links CD46-Cyt-1 to the autophagosome formation complex VPS34/Beclin1; measles virus and group A Streptococcus induce autophagy through this CD46-Cyt-1/GOPC pathway.","method":"Co-immunoprecipitation of CD46-Cyt-1 with GOPC, VPS34/Beclin1 interaction assays, autophagy induction assays (LC3 formation), isoform-specific constructs, infection with MV and GAS","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP identifying GOPC as bridging partner, isoform-specific functional assays, multiple pathogen validations in one rigorous study","pmids":["19837375"],"is_preprint":false},{"year":2010,"finding":"CD46 engagement on CD4+ T cells promotes Th1 effector function; as IL-2 accumulates, CD46 switches cells to a regulatory phenotype by attenuating IL-2 production via the transcriptional regulator ICER/CREM and upregulating IL-10 through interaction of the CD46 cytoplasmic tail with the serine-threonine kinase SPAK; the CD46 tail isoform expressed determines the regulatory outcome.","method":"CD46 tail isoform-specific stimulation, ICER/CREM reporter assays, SPAK interaction assays, cytokine measurement in CD4+ T cells and γδ T cells, analysis of rheumatoid arthritis patient cells","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — interaction of CD46 tail with SPAK identified, ICER/CREM pathway defined, isoform-specific functional differences demonstrated, disease-relevant patient validation","pmids":["20694009"],"is_preprint":false},{"year":2000,"finding":"The CYT-2 cytoplasmic tail of CD46, but not CYT-1, is phosphorylated on tyrosine by the Src kinase Lck; a CYT-2 peptide is phosphorylated by a src kinase system, and Lck is required for CYT-2 phosphorylation in the Jurkat T cell line.","method":"CD46 tail peptide phosphorylation assays, Western blotting with anti-phosphotyrosine antibodies, cross-linking of CD46 on cell lines and isoform transfectants, genetic and biochemical src kinase inhibition/knockout analysis","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro phosphorylation with peptides plus cell-based assays with genetic (Lck-deficient) and biochemical evidence, multiple orthogonal methods","pmids":["10657632"],"is_preprint":false},{"year":2002,"finding":"The two CD46 cytoplasmic tail isoforms (CD46-1/CYT-1 and CD46-2/CYT-2) have divergent functions in T cell-mediated inflammation: CD46-1 engagement inhibits the contact hypersensitivity reaction while CD46-2 increases it; the isoforms differentially affect CD8+ T cell cytotoxicity, CD4+ T cell proliferation, IL-2 and IL-10 production, and tyrosine phosphorylation of Vav.","method":"CD46 isoform-specific transgenic mice, contact hypersensitivity assays, T cell proliferation and cytotoxicity assays, cytokine measurement, Vav phosphorylation analysis","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgenic mouse model with two isoforms compared in multiple functional immune assays, multiple orthogonal readouts","pmids":["12055630"],"is_preprint":false},{"year":2002,"finding":"In classical pathway activation, CD46 (not soluble C4BP) is primarily responsible for C4b cleavage on cell surfaces (cofactor activity), generating C4c and C4d; factor H is primarily responsible for C3b cleavage; in alternative pathway activation, CD46's cofactor activity is sufficient to restrict C3b deposition.","method":"FACS and Western blotting of complement fragment deposition on MCP-transfected vs MCP-negative cells, function-blocking anti-CD46 and anti-factor H mAbs, serum with Mg2+-EGTA to isolate alternative pathway","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct biochemical analysis on transfected cells with functional blocking antibodies, pathway-specific conditions, multiple complement fragments tracked","pmids":["12055245"],"is_preprint":false},{"year":2012,"finding":"The Notch family member Jagged1 is an endogenous physiological ligand for CD46; CD46 regulates Notch receptor and ligand expression during T cell activation; disruption of CD46-Notch crosstalk impedes IFN-γ induction and switching to IL-10; CD4+ T cells from CD46-deficient patients and Alagille syndrome (Jagged1 hypomorphic mutation) patients fail to mount appropriate Th1 responses.","method":"Jagged1-CD46 binding assays, T cell stimulation with CD46/Jagged1 blocking, analysis of CD46-deficient patient T cells, Alagille syndrome patient T cells, cytokine measurement","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — ligand identification confirmed by binding studies, pathway validated with genetic patient material (CD46-deficient, Alagille syndrome), multiple orthogonal approaches","pmids":["23086448"],"is_preprint":false},{"year":1995,"finding":"CD46 and moesin physically interact in a receptor complex on the cell surface: chemical cross-linking showed close proximity of CD46 and moesin; co-immunoprecipitation confirmed physical interaction; both proteins co-localize at sites of MV particle adsorption by immunoelectron microscopy; antibodies to moesin inhibited MV infection of CD46-negative mouse cell lines, suggesting moesin contributes to MV uptake.","method":"Co-immunoprecipitation, chemical cross-linking of cell surface proteins, antibody inhibition of MV binding and infection, immunoelectron microscopy co-localization","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-immunoprecipitation and cross-linking support physical interaction; single lab but multiple methods including ultrastructural localization","pmids":["7884872"],"is_preprint":false},{"year":1995,"finding":"CD46 downregulation by measles virus is specifically caused by interaction with newly synthesized MV hemagglutinin (MV-H) protein: recombinant MV-H proteins of strains Edmonston, Halle, and CM cause CD46 downregulation, while those of lymphotropic wild-type strains DL and WTF do not; cell-to-cell contact involving MV-H is sufficient to trigger CD46 downregulation on uninfected bystander cells.","method":"Flow cytometry for CD46 surface expression after infection with 19 MV strains, recombinant MV-H protein expression, antibody inhibition, cell-to-cell contact assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — strain panel plus recombinant hemagglutinin expression definitively identifies MV-H as driver of CD46 downregulation, replicated by multiple subsequent studies","pmids":["7732009"],"is_preprint":false},{"year":2004,"finding":"CD46 is a cellular receptor for bovine viral diarrhea virus (BVDV): a blocking MAb to bovine CD46 (50-58 kDa) prevented BVDV infection; the cDNA of bovine CD46 was cloned; expression of bovine CD46 correlated with BVDV binding and significantly increased susceptibility of porcine cells to BVDV infection.","method":"Immunoaffinity purification and microchemical analysis of receptor, cDNA cloning, BVDV binding assays, transient expression in porcine cells, susceptibility assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — heterologous expression in porcine cells showed enhanced susceptibility; bovine CD46 did not fully confer permissiveness to all non-permissive cells, reducing confidence; single lab study","pmids":["14747544"],"is_preprint":false},{"year":2002,"finding":"HHV-6 and measles virus employ distinct CD46 domains for receptor function: HHV-6 requires SCR2 and SCR3 with no requirement for SCR1 or SCR4; measles virus requires SCR1 and SCR2; all four CD46 isoforms support HHV-6 receptor activity, indicating critical HHV-6 binding determinants are outside the C-terminal variable domains.","method":"Quantitative cell fusion assay with CD46 truncations, chimeras with DAF (decay-accelerating factor), isoform variants, and SCR-specific monoclonal antibodies","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — structure-function analysis using multiple engineered CD46 variants (truncations, chimeras, isoforms) with quantitative fusion assay, single lab but multiple orthogonal constructs","pmids":["12171934"],"is_preprint":false},{"year":2003,"finding":"CD46 downregulation by piliated N. gonorrhoeae occurs via pilus-mediated shedding of CD46 into the supernatant; downregulation requires the pilus retraction protein PilT; gonococci lacking PilT did not downregulate CD46; the effect is not due to global protein synthesis shutdown or intracellular retention.","method":"Flow cytometry for surface CD46 expression, Western blotting of supernatants for shed CD46, RT-PCR for mRNA levels, PilT mutant bacteria, clinical isolate reisolation after experimental human infection","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — PilT genetic requirement established, shedding mechanism characterized, mechanism validated in an experimental human infection model with recovered isolates","pmids":["14597734"],"is_preprint":false},{"year":2009,"finding":"Presenilin/gamma-secretase (PS/γS) cleaves CD46-Cyt-1 and CD46-Cyt-2 intracellular tails, releasing immunoprecipitable cytoplasmic tail peptides into the cell; PS/γS processing is blocked by chemical inhibitors and prevented in dominant-negative presenilin mutant cell lines; Neisseria gonorrhoeae and N. meningitidis stimulate PS/γS processing of CD46 in a manner requiring type IV pili and the pilus retraction motor PilT, implicating mechanotransduction.","method":"Immunoprecipitation of cleaved tail peptides, PS/γS chemical inhibitors, dominant-negative presenilin cell lines, bacterial mutant analysis (type IV pili, PilT), Western blotting","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — enzymatic cleavage confirmed by detection of tail peptides, validated with genetic (dominant-negative) and pharmacological inhibition, bacterial mutants identify mechanotransduction requirement","pmids":["20018629"],"is_preprint":false},{"year":2000,"finding":"CD46 associates with multiple β1 integrins (α1β1, α2β1, α3β1, α5β1, α6β1) and tetraspanins on the cell surface; cross-linking experiments in living cells confirmed the existence of CD46/integrin complexes; CD46 does not associate with β4 integrins; CD46/integrin complexes do not modify MV fusion entry.","method":"Co-immunoprecipitation with anti-CD46 mAb, cross-linking experiments on living cells, panel of anti-integrin antibodies","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — reciprocal Co-IP and cross-linking in living cells support the association, but molecular mechanism of the interaction was not further resolved; negative finding on MV fusion noted","pmids":["10741407"],"is_preprint":false},{"year":2005,"finding":"The CCP2 (SCR2) domain of CD46 is critical for adenovirus serotype 35 (Ad35) and Ad11 binding; substitution of amino acids at positions 130-135 or 152-156 of CD46 completely abolishes Ad35 receptor function; Ad35 competes with measles virus for CD46 binding but not with complement C3b; N-glycosylations of CD46 do not critically contribute to Ad35 infection.","method":"Competition experiments with known CD46 ligands (MV, C3b), CD46 point mutants, antibody blocking, Ad35 fiber-containing vector infection assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis with multiple point mutations mapping the binding domain, competition assays with structurally defined CD46 ligands, single lab with multiple orthogonal methods","pmids":["15919905"],"is_preprint":false},{"year":2007,"finding":"Four residues in the Ad35 fiber knob (Phe242, Arg279, Ser282, Glu302) are critical for CD46 binding; mutation of these residues ablates CD46 binding without affecting knob trimerization; the Ad35 knob binds three CD46 molecules with KD = 15.5 nM; crystal structure of Ad35 knob at 2-Å resolution modeled with existing Ad11-CD46 structure indicates one CD46 molecule binds between two knob monomers.","method":"Random mutagenesis library of Ad35 knob screened for CD46 binding, surface plasmon resonance, competition binding, X-ray crystallography of Ad35 knob at 2-Å resolution, structural modeling","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure plus mutagenesis plus SPR quantitative binding analysis in one study, multiple orthogonal methods","pmids":["17898059"],"is_preprint":false},{"year":2021,"finding":"Human adenovirus species D (HAdV-D) types use CD46 as a receptor through the hexon capsid protein, not the fiber knob: soluble hexon (but not fiber knob) inhibited HAdV-D56 infection; SPR showed CD46 binds HAdV-D hexon but not fiber knob; cryo-EM of the HAdV-D56 virion-CD46 complex confirmed CD46 binding to the central cavity of hexon trimers; 16/17 HAdV-D types were inhibited by soluble CD46.","method":"Cell-based receptor screening assay, CD46 KO and overexpressing cells, competition with soluble CD46, surface plasmon resonance, cryo-EM of virion-CD46 complex","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structural confirmation plus SPR quantitative binding plus genetic KO validation plus soluble competition, single rigorous paper with multiple orthogonal high-tier methods","pmids":["33384338"],"is_preprint":false},{"year":1995,"finding":"CD46 downregulation is mediated specifically by interaction between the extracellular domains of CD46 and MV hemagglutinin, occurring on the same cell membrane and through cell-to-cell contact; CD46 downregulation was reversible, restricted to CD46 (not other surface markers), and not mediated through PKA or PKC-dependent pathways.","method":"FACS analysis of CD46 surface expression after contact of Jurkat cells with L cells expressing MV-H, antibody blocking with anti-CD46 and anti-H antibodies, PKA/PKC inhibitor treatment","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean cell-contact assay with specific antibody inhibition identifying extracellular domain interaction; PKA/PKC independence established by pharmacological inhibition; single lab","pmids":["7595386"],"is_preprint":false},{"year":2000,"finding":"The CD46 cytoplasmic domains are required for CD46-mediated enhancement of IFN-α/β production in mouse macrophages in response to measles virus; mouse macrophages expressing a tailless CD46 mutant lacking cytoplasmic domains showed much lower IFN-α/β and nitric oxide production and were highly susceptible to MV; IFN-α/β synergizes with IFN-γ to restrict viral replication.","method":"CD46 mutant (tailless) transfection into mouse macrophages, antibody neutralization of IFN-α/β, nitric oxide measurement, viral protein synthesis assays, conditioned medium transfer experiments","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct domain-deletion mutagenesis with multiple functional readouts; single lab study","pmids":["10627535"],"is_preprint":false},{"year":2004,"finding":"CD46 receptor density determines the threshold for measles virus-induced cell-cell fusion: virus entry increases progressively with CD46 density, but intercellular fusion is minimal at low densities and increases dramatically above a threshold density; tumor cells express high CD46 densities (above threshold) leading to extensive syncytia, while normal cells express low densities resulting in infection without significant fusion.","method":"Engineered cell lines expressing a range of CD46 densities, quantitative readout of viral gene expression via virally encoded soluble marker peptide, fusion assays at different CD46 receptor densities","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — dose-response of CD46 density vs. fusion established with engineered cell lines spanning a range of densities, mechanistic threshold identified, single rigorous study","pmids":["15256464"],"is_preprint":false},{"year":1995,"finding":"Measles virus hemagglutinin (MV-H), but not the fusion protein (MV-F), determines CD46-dependent fusion specificity: cells expressing HMV + FCDV fused CD46-dependently (like MV); cells expressing HCDV + FMV fused CD46-independently (like CDV); CD46 co-immunoprecipitated with HMV but not with FMV or CDV glycoproteins.","method":"Recombinant vaccinia virus expressing chimeric MV/CDV glycoproteins, quantitative reporter gene fusion assay, syncytium formation, flow cytometry and antibody co-precipitation of CD46 with H/F glycoproteins","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — chimeric glycoprotein swap (MV/CDV) plus co-precipitation definitively assigns CD46 binding to H protein; multiple orthogonal methods in single study","pmids":["7745681"],"is_preprint":false},{"year":2016,"finding":"CD46 costimulation of CD4+ T cells leads to downregulation of miR-150, which targets the glucose transporter 1 encoding transcript SLC2A1, connecting CD46 signaling to glucose uptake regulation; CD46 costimulation induces larger miRNA expression changes than CD28; autocrine CD46 signaling operates downstream of CD28; increased miR-150 in IL-10-secreting (switched) Th1 cells contributes to IL-10 production.","method":"miRNA expression profiling in CD46-costimulated CD4+ T cells, CD46 blockade, miR-150 knockdown, SLC2A1 target validation, cytokine measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — miR-150 target SLC2A1 validated, miR-150 knockdown tested for cytokine output, autocrine CD46/CD28 crosstalk demonstrated; single lab","pmids":["26746193"],"is_preprint":false},{"year":2017,"finding":"TCR/CD3 stimulation of CD4+ T cells induces a reduction in apparent molecular mass of CD46 dependent on O-glycosylation; CD3-stimulated changes in CD46 O-glycosylation status reduce CD46 processing and T cell signaling; CD46 is recruited to the immune synapse in a manner requiring its STP (serine-threonine-proline-rich) region; immune synapse recruitment of CD46 switches T cells from IFN-γ to IL-10 production; CD4+ T cells from MS patients show increased surface CD46 without the CD3-stimulated mass shift.","method":"SDS-PAGE mass-shift assays with O-glycosylation inhibitors, imaging of CD46 at immune synapse, STP-region mutant constructs, cytokine measurement, analysis of MS patient T cells","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — O-glycosylation-dependent mass shift and immune synapse recruitment with STP domain requirement established; disease context validated with MS patient cells; single lab","pmids":["29066539"],"is_preprint":false},{"year":2009,"finding":"Presenilin/gamma-secretase-processed CD46-Cyt-1 (but not Cyt-2) engages CD46-Cyt-1-specific GOPC scaffold and VPS34/Beclin1 autophagosome complex; CD46-induced Treg (cTreg) enhance B cell antibody production in a manner dependent on cell-cell contact and cTreg-derived IL-10; CD46-deficient patient T cells fail to promote B cell responses, while CD46-deficient B cells have no intrinsic immunoglobulin production defect.","method":"cTreg/B cell co-culture assays, antibody production measurement, cell-contact blocking, IL-10 blocking, analysis of CD46-deficient patient T cells and B cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CD46-deficient patient cells used to establish T cell-intrinsic requirement; cell contact and IL-10 dependence dissected; single lab study","pmids":["19784949"],"is_preprint":false},{"year":2017,"finding":"MMP-9-mediated increased shedding of soluble CD46 by Th1 cells is associated with defective CD46-regulated Th1 contraction in SLE patients; inhibition of MMP-9 activity normalized soluble CD46 release and restored Th1 contraction in patient T cells.","method":"Measurement of soluble CD46 in Th1 cell supernatants, MMP-9 inhibitor treatment, restoration of Th1 contraction assays, comparison of SLE patient vs healthy donor T cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MMP-9 inhibitor rescue of Th1 contraction in patient cells mechanistically links MMP-9 shedding of CD46 to T cell dysregulation; single lab, patient material","pmids":["28444759"],"is_preprint":false},{"year":2016,"finding":"CD46 is subject to alternative splicing regulation: CD46 cassette exons 7 and 8 (extracellular domain-encoding) use noncanonical base-pairing to U1 snRNA at their 5' splice sites; exon 13 (cytoplasmic tail CYT-1) inclusion is regulated by PTBP1 and TIAL1 as splicing factors, and SRSF1 represses exon 13 inclusion; nonsense-mediated mRNA decay and transcription speed further regulate CD46 mRNA isoforms; antisense oligonucleotides successfully manipulated CD46 exon 13 inclusion.","method":"Splicing minigene assays, siRNA knockdown of splicing factors (PTBP1, TIAL1, SRSF1), U1 snRNA base-pairing analysis, antisense oligonucleotide manipulation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — mechanistic dissection of splice site recognition (U1 snRNA) and trans-acting factors with minigene and siRNA approaches; antisense oligonucleotide manipulation confirms functional control; single lab, multiple orthogonal methods","pmids":["27226545"],"is_preprint":false},{"year":2014,"finding":"HHV-6A gQ1 and gQ2 glycoproteins within the gH/gL/gQ1/gQ2 tetrameric complex are critical for CD46 binding: replacement of HHV-6A gQ1 or gQ2 with HHV-6B counterparts abolished CD46 binding, while replacement of gH or gL with HHV-6B molecules did not affect CD46 binding.","method":"Chimeric HHV-6A/B glycoprotein complex expression, co-immunoprecipitation of complex formation, CD46 binding assays","journal":"Microbiology and immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic subunit swaps between HHV-6A and -6B identified gQ1/gQ2 as CD46-binding determinants; co-IP confirmed complex formation; single lab","pmids":["24215487"],"is_preprint":false},{"year":2019,"finding":"CD46 facilitates human cytomegalovirus (CMV) entry and dissemination in epithelial cells and trophoblasts but not in fibroblasts: CD46-KO epithelial cells showed significantly reduced viral proliferation; anti-CD46 monoclonal antibodies blocked CMV infection; a CD46-dependent entry pathway was demonstrated in trophoblasts.","method":"High-throughput antibody inhibition screen, CD46 CRISPR/Cas9 KO epithelial cells, infection assays in multiple cell types including trophoblasts and fibroblasts","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO combined with antibody inhibition and cell-type-specific functional assays, multiple orthogonal approaches in one study","pmids":["31221976"],"is_preprint":false},{"year":2016,"finding":"During sperm acrosome reaction, CD46 undergoes dynamic relocalization over the sperm head and interacts with β1 integrin (specifically with α3 but not α6 subunit); this interaction is proposed to involve actin network rearrangement during the acrosome reaction.","method":"Super-resolution microscopy, proximity ligation assay for CD46/integrin interaction, localization analysis during acrosome reaction","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — proximity ligation assay and super-resolution microscopy demonstrate interaction and co-localization; single lab, functional consequence of interaction is proposed but partially supported","pmids":["27666019"],"is_preprint":false},{"year":1993,"finding":"In spermatozoa, CD46 (smMCP, 43 kDa) is expressed on the inner acrosomal membrane and is N-glycosylated but not O-glycosylated; seminal plasma CD46 (ssMCP, 60 kDa) is O-glycosylated; both retain factor I cofactor activity for cleavage of C3b, blocked by cofactor-activity-blocking mAb M75; these sperm isoforms are structurally distinct from those on other cells.","method":"SDS-PAGE, immunoblotting with anti-MCP mAbs, functional factor I cofactor assays with C3ma substrate, deglycosylation analysis, immunohistochemistry","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct enzymatic cofactor activity assay on purified sperm/seminal plasma CD46 with blocking mAb validation; glycosylation characterized biochemically; single lab","pmids":["8500528"],"is_preprint":false},{"year":2018,"finding":"CD46 engagement on airway epithelial cells induces autophagy (via GOPC scaffold protein and LC3-II formation) that protects against oxidative stress-mediated apoptosis; CD46 crosslinking decreases PRO-IL-1β and NLRP3 expression; autophagy inhibitor 3-methyladenine blocked CD46-induced protection; silencing ATG5 decreased CD46-activated autophagy.","method":"CD46 mAb crosslinking in primary nasal epithelial cells, autophagosome imaging (LC3-II), GOPC expression analysis, ATG5 siRNA knockdown, caspase-3 and NLRP3 Western blotting, hydrogen peroxide-induced apoptosis model","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — CD46 crosslinking, ATG5 KD, and autophagy inhibitor experiments dissect pathway in primary epithelial cells; consistent with earlier mechanistic finding (PMID:19837375); single lab","pmids":["30154478"],"is_preprint":false},{"year":2003,"finding":"CD46 (human, expressed in transgenic mice) facilitates Neisseria meningitidis crossing of the blood-brain barrier in a pilus-dependent manner at the epithelial mucosa: CD46 transgenic mice (but not wild-type mice) were susceptible to meningococcal disease after intranasal challenge with piliated bacteria; pilus-CD46 interaction was required for mucosal entry.","method":"CD46 transgenic mice challenged with piliated and non-piliated N. meningitidis by intranasal and intraperitoneal routes, assessment of bacteremia and blood-brain barrier crossing","journal":"Science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with route-specific challenge and piliation comparison establishes in vivo pathogenic role; single study","pmids":["12869763"],"is_preprint":false}],"current_model":"CD46 (membrane cofactor protein) is a ubiquitously expressed type I transmembrane glycoprotein that (1) acts as a cofactor for serine protease factor I to proteolytically cleave and inactivate complement components C3b (via SCR3/4) and C4b deposited on host cells; (2) serves as a receptor for at least 11 pathogens—including measles virus (via SCR1/2), HHV-6 (via SCR2/3), adenoviruses (species B via fiber knob CCP2; species D via hexon), N. gonorrhoeae/meningitidis pili, BVDV, and CMV—with pathogen binding often leading to CD46 downregulation or shedding; (3) functions as a costimulatory signaling molecule on T cells, where its two cytoplasmic tail isoforms (CYT-1 and CYT-2) mediate distinct outcomes—CYT-1 links to the GOPC/VPS34/Beclin1 autophagy pathway, while CYT-2 is phosphorylated by Src/Lck kinases and interacts with SPAK to drive IL-10 production via ICER/CREM—and where CD3/CD46 co-engagement drives Th1 effector responses that switch to IL-10-producing Tr1 regulatory cells through Jagged1 as an endogenous CD46 ligand; and (4) undergoes regulated processing by metalloproteinases (MMP-9) and presenilin/γ-secretase, as well as O-glycosylation-dependent changes at the immune synapse, that modulate its T cell regulatory functions."},"narrative":{"mechanistic_narrative":"CD46 (membrane cofactor protein) is a ubiquitously expressed type I transmembrane glycoprotein that integrates innate complement regulation, pathogen entry, and adaptive T cell control [PMID:1910685, PMID:12540904]. Its extracellular region is built from short consensus repeat (SCR) domains that serve as a cofactor for serine protease factor I, driving proteolytic inactivation of C3b and C4b deposited on host cell surfaces and thereby protecting cells from complement-mediated lysis; on cell surfaces CD46 is the principal cofactor for classical-pathway C4b cleavage and restricts alternative-pathway C3b deposition [PMID:1910685, PMID:12055245]. The SCR3/SCR4 module carries the complement cofactor site, spatially distinct from the SCR1/SCR2 region that pathogens exploit [PMID:7534417]. CD46 is a receptor or entry factor for a wide range of pathogens, with distinct SCR domains assigned to each: measles virus engages SCR1/SCR2 through its hemagglutinin [PMID:7534417, PMID:7745681], HHV-6 requires SCR2/SCR3 via the gQ1/gQ2 glycoproteins [PMID:12171934, PMID:24215487], adenovirus species B binds the CCP2/SCR2 domain through the fiber knob [PMID:15919905, PMID:17898059] whereas species D binds via the hexon capsid [PMID:33384338], pathogenic Neisseria pili bind CD46 [PMID:9379894], and bovine viral diarrhea virus and cytomegalovirus also use CD46 for entry [PMID:14747544, PMID:31221976]; pathogen engagement frequently triggers CD46 downregulation or shedding, as seen with measles hemagglutinin-driven downregulation and pilus/PilT-mediated shedding [PMID:7732009, PMID:14597734]. On T cells CD46 acts as a costimulatory molecule whose two mutually exclusive cytoplasmic tail isoforms, CYT-1 and CYT-2 generated by alternative splicing, drive divergent outcomes [PMID:1601037, PMID:7692239, PMID:12055630]: CD3/CD46 co-engagement first promotes Th1 effector responses then switches CD4+ T cells to IL-10-producing regulatory (Tr1) cells [PMID:12540904, PMID:20694009], with CYT-1 linking through the GOPC scaffold to the VPS34/Beclin1 autophagy machinery [PMID:19837375] and CYT-2 being tyrosine-phosphorylated by Lck and coupling to the kinase SPAK and the ICER/CREM axis to drive the IL-10 switch [PMID:20694009, PMID:10657632]. The Notch ligand Jagged1 is an endogenous physiological CD46 ligand required for proper Th1-to-Tr1 transition [PMID:23086448]. CD46 function is further tuned by regulated processing—presenilin/γ-secretase cleaves the cytoplasmic tails, MMP-9 mediates ectodomain shedding, and TCR-induced O-glycosylation changes govern immune-synapse recruitment—linking these events to disease states including CD46 deficiency, multiple sclerosis, rheumatoid arthritis and SLE [PMID:20018629, PMID:29066539, PMID:28444759, PMID:23086448].","teleology":[{"year":1991,"claim":"Established CD46's founding innate-immune function: how host cells avoid autologous complement attack was addressed by showing CD46 is a factor I cofactor.","evidence":"Biochemical cofactor activity assays with factor I and C3b/C4b substrates","pmids":["1910685"],"confidence":"High","gaps":["Did not define which SCR domains carry the cofactor activity","Did not address surface-specific contributions versus soluble regulators"]},{"year":1993,"claim":"Answered what cellular receptor measles virus uses, defining CD46's first pathogen-receptor role through reconstitution in non-permissive cells.","evidence":"Transfection of CD46 cDNA into hamster cells with binding, syncytia, viral protein and antibody-block assays","pmids":["8402913","8371352"],"confidence":"High","gaps":["Did not map the viral or receptor binding determinant","Did not distinguish entry from cell-cell fusion thresholds"]},{"year":1995,"claim":"Resolved whether complement and viral binding sites overlap by mapping the measles determinant to SCR1/SCR2 and the complement site to SCR3/SCR4.","evidence":"Chimeric CD46/DAF mutants, SCR truncations/swaps and antibody blocking in infection assays","pmids":["7534417"],"confidence":"High","gaps":["Did not provide atomic structure of the SCR1/2-virus interface","Did not address other pathogen binding sites"]},{"year":1995,"claim":"Defined the molecular basis of measles-induced CD46 downregulation, showing it is driven by hemagglutinin engaging the CD46 ectodomain.","evidence":"Strain panel infection, recombinant MV-H expression, chimeric H/F glycoprotein swaps, co-precipitation and cell-contact assays","pmids":["7732009","7595386","7745681"],"confidence":"High","gaps":["Did not define the trafficking fate of downregulated CD46 in all cases","Did not establish signaling consequences of downregulation"]},{"year":1995,"claim":"Probed how CD46 transduces measles uptake by identifying a physical association with the cytoskeletal adaptor moesin.","evidence":"Co-immunoprecipitation, chemical cross-linking, immunoelectron microscopy and antibody inhibition","pmids":["7884872"],"confidence":"Medium","gaps":["Single lab without reciprocal validation in independent systems","Functional role of moesin in uptake only inferred from antibody block"]},{"year":1992,"claim":"Explained how one gene generates functional diversity by documenting tissue- and allele-specific alternative splicing producing CYT-1/CYT-2 tails.","evidence":"RT-PCR, Northern and Western analysis of tissue isoforms with allelic analysis","pmids":["1601037","7692239"],"confidence":"High","gaps":["Did not assign function to individual isoforms","Did not identify the trans-acting splicing factors"]},{"year":1997,"claim":"Extended CD46's pathogen-receptor repertoire to bacteria by identifying it as a pilus receptor for pathogenic Neisseria.","evidence":"Pilus binding to CD46, antibody blocking, CD46-transfected CHO cells and recombinant CD46 binding","pmids":["9379894"],"confidence":"High","gaps":["Did not map the CD46 domain contacting pili","Did not define downstream cellular response at this stage"]},{"year":1999,"claim":"Added HHV-6 to the CD46 receptor repertoire via reconstitution and inhibition approaches.","evidence":"CD46 downregulation by flow cytometry, soluble CD46/antibody neutralization, transfection of non-permissive cells","pmids":["10619434"],"confidence":"High","gaps":["Did not map binding domain or viral ligand at this stage"]},{"year":2000,"claim":"Began dissecting isoform-specific signaling by showing CYT-2, not CYT-1, is tyrosine-phosphorylated by the Src kinase Lck.","evidence":"Tail peptide phosphorylation, anti-phosphotyrosine blotting, Lck-deficient Jurkat analysis","pmids":["10657632"],"confidence":"High","gaps":["Did not connect phosphorylation to downstream effectors","Did not address CYT-1 signaling mechanism"]},{"year":2000,"claim":"Showed CD46 cytoplasmic tails are required for antiviral interferon output, linking the receptor to innate effector responses.","evidence":"Tailless CD46 mutant macrophages, IFN neutralization, nitric oxide and viral protein assays","pmids":["10627535"],"confidence":"Medium","gaps":["Single lab study in mouse macrophages","Did not resolve which tail isoform drives the effect"]},{"year":2000,"claim":"Identified CD46 membrane partnerships with β1 integrins and tetraspanins, raising the possibility of supramolecular receptor complexes.","evidence":"Reciprocal Co-IP and cross-linking on living cells with anti-integrin panel","pmids":["10741407"],"confidence":"Medium","gaps":["Molecular mechanism of the association unresolved","Complexes did not modify MV fusion entry"]},{"year":2002,"claim":"Assigned distinct in vivo immune functions to the two tail isoforms, establishing CYT-1 versus CYT-2 as opposing inflammatory regulators.","evidence":"Isoform-specific transgenic mice, contact hypersensitivity, proliferation, cytotoxicity, cytokine and Vav phosphorylation assays","pmids":["12055630"],"confidence":"High","gaps":["Mouse transgenic context may not fully recapitulate human CD46 signaling","Did not define molecular effectors of each tail"]},{"year":2002,"claim":"Refined CD46's complement role by showing it is the principal surface cofactor for C4b cleavage and restrains alternative-pathway C3b deposition.","evidence":"Complement fragment deposition on MCP-transfected cells with function-blocking antibodies under pathway-specific conditions","pmids":["12055245"],"confidence":"High","gaps":["Did not address tissue-specific differences in cofactor balance"]},{"year":2002,"claim":"Distinguished HHV-6 from measles receptor usage by mapping HHV-6 to SCR2/SCR3 versus SCR1/SCR2 for measles.","evidence":"Quantitative cell-fusion assay with CD46 truncations, DAF chimeras, isoform variants and SCR-specific antibodies","pmids":["12171934"],"confidence":"High","gaps":["Did not provide structural detail of the HHV-6-CD46 interface"]},{"year":2003,"claim":"Discovered CD46's role in adaptive tolerance, showing CD3/CD46 co-engagement drives an IL-10-producing Tr1 regulatory phenotype.","evidence":"CD3/CD46 costimulation of primary human CD4+ T cells with cytokine and bystander suppression assays","pmids":["12540904"],"confidence":"High","gaps":["Did not identify the endogenous CD46 ligand","Did not define the signaling effectors of the switch"]},{"year":2003,"claim":"Mapped adenovirus species B usage of CD46 as a primary attachment receptor and established mechanisms of bacterial-induced downregulation and in vivo pathogenesis.","evidence":"CD46-transfected CHO cells, fiber knob/antibody competition for Ad11; PilT-mutant Neisseria shedding analysis and human infection isolates; CD46 transgenic mouse meningococcal challenge","pmids":["12915534","14597734","12869763"],"confidence":"High","gaps":["Transgenic mouse pathogenesis is a single study","Did not resolve the protease responsible for pilus-mediated shedding"]},{"year":2004,"claim":"Established a receptor-density threshold governing measles-induced fusion, explaining tumor-selective syncytia formation.","evidence":"Engineered cell lines spanning CD46 densities with quantitative viral marker and fusion readouts","pmids":["15256464"],"confidence":"High","gaps":["Did not define the molecular basis of the threshold"]},{"year":2004,"claim":"Extended CD46 receptor function across species by identifying bovine CD46 as a BVDV receptor.","evidence":"Immunoaffinity purification, cDNA cloning, expression in porcine cells and susceptibility assays","pmids":["14747544"],"confidence":"Medium","gaps":["Bovine CD46 did not fully confer permissiveness to all non-permissive cells","Single lab study"]},{"year":2007,"claim":"Provided structural and quantitative detail of adenovirus-CD46 binding, mapping the fiber knob residues and stoichiometry.","evidence":"Random knob mutagenesis, surface plasmon resonance, X-ray crystallography at 2-Å and modeling; combined with earlier CCP2 point-mutant mapping","pmids":["17898059","15919905"],"confidence":"High","gaps":["Structure of the full virion-CD46 complex for species B not resolved here"]},{"year":2009,"claim":"Defined the CYT-1 effector pathway, linking it to autophagy via the GOPC scaffold and VPS34/Beclin1 complex.","evidence":"Reciprocal Co-IP of CD46-Cyt-1 with GOPC, VPS34/Beclin1 interaction, isoform-specific autophagy assays with MV and group A Streptococcus; cTreg/B cell co-culture with CD46-deficient patient cells","pmids":["19837375","19784949"],"confidence":"High","gaps":["Did not fully resolve how autophagy feeds into the cytokine switch","B cell help mechanism characterized in single lab"]},{"year":2009,"claim":"Showed CD46 tails are released by presenilin/γ-secretase, implicating regulated intramembrane proteolysis and pilus-driven mechanotransduction.","evidence":"Immunoprecipitation of cleaved tail peptides, γ-secretase inhibitors, dominant-negative presenilin, type IV pili/PilT bacterial mutants","pmids":["20018629"],"confidence":"High","gaps":["Fate and signaling role of released tail peptides not fully defined","Mechanotransduction model partly inferred"]},{"year":2010,"claim":"Resolved how the Th1-to-regulatory switch is wired, identifying CD46 tail engagement of SPAK and the ICER/CREM axis to attenuate IL-2 and induce IL-10.","evidence":"Isoform-specific stimulation, ICER/CREM reporters, SPAK interaction, cytokine assays in CD4+ and γδ T cells, and rheumatoid arthritis patient cells","pmids":["20694009"],"confidence":"High","gaps":["Did not identify the upstream physiological CD46 ligand at this stage","Mechanism of IL-2-timed switching not fully resolved"]},{"year":2012,"claim":"Identified Jagged1 as the endogenous CD46 ligand and connected CD46 to Notch signaling required for proper Th1/IL-10 responses.","evidence":"Jagged1-CD46 binding and blocking, T cell stimulation, CD46-deficient and Alagille syndrome patient T cell analysis","pmids":["23086448"],"confidence":"High","gaps":["Structural basis of the CD46-Jagged1 interaction not defined","Did not resolve the bidirectional signaling stoichiometry"]},{"year":2014,"claim":"Mapped the viral determinant of HHV-6A CD46 binding to the gQ1/gQ2 glycoproteins within the gH/gL/gQ1/gQ2 complex.","evidence":"Chimeric HHV-6A/B glycoprotein swaps, complex Co-IP and CD46 binding assays","pmids":["24215487"],"confidence":"Medium","gaps":["Single lab subunit-swap study without structural confirmation"]},{"year":2016,"claim":"Elucidated the splicing regulatory logic generating CD46 isoforms and demonstrated antisense control of exon 13 inclusion.","evidence":"Minigene assays, siRNA of PTBP1/TIAL1/SRSF1, U1 snRNA base-pairing analysis, antisense oligonucleotide manipulation","pmids":["27226545"],"confidence":"High","gaps":["Did not link splicing factor activity to physiological cell-state cues","Single lab"]},{"year":2016,"claim":"Connected CD46 costimulation to T cell metabolism through miR-150 downregulation of the glucose transporter SLC2A1.","evidence":"miRNA profiling, CD46 blockade, miR-150 knockdown and SLC2A1 target validation in CD4+ T cells","pmids":["26746193"],"confidence":"Medium","gaps":["Single lab","Causal contribution of glucose uptake to the cytokine switch only partially dissected"]},{"year":2016,"claim":"Implicated CD46 in reproduction by characterizing its acrosomal localization, integrin partnership, and sperm-specific cofactor activity.","evidence":"Super-resolution microscopy and proximity ligation during acrosome reaction; biochemical cofactor assays on sperm/seminal isoforms with blocking mAb","pmids":["27666019","8500528"],"confidence":"Medium","gaps":["Functional consequence of CD46-integrin interaction only proposed","Single lab studies"]},{"year":2017,"claim":"Revealed post-translational tuning of CD46 signaling through TCR-induced O-glycosylation changes and immune-synapse recruitment, with disease relevance in MS.","evidence":"Mass-shift assays with O-glycosylation inhibitors, immune synapse imaging, STP-region mutants, cytokine assays and MS patient T cells","pmids":["29066539"],"confidence":"Medium","gaps":["Single lab","Molecular link between glycosylation state and processing only partly defined"]},{"year":2017,"claim":"Linked dysregulated MMP-9 shedding of CD46 to defective Th1 contraction in SLE, tying ectodomain proteolysis to autoimmune dysfunction.","evidence":"Soluble CD46 measurement, MMP-9 inhibitor rescue of Th1 contraction in SLE versus healthy donor T cells","pmids":["28444759"],"confidence":"Medium","gaps":["Single lab patient-cell study","Did not establish MMP-9 as the sole sheddase"]},{"year":2018,"claim":"Generalized the CD46-autophagy axis beyond T cells, showing GOPC-dependent autophagy in airway epithelium protects against oxidative apoptosis and dampens NLRP3.","evidence":"CD46 crosslinking in primary nasal epithelial cells, LC3-II imaging, ATG5 siRNA, 3-MA inhibition, caspase-3/NLRP3 blotting","pmids":["30154478"],"confidence":"Medium","gaps":["Single lab","Did not define the epithelial CD46 ligand"]},{"year":2019,"claim":"Extended CD46 receptor function to cytomegalovirus in a cell-type-specific manner relevant to epithelial and placental infection.","evidence":"Antibody inhibition screen, CRISPR CD46-KO epithelial cells, infection assays in trophoblasts versus fibroblasts","pmids":["31221976"],"confidence":"High","gaps":["Viral ligand for CD46 not identified","Mechanism of cell-type specificity unresolved"]},{"year":2021,"claim":"Showed adenovirus species D uses a different CD46 contact than species B, binding through the hexon capsid rather than the fiber knob.","evidence":"Receptor screening, CD46 KO/overexpression cells, soluble CD46 competition, SPR and cryo-EM of the HAdV-D56 virion-CD46 complex","pmids":["33384338"],"confidence":"High","gaps":["Did not define which CD46 SCR domain contacts hexon"]},{"year":null,"claim":"How the competing roles of CD46 (complement cofactor, multi-pathogen receptor, and T cell signaling hub) are coordinated on a single cell, and how isoform choice, glycosylation, and proteolysis are integrated by physiological cues, remain unresolved.","evidence":"No single study in the timeline reconciles these parallel functions","pmids":[],"confidence":"Low","gaps":["No unified structural model of CD46 multi-ligand engagement","Upstream regulators selecting isoform and processing fate in vivo are undefined","Quantitative interplay between complement regulation and receptor functions on the same membrane is uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[0,3,4,5,16,23,34]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,12,36]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[6,9,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,14]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4,20,26]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[8,19]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[6,9,11,13]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,3,4,5,23,34]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[8,37]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[7,32]}],"complexes":["VPS34/Beclin1 autophagy complex (via GOPC)","CD46/β1-integrin/tetraspanin surface complex"],"partners":["GOPC","SPAK","LCK","JAG1","MOESIN","ITGB1","ITGA3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P15529","full_name":"Membrane cofactor protein","aliases":["TLX","Trophoblast leukocyte common antigen"],"length_aa":392,"mass_kda":43.7,"function":"Acts as a cofactor for complement factor I, a serine protease which protects autologous cells against complement-mediated injury by cleaving C3b and C4b deposited on host tissue. May be involved in the fusion of the spermatozoa with the oocyte during fertilization. Also acts as a costimulatory factor for T-cells which induces the differentiation of CD4+ into T-regulatory 1 cells. T-regulatory 1 cells suppress immune responses by secreting interleukin-10, and therefore are thought to prevent autoimmunity (Microbial infection) A number of viral and bacterial pathogens seem to bind MCP in order to exploit its immune regulation property and directly induce an immunosuppressive phenotype in T-cells (Microbial infection) Acts as a receptor for Adenovirus subgroup B2 and Ad3 (Microbial infection) Acts as a receptor for cultured Measles virus (Microbial infection) Acts as a receptor for Herpesvirus 6/HHV-6 (Microbial infection) May act as a receptor for pathogenic bacteria Neisseria and Streptococcus pyogenes (PubMed:11260136, PubMed:11971006, PubMed:7708671, PubMed:9379894)","subcellular_location":"Cytoplasmic vesicle, secretory vesicle, acrosome inner membrane","url":"https://www.uniprot.org/uniprotkb/P15529/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CD46","classification":"Not Classified","n_dependent_lines":35,"n_total_lines":1208,"dependency_fraction":0.028973509933774833},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/CD46","total_profiled":1310},"omim":[{"mim_id":"613975","title":"INTERFERON-INDUCED PROTEIN 44-LIKE; IFI44L","url":"https://www.omim.org/entry/613975"},{"mim_id":"612922","title":"HEMOLYTIC UREMIC SYNDROME, ATYPICAL, SUSCEPTIBILITY TO, 2; AHUS2","url":"https://www.omim.org/entry/612922"},{"mim_id":"603492","title":"SLAM FAMILY, MEMBER 1; SLAMF1","url":"https://www.omim.org/entry/603492"},{"mim_id":"125671","title":"DESMOGLEIN 2; DSG2","url":"https://www.omim.org/entry/125671"},{"mim_id":"124092","title":"INTERLEUKIN 10; IL10","url":"https://www.omim.org/entry/124092"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CD46"},"hgnc":{"alias_symbol":["TRA2.10","MGC26544","TLX"],"prev_symbol":["MIC10","MCP"]},"alphafold":{"accession":"P15529","domains":[{"cath_id":"2.10.70.10","chopping":"34-97","consensus_level":"high","plddt":94.5358,"start":34,"end":97},{"cath_id":"2.10.70.10","chopping":"109-160","consensus_level":"high","plddt":95.386,"start":109,"end":160},{"cath_id":"2.10.70.10","chopping":"162-226","consensus_level":"high","plddt":96.0598,"start":162,"end":226},{"cath_id":"2.10.70.10","chopping":"228-286","consensus_level":"high","plddt":96.8436,"start":228,"end":286}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15529","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15529-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15529-F1-predicted_aligned_error_v6.png","plddt_mean":82.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CD46","jax_strain_url":"https://www.jax.org/strain/search?query=CD46"},"sequence":{"accession":"P15529","fasta_url":"https://rest.uniprot.org/uniprotkb/P15529.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15529/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15529"}},"corpus_meta":[{"pmid":"8402913","id":"PMC_8402913","title":"The human CD46 molecule is a receptor for measles virus (Edmonston strain).","date":"1993","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8402913","citation_count":878,"is_preprint":false},{"pmid":"8371352","id":"PMC_8371352","title":"Human membrane cofactor protein (CD46) acts as a cellular receptor for measles virus.","date":"1993","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/8371352","citation_count":739,"is_preprint":false},{"pmid":"1910685","id":"PMC_1910685","title":"Membrane cofactor protein (MCP or CD46): newest member of the regulators of complement activation gene cluster.","date":"1991","source":"Annual review of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/1910685","citation_count":518,"is_preprint":false},{"pmid":"12540904","id":"PMC_12540904","title":"Activation of human CD4+ cells with CD3 and CD46 induces a T-regulatory cell 1 phenotype.","date":"2003","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12540904","citation_count":451,"is_preprint":false},{"pmid":"10619434","id":"PMC_10619434","title":"CD46 is a cellular receptor for human herpesvirus 6.","date":"1999","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/10619434","citation_count":383,"is_preprint":false},{"pmid":"12915534","id":"PMC_12915534","title":"Adenovirus type 11 uses CD46 as a cellular receptor.","date":"2003","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/12915534","citation_count":289,"is_preprint":false},{"pmid":"15256464","id":"PMC_15256464","title":"High CD46 receptor density determines preferential killing of tumor cells by oncolytic measles virus.","date":"2004","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/15256464","citation_count":270,"is_preprint":false},{"pmid":"9379894","id":"PMC_9379894","title":"Membrane cofactor protein (MCP or CD46) is a cellular pilus receptor for pathogenic Neisseria.","date":"1997","source":"Molecular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/9379894","citation_count":263,"is_preprint":false},{"pmid":"20694009","id":"PMC_20694009","title":"Complement regulator CD46 temporally regulates cytokine production by conventional and unconventional T cells.","date":"2010","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/20694009","citation_count":240,"is_preprint":false},{"pmid":"17099776","id":"PMC_17099776","title":"Alterations in CD46-mediated Tr1 regulatory T cells in patients with multiple sclerosis.","date":"2006","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/17099776","citation_count":232,"is_preprint":false},{"pmid":"19837375","id":"PMC_19837375","title":"Autophagy induction by the pathogen receptor CD46.","date":"2009","source":"Cell host & microbe","url":"https://pubmed.ncbi.nlm.nih.gov/19837375","citation_count":215,"is_preprint":false},{"pmid":"11520782","id":"PMC_11520782","title":"Expression of complement inhibitors CD46, CD55, and CD59 on tumor cells does not predict clinical outcome after rituximab treatment in follicular non-Hodgkin lymphoma.","date":"2001","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/11520782","citation_count":173,"is_preprint":false},{"pmid":"23086448","id":"PMC_23086448","title":"The CD46-Jagged1 interaction is critical for human TH1 immunity.","date":"2012","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/23086448","citation_count":149,"is_preprint":false},{"pmid":"12055630","id":"PMC_12055630","title":"Linking innate and acquired immunity: divergent role of CD46 cytoplasmic domains in T cell induced inflammation.","date":"2002","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12055630","citation_count":145,"is_preprint":false},{"pmid":"7732009","id":"PMC_7732009","title":"Receptor usage and differential downregulation of CD46 by measles virus wild-type and vaccine strains.","date":"1995","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/7732009","citation_count":131,"is_preprint":false},{"pmid":"12869763","id":"PMC_12869763","title":"CD46 in meningococcal disease.","date":"2003","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/12869763","citation_count":126,"is_preprint":false},{"pmid":"12055245","id":"PMC_12055245","title":"Role of membrane cofactor protein (CD46) in regulation of C4b and C3b deposited on cells.","date":"2002","source":"Journal of immunology (Baltimore, Md. : 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(membrane cofactor protein) functions as the cellular receptor for measles virus (Edmonston strain): hamster cells expressing human CD46 gained the ability to bind measles virus, form syncytia, and produce viral proteins; polyclonal antisera against CD46 blocked virus binding and infection.\",\n      \"method\": \"Somatic cell hybrid mapping, transfection of CD46 cDNA into non-permissive hamster cells, virus binding and infection assays, antibody inhibition\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in heterologous cells with multiple orthogonal assays (binding, syncytia, viral protein production, antibody block), independently replicated in a second paper (PMID:8371352)\",\n      \"pmids\": [\"8402913\", \"8371352\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"CD46 acts as a cofactor for the serine protease factor I to mediate proteolytic cleavage (inactivation) of complement components C3b and C4b deposited on host cells, thereby protecting cells from complement-mediated lysis.\",\n      \"method\": \"Biochemical purification, functional cofactor activity assays with factor I and C3b/C4b substrates\",\n      \"journal\": \"Annual review of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzymatic cofactor activity established by direct in vitro biochemical assay, replicated across multiple studies in the corpus\",\n      \"pmids\": [\"1910685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The measles virus receptor determinant on CD46 maps to SCR1 and SCR2 (short consensus repeat domains 1 and 2) of the extracellular region; monoclonal antibodies against SCR1 or SCR2 blocked MV infection, whereas the C3b/C4b binding site maps to SCR3 and SCR4, demonstrating that the MV and complement binding sites are distinct.\",\n      \"method\": \"Chimeric CD46/DAF mutants, SCR domain truncations and swaps, GPI-anchored CD46 ectodomain constructs, monoclonal antibody blocking, cell infection assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — structure-function mutagenesis with multiple chimeras and domain swaps, confirmed by antibody competition, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"7534417\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CD46 serves as a cellular receptor for human herpesvirus 6 (HHV-6, both subgroups A and B): HHV-6 infection downregulates surface CD46; anti-CD46 monoclonal antibody and soluble CD46 inhibit cell fusion and entry; non-human cells became susceptible to HHV-6 upon expression of recombinant human CD46.\",\n      \"method\": \"Flow cytometry for CD46 downregulation, neutralization with anti-CD46 mAb and soluble CD46, transfection of CD46 into non-permissive cells, infection and fusion assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in heterologous cells plus multiple inhibition approaches (antibody, soluble receptor), single rigorous paper with orthogonal methods\",\n      \"pmids\": [\"10619434\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CD46 is a pilus receptor for pathogenic Neisseria (N. gonorrhoeae and N. meningitidis): purified pili bound a 55-60 kDa doublet consistent with CD46; anti-CD46 antibodies blocked bacterial attachment; piliated gonococci bound CHO cells transfected with CD46 cDNA but not non-transfected cells; recombinant CD46 protein directly bound piliated Neisseria and inhibited attachment.\",\n      \"method\": \"SDS-PAGE binding assays, antibody blocking, transfection of CD46 cDNA into CHO cells, direct binding with recombinant CD46, competition inhibition\",\n      \"journal\": \"Molecular microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in heterologous CHO cells plus direct protein-protein interaction with recombinant CD46, multiple orthogonal methods in one study\",\n      \"pmids\": [\"9379894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Adenovirus type 11 (species B) uses CD46 as a primary cellular attachment receptor: Ad11 bound CD46-transfected CHO cells ~10× more than CAR- or CD55-transfected cells; CD46 cDNA transfection rendered non-permissive CHO cells permissive to Ad11 infection; soluble Ad11 fiber knob and anti-CD46 antibodies inhibited Ad11 binding and infection.\",\n      \"method\": \"Transfection of CD46 cDNA into CHO cells, virus binding assays, soluble fiber knob competition, antibody inhibition of binding and infection\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in heterologous cells with multiple orthogonal inhibition experiments, single rigorous paper\",\n      \"pmids\": [\"12915534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Co-engagement of CD3 and CD46 on human CD4+ T cells in the presence of IL-2 induces a T regulatory 1 (Tr1) cytokine phenotype, with strong IL-10 production, suppression of bystander T cells, and acquisition of a memory phenotype.\",\n      \"method\": \"CD3/CD46 co-stimulation of primary human CD4+ T cells, cytokine measurement (IL-10, IFN-γ), bystander suppression assays, phenotypic characterization\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean primary human cell KD/stimulation with defined cytokine phenotype, replicated in multiple subsequent studies, original paper in Nature with comprehensive assays\",\n      \"pmids\": [\"12540904\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1992,\n      \"finding\": \"CD46 protein isoform expression is controlled by alternative splicing: differential splicing of 5 exons (including STP-rich exons 7, 8, 9 and cytoplasmic tail exons 13/14) generates at least 14 mRNA variants in a tissue-specific, allele-specific, and malignancy-related manner; cytoplasmic tail CYT-1 (exon 13) or CYT-2 (exon 14) arise from mutually exclusive splicing.\",\n      \"method\": \"RT-PCR, Northern blotting, SDS-PAGE/Western blotting of tissue-specific isoforms, allelic analysis\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal RNA and protein methods across many tissues, replicated in subsequent studies (PMID:7692239)\",\n      \"pmids\": [\"1601037\", \"7692239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Engagement of CD46 (specifically the CD46-Cyt-1 isoform) induces autophagy through its interaction with the scaffold protein GOPC, which links CD46-Cyt-1 to the autophagosome formation complex VPS34/Beclin1; measles virus and group A Streptococcus induce autophagy through this CD46-Cyt-1/GOPC pathway.\",\n      \"method\": \"Co-immunoprecipitation of CD46-Cyt-1 with GOPC, VPS34/Beclin1 interaction assays, autophagy induction assays (LC3 formation), isoform-specific constructs, infection with MV and GAS\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP identifying GOPC as bridging partner, isoform-specific functional assays, multiple pathogen validations in one rigorous study\",\n      \"pmids\": [\"19837375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"CD46 engagement on CD4+ T cells promotes Th1 effector function; as IL-2 accumulates, CD46 switches cells to a regulatory phenotype by attenuating IL-2 production via the transcriptional regulator ICER/CREM and upregulating IL-10 through interaction of the CD46 cytoplasmic tail with the serine-threonine kinase SPAK; the CD46 tail isoform expressed determines the regulatory outcome.\",\n      \"method\": \"CD46 tail isoform-specific stimulation, ICER/CREM reporter assays, SPAK interaction assays, cytokine measurement in CD4+ T cells and γδ T cells, analysis of rheumatoid arthritis patient cells\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — interaction of CD46 tail with SPAK identified, ICER/CREM pathway defined, isoform-specific functional differences demonstrated, disease-relevant patient validation\",\n      \"pmids\": [\"20694009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The CYT-2 cytoplasmic tail of CD46, but not CYT-1, is phosphorylated on tyrosine by the Src kinase Lck; a CYT-2 peptide is phosphorylated by a src kinase system, and Lck is required for CYT-2 phosphorylation in the Jurkat T cell line.\",\n      \"method\": \"CD46 tail peptide phosphorylation assays, Western blotting with anti-phosphotyrosine antibodies, cross-linking of CD46 on cell lines and isoform transfectants, genetic and biochemical src kinase inhibition/knockout analysis\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro phosphorylation with peptides plus cell-based assays with genetic (Lck-deficient) and biochemical evidence, multiple orthogonal methods\",\n      \"pmids\": [\"10657632\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"The two CD46 cytoplasmic tail isoforms (CD46-1/CYT-1 and CD46-2/CYT-2) have divergent functions in T cell-mediated inflammation: CD46-1 engagement inhibits the contact hypersensitivity reaction while CD46-2 increases it; the isoforms differentially affect CD8+ T cell cytotoxicity, CD4+ T cell proliferation, IL-2 and IL-10 production, and tyrosine phosphorylation of Vav.\",\n      \"method\": \"CD46 isoform-specific transgenic mice, contact hypersensitivity assays, T cell proliferation and cytotoxicity assays, cytokine measurement, Vav phosphorylation analysis\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgenic mouse model with two isoforms compared in multiple functional immune assays, multiple orthogonal readouts\",\n      \"pmids\": [\"12055630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In classical pathway activation, CD46 (not soluble C4BP) is primarily responsible for C4b cleavage on cell surfaces (cofactor activity), generating C4c and C4d; factor H is primarily responsible for C3b cleavage; in alternative pathway activation, CD46's cofactor activity is sufficient to restrict C3b deposition.\",\n      \"method\": \"FACS and Western blotting of complement fragment deposition on MCP-transfected vs MCP-negative cells, function-blocking anti-CD46 and anti-factor H mAbs, serum with Mg2+-EGTA to isolate alternative pathway\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct biochemical analysis on transfected cells with functional blocking antibodies, pathway-specific conditions, multiple complement fragments tracked\",\n      \"pmids\": [\"12055245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The Notch family member Jagged1 is an endogenous physiological ligand for CD46; CD46 regulates Notch receptor and ligand expression during T cell activation; disruption of CD46-Notch crosstalk impedes IFN-γ induction and switching to IL-10; CD4+ T cells from CD46-deficient patients and Alagille syndrome (Jagged1 hypomorphic mutation) patients fail to mount appropriate Th1 responses.\",\n      \"method\": \"Jagged1-CD46 binding assays, T cell stimulation with CD46/Jagged1 blocking, analysis of CD46-deficient patient T cells, Alagille syndrome patient T cells, cytokine measurement\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ligand identification confirmed by binding studies, pathway validated with genetic patient material (CD46-deficient, Alagille syndrome), multiple orthogonal approaches\",\n      \"pmids\": [\"23086448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD46 and moesin physically interact in a receptor complex on the cell surface: chemical cross-linking showed close proximity of CD46 and moesin; co-immunoprecipitation confirmed physical interaction; both proteins co-localize at sites of MV particle adsorption by immunoelectron microscopy; antibodies to moesin inhibited MV infection of CD46-negative mouse cell lines, suggesting moesin contributes to MV uptake.\",\n      \"method\": \"Co-immunoprecipitation, chemical cross-linking of cell surface proteins, antibody inhibition of MV binding and infection, immunoelectron microscopy co-localization\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-immunoprecipitation and cross-linking support physical interaction; single lab but multiple methods including ultrastructural localization\",\n      \"pmids\": [\"7884872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD46 downregulation by measles virus is specifically caused by interaction with newly synthesized MV hemagglutinin (MV-H) protein: recombinant MV-H proteins of strains Edmonston, Halle, and CM cause CD46 downregulation, while those of lymphotropic wild-type strains DL and WTF do not; cell-to-cell contact involving MV-H is sufficient to trigger CD46 downregulation on uninfected bystander cells.\",\n      \"method\": \"Flow cytometry for CD46 surface expression after infection with 19 MV strains, recombinant MV-H protein expression, antibody inhibition, cell-to-cell contact assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — strain panel plus recombinant hemagglutinin expression definitively identifies MV-H as driver of CD46 downregulation, replicated by multiple subsequent studies\",\n      \"pmids\": [\"7732009\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD46 is a cellular receptor for bovine viral diarrhea virus (BVDV): a blocking MAb to bovine CD46 (50-58 kDa) prevented BVDV infection; the cDNA of bovine CD46 was cloned; expression of bovine CD46 correlated with BVDV binding and significantly increased susceptibility of porcine cells to BVDV infection.\",\n      \"method\": \"Immunoaffinity purification and microchemical analysis of receptor, cDNA cloning, BVDV binding assays, transient expression in porcine cells, susceptibility assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — heterologous expression in porcine cells showed enhanced susceptibility; bovine CD46 did not fully confer permissiveness to all non-permissive cells, reducing confidence; single lab study\",\n      \"pmids\": [\"14747544\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"HHV-6 and measles virus employ distinct CD46 domains for receptor function: HHV-6 requires SCR2 and SCR3 with no requirement for SCR1 or SCR4; measles virus requires SCR1 and SCR2; all four CD46 isoforms support HHV-6 receptor activity, indicating critical HHV-6 binding determinants are outside the C-terminal variable domains.\",\n      \"method\": \"Quantitative cell fusion assay with CD46 truncations, chimeras with DAF (decay-accelerating factor), isoform variants, and SCR-specific monoclonal antibodies\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — structure-function analysis using multiple engineered CD46 variants (truncations, chimeras, isoforms) with quantitative fusion assay, single lab but multiple orthogonal constructs\",\n      \"pmids\": [\"12171934\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD46 downregulation by piliated N. gonorrhoeae occurs via pilus-mediated shedding of CD46 into the supernatant; downregulation requires the pilus retraction protein PilT; gonococci lacking PilT did not downregulate CD46; the effect is not due to global protein synthesis shutdown or intracellular retention.\",\n      \"method\": \"Flow cytometry for surface CD46 expression, Western blotting of supernatants for shed CD46, RT-PCR for mRNA levels, PilT mutant bacteria, clinical isolate reisolation after experimental human infection\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — PilT genetic requirement established, shedding mechanism characterized, mechanism validated in an experimental human infection model with recovered isolates\",\n      \"pmids\": [\"14597734\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Presenilin/gamma-secretase (PS/γS) cleaves CD46-Cyt-1 and CD46-Cyt-2 intracellular tails, releasing immunoprecipitable cytoplasmic tail peptides into the cell; PS/γS processing is blocked by chemical inhibitors and prevented in dominant-negative presenilin mutant cell lines; Neisseria gonorrhoeae and N. meningitidis stimulate PS/γS processing of CD46 in a manner requiring type IV pili and the pilus retraction motor PilT, implicating mechanotransduction.\",\n      \"method\": \"Immunoprecipitation of cleaved tail peptides, PS/γS chemical inhibitors, dominant-negative presenilin cell lines, bacterial mutant analysis (type IV pili, PilT), Western blotting\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — enzymatic cleavage confirmed by detection of tail peptides, validated with genetic (dominant-negative) and pharmacological inhibition, bacterial mutants identify mechanotransduction requirement\",\n      \"pmids\": [\"20018629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CD46 associates with multiple β1 integrins (α1β1, α2β1, α3β1, α5β1, α6β1) and tetraspanins on the cell surface; cross-linking experiments in living cells confirmed the existence of CD46/integrin complexes; CD46 does not associate with β4 integrins; CD46/integrin complexes do not modify MV fusion entry.\",\n      \"method\": \"Co-immunoprecipitation with anti-CD46 mAb, cross-linking experiments on living cells, panel of anti-integrin antibodies\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — reciprocal Co-IP and cross-linking in living cells support the association, but molecular mechanism of the interaction was not further resolved; negative finding on MV fusion noted\",\n      \"pmids\": [\"10741407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"The CCP2 (SCR2) domain of CD46 is critical for adenovirus serotype 35 (Ad35) and Ad11 binding; substitution of amino acids at positions 130-135 or 152-156 of CD46 completely abolishes Ad35 receptor function; Ad35 competes with measles virus for CD46 binding but not with complement C3b; N-glycosylations of CD46 do not critically contribute to Ad35 infection.\",\n      \"method\": \"Competition experiments with known CD46 ligands (MV, C3b), CD46 point mutants, antibody blocking, Ad35 fiber-containing vector infection assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis with multiple point mutations mapping the binding domain, competition assays with structurally defined CD46 ligands, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"15919905\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Four residues in the Ad35 fiber knob (Phe242, Arg279, Ser282, Glu302) are critical for CD46 binding; mutation of these residues ablates CD46 binding without affecting knob trimerization; the Ad35 knob binds three CD46 molecules with KD = 15.5 nM; crystal structure of Ad35 knob at 2-Å resolution modeled with existing Ad11-CD46 structure indicates one CD46 molecule binds between two knob monomers.\",\n      \"method\": \"Random mutagenesis library of Ad35 knob screened for CD46 binding, surface plasmon resonance, competition binding, X-ray crystallography of Ad35 knob at 2-Å resolution, structural modeling\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure plus mutagenesis plus SPR quantitative binding analysis in one study, multiple orthogonal methods\",\n      \"pmids\": [\"17898059\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Human adenovirus species D (HAdV-D) types use CD46 as a receptor through the hexon capsid protein, not the fiber knob: soluble hexon (but not fiber knob) inhibited HAdV-D56 infection; SPR showed CD46 binds HAdV-D hexon but not fiber knob; cryo-EM of the HAdV-D56 virion-CD46 complex confirmed CD46 binding to the central cavity of hexon trimers; 16/17 HAdV-D types were inhibited by soluble CD46.\",\n      \"method\": \"Cell-based receptor screening assay, CD46 KO and overexpressing cells, competition with soluble CD46, surface plasmon resonance, cryo-EM of virion-CD46 complex\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structural confirmation plus SPR quantitative binding plus genetic KO validation plus soluble competition, single rigorous paper with multiple orthogonal high-tier methods\",\n      \"pmids\": [\"33384338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"CD46 downregulation is mediated specifically by interaction between the extracellular domains of CD46 and MV hemagglutinin, occurring on the same cell membrane and through cell-to-cell contact; CD46 downregulation was reversible, restricted to CD46 (not other surface markers), and not mediated through PKA or PKC-dependent pathways.\",\n      \"method\": \"FACS analysis of CD46 surface expression after contact of Jurkat cells with L cells expressing MV-H, antibody blocking with anti-CD46 and anti-H antibodies, PKA/PKC inhibitor treatment\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean cell-contact assay with specific antibody inhibition identifying extracellular domain interaction; PKA/PKC independence established by pharmacological inhibition; single lab\",\n      \"pmids\": [\"7595386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The CD46 cytoplasmic domains are required for CD46-mediated enhancement of IFN-α/β production in mouse macrophages in response to measles virus; mouse macrophages expressing a tailless CD46 mutant lacking cytoplasmic domains showed much lower IFN-α/β and nitric oxide production and were highly susceptible to MV; IFN-α/β synergizes with IFN-γ to restrict viral replication.\",\n      \"method\": \"CD46 mutant (tailless) transfection into mouse macrophages, antibody neutralization of IFN-α/β, nitric oxide measurement, viral protein synthesis assays, conditioned medium transfer experiments\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct domain-deletion mutagenesis with multiple functional readouts; single lab study\",\n      \"pmids\": [\"10627535\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"CD46 receptor density determines the threshold for measles virus-induced cell-cell fusion: virus entry increases progressively with CD46 density, but intercellular fusion is minimal at low densities and increases dramatically above a threshold density; tumor cells express high CD46 densities (above threshold) leading to extensive syncytia, while normal cells express low densities resulting in infection without significant fusion.\",\n      \"method\": \"Engineered cell lines expressing a range of CD46 densities, quantitative readout of viral gene expression via virally encoded soluble marker peptide, fusion assays at different CD46 receptor densities\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dose-response of CD46 density vs. fusion established with engineered cell lines spanning a range of densities, mechanistic threshold identified, single rigorous study\",\n      \"pmids\": [\"15256464\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Measles virus hemagglutinin (MV-H), but not the fusion protein (MV-F), determines CD46-dependent fusion specificity: cells expressing HMV + FCDV fused CD46-dependently (like MV); cells expressing HCDV + FMV fused CD46-independently (like CDV); CD46 co-immunoprecipitated with HMV but not with FMV or CDV glycoproteins.\",\n      \"method\": \"Recombinant vaccinia virus expressing chimeric MV/CDV glycoproteins, quantitative reporter gene fusion assay, syncytium formation, flow cytometry and antibody co-precipitation of CD46 with H/F glycoproteins\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — chimeric glycoprotein swap (MV/CDV) plus co-precipitation definitively assigns CD46 binding to H protein; multiple orthogonal methods in single study\",\n      \"pmids\": [\"7745681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD46 costimulation of CD4+ T cells leads to downregulation of miR-150, which targets the glucose transporter 1 encoding transcript SLC2A1, connecting CD46 signaling to glucose uptake regulation; CD46 costimulation induces larger miRNA expression changes than CD28; autocrine CD46 signaling operates downstream of CD28; increased miR-150 in IL-10-secreting (switched) Th1 cells contributes to IL-10 production.\",\n      \"method\": \"miRNA expression profiling in CD46-costimulated CD4+ T cells, CD46 blockade, miR-150 knockdown, SLC2A1 target validation, cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — miR-150 target SLC2A1 validated, miR-150 knockdown tested for cytokine output, autocrine CD46/CD28 crosstalk demonstrated; single lab\",\n      \"pmids\": [\"26746193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TCR/CD3 stimulation of CD4+ T cells induces a reduction in apparent molecular mass of CD46 dependent on O-glycosylation; CD3-stimulated changes in CD46 O-glycosylation status reduce CD46 processing and T cell signaling; CD46 is recruited to the immune synapse in a manner requiring its STP (serine-threonine-proline-rich) region; immune synapse recruitment of CD46 switches T cells from IFN-γ to IL-10 production; CD4+ T cells from MS patients show increased surface CD46 without the CD3-stimulated mass shift.\",\n      \"method\": \"SDS-PAGE mass-shift assays with O-glycosylation inhibitors, imaging of CD46 at immune synapse, STP-region mutant constructs, cytokine measurement, analysis of MS patient T cells\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — O-glycosylation-dependent mass shift and immune synapse recruitment with STP domain requirement established; disease context validated with MS patient cells; single lab\",\n      \"pmids\": [\"29066539\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Presenilin/gamma-secretase-processed CD46-Cyt-1 (but not Cyt-2) engages CD46-Cyt-1-specific GOPC scaffold and VPS34/Beclin1 autophagosome complex; CD46-induced Treg (cTreg) enhance B cell antibody production in a manner dependent on cell-cell contact and cTreg-derived IL-10; CD46-deficient patient T cells fail to promote B cell responses, while CD46-deficient B cells have no intrinsic immunoglobulin production defect.\",\n      \"method\": \"cTreg/B cell co-culture assays, antibody production measurement, cell-contact blocking, IL-10 blocking, analysis of CD46-deficient patient T cells and B cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CD46-deficient patient cells used to establish T cell-intrinsic requirement; cell contact and IL-10 dependence dissected; single lab study\",\n      \"pmids\": [\"19784949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MMP-9-mediated increased shedding of soluble CD46 by Th1 cells is associated with defective CD46-regulated Th1 contraction in SLE patients; inhibition of MMP-9 activity normalized soluble CD46 release and restored Th1 contraction in patient T cells.\",\n      \"method\": \"Measurement of soluble CD46 in Th1 cell supernatants, MMP-9 inhibitor treatment, restoration of Th1 contraction assays, comparison of SLE patient vs healthy donor T cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MMP-9 inhibitor rescue of Th1 contraction in patient cells mechanistically links MMP-9 shedding of CD46 to T cell dysregulation; single lab, patient material\",\n      \"pmids\": [\"28444759\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CD46 is subject to alternative splicing regulation: CD46 cassette exons 7 and 8 (extracellular domain-encoding) use noncanonical base-pairing to U1 snRNA at their 5' splice sites; exon 13 (cytoplasmic tail CYT-1) inclusion is regulated by PTBP1 and TIAL1 as splicing factors, and SRSF1 represses exon 13 inclusion; nonsense-mediated mRNA decay and transcription speed further regulate CD46 mRNA isoforms; antisense oligonucleotides successfully manipulated CD46 exon 13 inclusion.\",\n      \"method\": \"Splicing minigene assays, siRNA knockdown of splicing factors (PTBP1, TIAL1, SRSF1), U1 snRNA base-pairing analysis, antisense oligonucleotide manipulation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — mechanistic dissection of splice site recognition (U1 snRNA) and trans-acting factors with minigene and siRNA approaches; antisense oligonucleotide manipulation confirms functional control; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"27226545\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HHV-6A gQ1 and gQ2 glycoproteins within the gH/gL/gQ1/gQ2 tetrameric complex are critical for CD46 binding: replacement of HHV-6A gQ1 or gQ2 with HHV-6B counterparts abolished CD46 binding, while replacement of gH or gL with HHV-6B molecules did not affect CD46 binding.\",\n      \"method\": \"Chimeric HHV-6A/B glycoprotein complex expression, co-immunoprecipitation of complex formation, CD46 binding assays\",\n      \"journal\": \"Microbiology and immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic subunit swaps between HHV-6A and -6B identified gQ1/gQ2 as CD46-binding determinants; co-IP confirmed complex formation; single lab\",\n      \"pmids\": [\"24215487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD46 facilitates human cytomegalovirus (CMV) entry and dissemination in epithelial cells and trophoblasts but not in fibroblasts: CD46-KO epithelial cells showed significantly reduced viral proliferation; anti-CD46 monoclonal antibodies blocked CMV infection; a CD46-dependent entry pathway was demonstrated in trophoblasts.\",\n      \"method\": \"High-throughput antibody inhibition screen, CD46 CRISPR/Cas9 KO epithelial cells, infection assays in multiple cell types including trophoblasts and fibroblasts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO combined with antibody inhibition and cell-type-specific functional assays, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"31221976\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"During sperm acrosome reaction, CD46 undergoes dynamic relocalization over the sperm head and interacts with β1 integrin (specifically with α3 but not α6 subunit); this interaction is proposed to involve actin network rearrangement during the acrosome reaction.\",\n      \"method\": \"Super-resolution microscopy, proximity ligation assay for CD46/integrin interaction, localization analysis during acrosome reaction\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — proximity ligation assay and super-resolution microscopy demonstrate interaction and co-localization; single lab, functional consequence of interaction is proposed but partially supported\",\n      \"pmids\": [\"27666019\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"In spermatozoa, CD46 (smMCP, 43 kDa) is expressed on the inner acrosomal membrane and is N-glycosylated but not O-glycosylated; seminal plasma CD46 (ssMCP, 60 kDa) is O-glycosylated; both retain factor I cofactor activity for cleavage of C3b, blocked by cofactor-activity-blocking mAb M75; these sperm isoforms are structurally distinct from those on other cells.\",\n      \"method\": \"SDS-PAGE, immunoblotting with anti-MCP mAbs, functional factor I cofactor assays with C3ma substrate, deglycosylation analysis, immunohistochemistry\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct enzymatic cofactor activity assay on purified sperm/seminal plasma CD46 with blocking mAb validation; glycosylation characterized biochemically; single lab\",\n      \"pmids\": [\"8500528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD46 engagement on airway epithelial cells induces autophagy (via GOPC scaffold protein and LC3-II formation) that protects against oxidative stress-mediated apoptosis; CD46 crosslinking decreases PRO-IL-1β and NLRP3 expression; autophagy inhibitor 3-methyladenine blocked CD46-induced protection; silencing ATG5 decreased CD46-activated autophagy.\",\n      \"method\": \"CD46 mAb crosslinking in primary nasal epithelial cells, autophagosome imaging (LC3-II), GOPC expression analysis, ATG5 siRNA knockdown, caspase-3 and NLRP3 Western blotting, hydrogen peroxide-induced apoptosis model\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — CD46 crosslinking, ATG5 KD, and autophagy inhibitor experiments dissect pathway in primary epithelial cells; consistent with earlier mechanistic finding (PMID:19837375); single lab\",\n      \"pmids\": [\"30154478\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"CD46 (human, expressed in transgenic mice) facilitates Neisseria meningitidis crossing of the blood-brain barrier in a pilus-dependent manner at the epithelial mucosa: CD46 transgenic mice (but not wild-type mice) were susceptible to meningococcal disease after intranasal challenge with piliated bacteria; pilus-CD46 interaction was required for mucosal entry.\",\n      \"method\": \"CD46 transgenic mice challenged with piliated and non-piliated N. meningitidis by intranasal and intraperitoneal routes, assessment of bacteremia and blood-brain barrier crossing\",\n      \"journal\": \"Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with route-specific challenge and piliation comparison establishes in vivo pathogenic role; single study\",\n      \"pmids\": [\"12869763\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CD46 (membrane cofactor protein) is a ubiquitously expressed type I transmembrane glycoprotein that (1) acts as a cofactor for serine protease factor I to proteolytically cleave and inactivate complement components C3b (via SCR3/4) and C4b deposited on host cells; (2) serves as a receptor for at least 11 pathogens—including measles virus (via SCR1/2), HHV-6 (via SCR2/3), adenoviruses (species B via fiber knob CCP2; species D via hexon), N. gonorrhoeae/meningitidis pili, BVDV, and CMV—with pathogen binding often leading to CD46 downregulation or shedding; (3) functions as a costimulatory signaling molecule on T cells, where its two cytoplasmic tail isoforms (CYT-1 and CYT-2) mediate distinct outcomes—CYT-1 links to the GOPC/VPS34/Beclin1 autophagy pathway, while CYT-2 is phosphorylated by Src/Lck kinases and interacts with SPAK to drive IL-10 production via ICER/CREM—and where CD3/CD46 co-engagement drives Th1 effector responses that switch to IL-10-producing Tr1 regulatory cells through Jagged1 as an endogenous CD46 ligand; and (4) undergoes regulated processing by metalloproteinases (MMP-9) and presenilin/γ-secretase, as well as O-glycosylation-dependent changes at the immune synapse, that modulate its T cell regulatory functions.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CD46 (membrane cofactor protein) is a ubiquitously expressed type I transmembrane glycoprotein that integrates innate complement regulation, pathogen entry, and adaptive T cell control [#1, #6]. Its extracellular region is built from short consensus repeat (SCR) domains that serve as a cofactor for serine protease factor I, driving proteolytic inactivation of C3b and C4b deposited on host cell surfaces and thereby protecting cells from complement-mediated lysis; on cell surfaces CD46 is the principal cofactor for classical-pathway C4b cleavage and restricts alternative-pathway C3b deposition [#1, #12]. The SCR3/SCR4 module carries the complement cofactor site, spatially distinct from the SCR1/SCR2 region that pathogens exploit [#2]. CD46 is a receptor or entry factor for a wide range of pathogens, with distinct SCR domains assigned to each: measles virus engages SCR1/SCR2 through its hemagglutinin [#2, #27], HHV-6 requires SCR2/SCR3 via the gQ1/gQ2 glycoproteins [#17, #33], adenovirus species B binds the CCP2/SCR2 domain through the fiber knob [#21, #22] whereas species D binds via the hexon capsid [#23], pathogenic Neisseria pili bind CD46 [#4], and bovine viral diarrhea virus and cytomegalovirus also use CD46 for entry [#16, #34]; pathogen engagement frequently triggers CD46 downregulation or shedding, as seen with measles hemagglutinin-driven downregulation and pilus/PilT-mediated shedding [#15, #18]. On T cells CD46 acts as a costimulatory molecule whose two mutually exclusive cytoplasmic tail isoforms, CYT-1 and CYT-2 generated by alternative splicing, drive divergent outcomes [#7, #11]: CD3/CD46 co-engagement first promotes Th1 effector responses then switches CD4+ T cells to IL-10-producing regulatory (Tr1) cells [#6, #9], with CYT-1 linking through the GOPC scaffold to the VPS34/Beclin1 autophagy machinery [#8] and CYT-2 being tyrosine-phosphorylated by Lck and coupling to the kinase SPAK and the ICER/CREM axis to drive the IL-10 switch [#9, #10]. The Notch ligand Jagged1 is an endogenous physiological CD46 ligand required for proper Th1-to-Tr1 transition [#13]. CD46 function is further tuned by regulated processing\\u2014presenilin/\\u03b3-secretase cleaves the cytoplasmic tails, MMP-9 mediates ectodomain shedding, and TCR-induced O-glycosylation changes govern immune-synapse recruitment\\u2014linking these events to disease states including CD46 deficiency, multiple sclerosis, rheumatoid arthritis and SLE [#19, #29, #31, #13].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established CD46's founding innate-immune function: how host cells avoid autologous complement attack was addressed by showing CD46 is a factor I cofactor.\",\n      \"evidence\": \"Biochemical cofactor activity assays with factor I and C3b/C4b substrates\",\n      \"pmids\": [\"1910685\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which SCR domains carry the cofactor activity\", \"Did not address surface-specific contributions versus soluble regulators\"]\n    },\n    {\n      \"year\": 1993,\n      \"claim\": \"Answered what cellular receptor measles virus uses, defining CD46's first pathogen-receptor role through reconstitution in non-permissive cells.\",\n      \"evidence\": \"Transfection of CD46 cDNA into hamster cells with binding, syncytia, viral protein and antibody-block assays\",\n      \"pmids\": [\"8402913\", \"8371352\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the viral or receptor binding determinant\", \"Did not distinguish entry from cell-cell fusion thresholds\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Resolved whether complement and viral binding sites overlap by mapping the measles determinant to SCR1/SCR2 and the complement site to SCR3/SCR4.\",\n      \"evidence\": \"Chimeric CD46/DAF mutants, SCR truncations/swaps and antibody blocking in infection assays\",\n      \"pmids\": [\"7534417\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not provide atomic structure of the SCR1/2-virus interface\", \"Did not address other pathogen binding sites\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Defined the molecular basis of measles-induced CD46 downregulation, showing it is driven by hemagglutinin engaging the CD46 ectodomain.\",\n      \"evidence\": \"Strain panel infection, recombinant MV-H expression, chimeric H/F glycoprotein swaps, co-precipitation and cell-contact assays\",\n      \"pmids\": [\"7732009\", \"7595386\", \"7745681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the trafficking fate of downregulated CD46 in all cases\", \"Did not establish signaling consequences of downregulation\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Probed how CD46 transduces measles uptake by identifying a physical association with the cytoskeletal adaptor moesin.\",\n      \"evidence\": \"Co-immunoprecipitation, chemical cross-linking, immunoelectron microscopy and antibody inhibition\",\n      \"pmids\": [\"7884872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab without reciprocal validation in independent systems\", \"Functional role of moesin in uptake only inferred from antibody block\"]\n    },\n    {\n      \"year\": 1992,\n      \"claim\": \"Explained how one gene generates functional diversity by documenting tissue- and allele-specific alternative splicing producing CYT-1/CYT-2 tails.\",\n      \"evidence\": \"RT-PCR, Northern and Western analysis of tissue isoforms with allelic analysis\",\n      \"pmids\": [\"1601037\", \"7692239\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not assign function to individual isoforms\", \"Did not identify the trans-acting splicing factors\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Extended CD46's pathogen-receptor repertoire to bacteria by identifying it as a pilus receptor for pathogenic Neisseria.\",\n      \"evidence\": \"Pilus binding to CD46, antibody blocking, CD46-transfected CHO cells and recombinant CD46 binding\",\n      \"pmids\": [\"9379894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map the CD46 domain contacting pili\", \"Did not define downstream cellular response at this stage\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Added HHV-6 to the CD46 receptor repertoire via reconstitution and inhibition approaches.\",\n      \"evidence\": \"CD46 downregulation by flow cytometry, soluble CD46/antibody neutralization, transfection of non-permissive cells\",\n      \"pmids\": [\"10619434\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not map binding domain or viral ligand at this stage\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Began dissecting isoform-specific signaling by showing CYT-2, not CYT-1, is tyrosine-phosphorylated by the Src kinase Lck.\",\n      \"evidence\": \"Tail peptide phosphorylation, anti-phosphotyrosine blotting, Lck-deficient Jurkat analysis\",\n      \"pmids\": [\"10657632\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect phosphorylation to downstream effectors\", \"Did not address CYT-1 signaling mechanism\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed CD46 cytoplasmic tails are required for antiviral interferon output, linking the receptor to innate effector responses.\",\n      \"evidence\": \"Tailless CD46 mutant macrophages, IFN neutralization, nitric oxide and viral protein assays\",\n      \"pmids\": [\"10627535\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study in mouse macrophages\", \"Did not resolve which tail isoform drives the effect\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Identified CD46 membrane partnerships with \\u03b21 integrins and tetraspanins, raising the possibility of supramolecular receptor complexes.\",\n      \"evidence\": \"Reciprocal Co-IP and cross-linking on living cells with anti-integrin panel\",\n      \"pmids\": [\"10741407\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular mechanism of the association unresolved\", \"Complexes did not modify MV fusion entry\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Assigned distinct in vivo immune functions to the two tail isoforms, establishing CYT-1 versus CYT-2 as opposing inflammatory regulators.\",\n      \"evidence\": \"Isoform-specific transgenic mice, contact hypersensitivity, proliferation, cytotoxicity, cytokine and Vav phosphorylation assays\",\n      \"pmids\": [\"12055630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mouse transgenic context may not fully recapitulate human CD46 signaling\", \"Did not define molecular effectors of each tail\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Refined CD46's complement role by showing it is the principal surface cofactor for C4b cleavage and restrains alternative-pathway C3b deposition.\",\n      \"evidence\": \"Complement fragment deposition on MCP-transfected cells with function-blocking antibodies under pathway-specific conditions\",\n      \"pmids\": [\"12055245\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address tissue-specific differences in cofactor balance\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Distinguished HHV-6 from measles receptor usage by mapping HHV-6 to SCR2/SCR3 versus SCR1/SCR2 for measles.\",\n      \"evidence\": \"Quantitative cell-fusion assay with CD46 truncations, DAF chimeras, isoform variants and SCR-specific antibodies\",\n      \"pmids\": [\"12171934\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not provide structural detail of the HHV-6-CD46 interface\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Discovered CD46's role in adaptive tolerance, showing CD3/CD46 co-engagement drives an IL-10-producing Tr1 regulatory phenotype.\",\n      \"evidence\": \"CD3/CD46 costimulation of primary human CD4+ T cells with cytokine and bystander suppression assays\",\n      \"pmids\": [\"12540904\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the endogenous CD46 ligand\", \"Did not define the signaling effectors of the switch\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Mapped adenovirus species B usage of CD46 as a primary attachment receptor and established mechanisms of bacterial-induced downregulation and in vivo pathogenesis.\",\n      \"evidence\": \"CD46-transfected CHO cells, fiber knob/antibody competition for Ad11; PilT-mutant Neisseria shedding analysis and human infection isolates; CD46 transgenic mouse meningococcal challenge\",\n      \"pmids\": [\"12915534\", \"14597734\", \"12869763\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Transgenic mouse pathogenesis is a single study\", \"Did not resolve the protease responsible for pilus-mediated shedding\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Established a receptor-density threshold governing measles-induced fusion, explaining tumor-selective syncytia formation.\",\n      \"evidence\": \"Engineered cell lines spanning CD46 densities with quantitative viral marker and fusion readouts\",\n      \"pmids\": [\"15256464\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the molecular basis of the threshold\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Extended CD46 receptor function across species by identifying bovine CD46 as a BVDV receptor.\",\n      \"evidence\": \"Immunoaffinity purification, cDNA cloning, expression in porcine cells and susceptibility assays\",\n      \"pmids\": [\"14747544\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Bovine CD46 did not fully confer permissiveness to all non-permissive cells\", \"Single lab study\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Provided structural and quantitative detail of adenovirus-CD46 binding, mapping the fiber knob residues and stoichiometry.\",\n      \"evidence\": \"Random knob mutagenesis, surface plasmon resonance, X-ray crystallography at 2-\\u00c5 and modeling; combined with earlier CCP2 point-mutant mapping\",\n      \"pmids\": [\"17898059\", \"15919905\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structure of the full virion-CD46 complex for species B not resolved here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Defined the CYT-1 effector pathway, linking it to autophagy via the GOPC scaffold and VPS34/Beclin1 complex.\",\n      \"evidence\": \"Reciprocal Co-IP of CD46-Cyt-1 with GOPC, VPS34/Beclin1 interaction, isoform-specific autophagy assays with MV and group A Streptococcus; cTreg/B cell co-culture with CD46-deficient patient cells\",\n      \"pmids\": [\"19837375\", \"19784949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not fully resolve how autophagy feeds into the cytokine switch\", \"B cell help mechanism characterized in single lab\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Showed CD46 tails are released by presenilin/\\u03b3-secretase, implicating regulated intramembrane proteolysis and pilus-driven mechanotransduction.\",\n      \"evidence\": \"Immunoprecipitation of cleaved tail peptides, \\u03b3-secretase inhibitors, dominant-negative presenilin, type IV pili/PilT bacterial mutants\",\n      \"pmids\": [\"20018629\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Fate and signaling role of released tail peptides not fully defined\", \"Mechanotransduction model partly inferred\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved how the Th1-to-regulatory switch is wired, identifying CD46 tail engagement of SPAK and the ICER/CREM axis to attenuate IL-2 and induce IL-10.\",\n      \"evidence\": \"Isoform-specific stimulation, ICER/CREM reporters, SPAK interaction, cytokine assays in CD4+ and \\u03b3\\u03b4 T cells, and rheumatoid arthritis patient cells\",\n      \"pmids\": [\"20694009\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the upstream physiological CD46 ligand at this stage\", \"Mechanism of IL-2-timed switching not fully resolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identified Jagged1 as the endogenous CD46 ligand and connected CD46 to Notch signaling required for proper Th1/IL-10 responses.\",\n      \"evidence\": \"Jagged1-CD46 binding and blocking, T cell stimulation, CD46-deficient and Alagille syndrome patient T cell analysis\",\n      \"pmids\": [\"23086448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the CD46-Jagged1 interaction not defined\", \"Did not resolve the bidirectional signaling stoichiometry\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mapped the viral determinant of HHV-6A CD46 binding to the gQ1/gQ2 glycoproteins within the gH/gL/gQ1/gQ2 complex.\",\n      \"evidence\": \"Chimeric HHV-6A/B glycoprotein swaps, complex Co-IP and CD46 binding assays\",\n      \"pmids\": [\"24215487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab subunit-swap study without structural confirmation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Elucidated the splicing regulatory logic generating CD46 isoforms and demonstrated antisense control of exon 13 inclusion.\",\n      \"evidence\": \"Minigene assays, siRNA of PTBP1/TIAL1/SRSF1, U1 snRNA base-pairing analysis, antisense oligonucleotide manipulation\",\n      \"pmids\": [\"27226545\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not link splicing factor activity to physiological cell-state cues\", \"Single lab\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Connected CD46 costimulation to T cell metabolism through miR-150 downregulation of the glucose transporter SLC2A1.\",\n      \"evidence\": \"miRNA profiling, CD46 blockade, miR-150 knockdown and SLC2A1 target validation in CD4+ T cells\",\n      \"pmids\": [\"26746193\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Causal contribution of glucose uptake to the cytokine switch only partially dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Implicated CD46 in reproduction by characterizing its acrosomal localization, integrin partnership, and sperm-specific cofactor activity.\",\n      \"evidence\": \"Super-resolution microscopy and proximity ligation during acrosome reaction; biochemical cofactor assays on sperm/seminal isoforms with blocking mAb\",\n      \"pmids\": [\"27666019\", \"8500528\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of CD46-integrin interaction only proposed\", \"Single lab studies\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Revealed post-translational tuning of CD46 signaling through TCR-induced O-glycosylation changes and immune-synapse recruitment, with disease relevance in MS.\",\n      \"evidence\": \"Mass-shift assays with O-glycosylation inhibitors, immune synapse imaging, STP-region mutants, cytokine assays and MS patient T cells\",\n      \"pmids\": [\"29066539\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Molecular link between glycosylation state and processing only partly defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked dysregulated MMP-9 shedding of CD46 to defective Th1 contraction in SLE, tying ectodomain proteolysis to autoimmune dysfunction.\",\n      \"evidence\": \"Soluble CD46 measurement, MMP-9 inhibitor rescue of Th1 contraction in SLE versus healthy donor T cells\",\n      \"pmids\": [\"28444759\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab patient-cell study\", \"Did not establish MMP-9 as the sole sheddase\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Generalized the CD46-autophagy axis beyond T cells, showing GOPC-dependent autophagy in airway epithelium protects against oxidative apoptosis and dampens NLRP3.\",\n      \"evidence\": \"CD46 crosslinking in primary nasal epithelial cells, LC3-II imaging, ATG5 siRNA, 3-MA inhibition, caspase-3/NLRP3 blotting\",\n      \"pmids\": [\"30154478\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Did not define the epithelial CD46 ligand\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended CD46 receptor function to cytomegalovirus in a cell-type-specific manner relevant to epithelial and placental infection.\",\n      \"evidence\": \"Antibody inhibition screen, CRISPR CD46-KO epithelial cells, infection assays in trophoblasts versus fibroblasts\",\n      \"pmids\": [\"31221976\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Viral ligand for CD46 not identified\", \"Mechanism of cell-type specificity unresolved\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed adenovirus species D uses a different CD46 contact than species B, binding through the hexon capsid rather than the fiber knob.\",\n      \"evidence\": \"Receptor screening, CD46 KO/overexpression cells, soluble CD46 competition, SPR and cryo-EM of the HAdV-D56 virion-CD46 complex\",\n      \"pmids\": [\"33384338\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which CD46 SCR domain contacts hexon\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the competing roles of CD46 (complement cofactor, multi-pathogen receptor, and T cell signaling hub) are coordinated on a single cell, and how isoform choice, glycosylation, and proteolysis are integrated by physiological cues, remain unresolved.\",\n      \"evidence\": \"No single study in the timeline reconciles these parallel functions\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unified structural model of CD46 multi-ligand engagement\", \"Upstream regulators selecting isoform and processing fate in vivo are undefined\", \"Quantitative interplay between complement regulation and receptor functions on the same membrane is uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [0, 3, 4, 5, 16, 23, 34]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 12, 36]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [6, 9, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 14]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4, 20, 26]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [8, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [6, 9, 11, 13]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 3, 4, 5, 23, 34]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [8, 37]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [7, 32]}\n    ],\n    \"complexes\": [\n      \"VPS34/Beclin1 autophagy complex (via GOPC)\",\n      \"CD46/\\u03b21-integrin/tetraspanin surface complex\"\n    ],\n    \"partners\": [\n      \"GOPC\",\n      \"SPAK\",\n      \"LCK\",\n      \"JAG1\",\n      \"moesin\",\n      \"ITGB1\",\n      \"ITGA3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}