{"gene":"LY6E","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2018,"finding":"LY6E is a GPI-anchored, IFN-inducible cell surface protein that enhances infection by multiple RNA viruses (influenza A, HIV, yellow fever virus) by promoting viral entry. Using influenza A virus as a model, the enhancing effect was narrowed to uncoating after endosomal escape. Structure-function analyses identified a single amino acid in a predicted loop region essential for viral enhancement. Diverse mammalian orthologs also enhance viral infectivity, indicating evolutionary conservation.","method":"Ectopic expression in multiple cell lines, influenza A virus uncoating assays, structure-function mutagenesis, ortholog testing","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (cell-based assays, mutagenesis, mechanistic dissection to uncoating step), replicated across cell backgrounds and orthologs","pmids":["30190477"],"is_preprint":false},{"year":2020,"finding":"LY6E potently restricts infection by multiple coronaviruses (SARS-CoV, SARS-CoV-2, MERS-CoV) by interfering with spike protein-mediated membrane fusion during viral entry. Mice lacking Ly6e in immune cells were highly susceptible to murine CoV (MHV), with loss of hepatic immune cells, higher splenic viral burden, and reduction in global antiviral gene pathways. Constitutive Ly6e directly protects primary B cells from murine CoV infection.","method":"Ectopic expression/knockdown assays, spike protein-mediated fusion assays, conditional knockout mice (Ly6e deleted in hematopoietic cells), in vivo murine CoV infection model","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mechanistic fusion assay plus in vivo KO mouse model, replicated across multiple CoV strains, confirmed by two independent publications (PMID:32704094 and preprint PMID:32511345)","pmids":["32704094","32511345"],"is_preprint":false},{"year":2020,"finding":"LY6E restricts HCoV-OC43 entry and the entry mediated by spike proteins of other human coronaviruses including SARS-CoV-2. Overexpression of TMPRSS2 or amphotericin treatment (which overcomes IFITM3 restriction) did not compromise LY6E's effect on CoV entry, indicating a mechanism distinct from IFITM3.","method":"Ectopic expression in HEK293, C3A, and A549 cells; LY6E knockdown in HepG2; spike-pseudovirus entry assays; comparison with TMPRSS2 overexpression and amphotericin treatment","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell lines, gain- and loss-of-function, mechanistic distinction from IFITM3 pathway established","pmids":["32641482"],"is_preprint":false},{"year":2023,"finding":"Ly6e is a pan-coronavirus restriction factor in the respiratory tract. Using conditional Ly6e knockout mice (seven different Cre lines), Ly6e expression in Lyz2-expressing cells, radioresistant Vav1-expressing cells, and non-haematopoietic cells conferred control of murine coronavirus and SARS-CoV-2. Ly6e protected secretory club and ciliated cells from SARS-CoV-2 infection and prevented virus-induced loss of an epithelial cell transcriptomic signature in the lung.","method":"Panel of seven conditional Ly6e knockout mouse lines, murine coronavirus and SARS-CoV-2 infection models, transcriptomic profiling of lung","journal":"Nature microbiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic conditional KO across seven cell lineages, in vivo infection models with transcriptomic readout, multiple cell-type-specific conclusions","pmids":["37443277"],"is_preprint":false},{"year":2017,"finding":"LY6E promotes HIV-1 infection by enhancing viral membrane fusion at the entry step. Additionally, LY6E enhances LTR-driven HIV-1 gene expression. Knockdown of LY6E in PBMCs, SupT1, and THP-1 cells diminishes HIV-1 replication. HIV-1 infection itself induces LY6E expression concomitant with type I IFN production.","method":"LY6E knockdown (RNAi) in multiple cell lines, virion-cell and cell-cell fusion assays, LTR-reporter assay, HIV-1 replication assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell lines, both fusion assay and gene expression assay, gain- and loss-of-function","pmids":["28130445"],"is_preprint":false},{"year":2019,"finding":"In low-CD4-expressing cells (Jurkat, MDMs), LY6E inhibits HIV-1 entry and spread by downregulating cell surface CD4 via enhanced CD4 internalization. LY6E colocalizes with CD4 on the plasma membrane. Artificially raising CD4 in Jurkat cells overcomes LY6E inhibition; blocking CD4 in SupT1 eliminates LY6E enhancement. Thus LY6E's effect on HIV-1 entry is CD4-level-dependent.","method":"LY6E knockdown and overexpression in Jurkat and MDMs, colocalization by microscopy, CD4 internalization assay, CD4 manipulation (overexpression and neutralizing antibody), HIV-1 entry assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (colocalization, internalization, CD4 manipulation), mechanistic model fully validated in two cell types","pmids":["30674630"],"is_preprint":false},{"year":2017,"finding":"LY6E (Ly6e) is identified as the receptor for mouse endogenous retroviral fusogenic protein Syncytin-A (SynA). Cell-cell fusion assay with cDNA library screening identified Ly6e as a GPI-anchored membrane protein sufficient to mediate SynA-induced cell fusion. siRNA knockdown of Ly6e greatly reduced SynA-induced fusion. Competition with soluble ectodomain of Ly6e confirmed direct interaction. No cross-reactive fusion with Syncytin-B was detected.","method":"Cell-cell fusion assay combined with cDNA library screening, transfection rescue, siRNA knockdown, competition assay with soluble Ly6e ectodomain","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — receptor identification by functional screen, confirmed by three independent methods (gain-of-function, siRNA, competition/decoy assay)","pmids":["28679758"],"is_preprint":false},{"year":2018,"finding":"Ly6e is essential for syncytiotrophoblast layer I (ST-I) fusion in the mouse placenta. Ly6e knockout causes embryonic lethality due to failure of syncytiotrophoblast layer I cell-cell fusion and defects in both fetal and maternal vasculature morphogenesis. Epiblast-specific (but not placenta-specific) Ly6e inactivation is compatible with embryonic development, indicating lethality is placental in origin.","method":"Ly6e global knockout mice, epiblast-specific and placenta-specific conditional Ly6e knockout, histological and morphological analysis of placenta","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with tissue-specific rescue clearly localizes the functional requirement to the placenta, consistent with receptor identification paper","pmids":["29500366"],"is_preprint":false},{"year":2013,"finding":"Ly6e mRNA is expressed in syncytiotrophoblast cells of the mouse placenta labyrinth, with expression correlating spatially with Syncytin-A. LY6E+ cells express Syncytin-A at higher levels than LY6E- cells. Expression increases with trophoblast differentiation.","method":"mRNA in situ hybridization, Northern blot, FACS isolation of LY6E+ cells, RT-PCR","journal":"Placenta","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization with cell-type fractionation, two orthogonal methods, but no functional manipulation","pmids":["23830620"],"is_preprint":false},{"year":2014,"finding":"LY6E in monocytes negatively modulates CD14 expression and dampens responsiveness to LPS stimulation. In the setting of chronic HIV infection, upregulation of LY6E correlates with reduced CD14 levels on monocytes, but the immunosuppressive effect is insufficient to remedy hyperactivation.","method":"LY6E knockdown/overexpression in monocytic cells, LPS stimulation assays, CD14 expression measurement, correlation with chronic HIV patient samples","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — in vitro gain- and loss-of-function with functional LPS response readout, single lab","pmids":["25225669"],"is_preprint":false},{"year":2023,"finding":"LY6E downregulates CD14 via ubiquitin-dependent proteasomal degradation. The LY6E protein interactome identified PHB1, which interacts with CD14 in a LY6E-dependent manner. TRIM21 was identified as the major ubiquitin E3 ligase mediating LY6E-dependent ubiquitination of CD14, forming a LY6E-PHB1-TRIM21 assembly.","method":"Proteasome inhibitor assays, LY6E interactome profiling (MS), co-immunoprecipitation, TRIM21 knockdown/overexpression, ubiquitination assays","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — mechanistic dissection with interactome MS, co-IP, ubiquitination assay, and E3 ligase identification; single lab but multiple orthogonal methods","pmids":["37250795"],"is_preprint":false},{"year":2016,"finding":"LY6E activates HIF-1 transcription principally at the transcriptional level, leading to upregulation of VEGFA and PDGFB. This occurs through decreased PTEN mRNA expression and subsequent activation of the PI3K/Akt pathway. The LY6E-HIF-1 axis increases tumor blood vessel density and promotes tumor growth in immunodeficient mice.","method":"LY6E overexpression/knockdown, HIF-1α reporter and mRNA analysis, PTEN/PI3K/Akt pathway analysis, in vivo xenograft tumor growth and angiogenesis assay","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — pathway dissection with multiple molecular readouts and in vivo model, single lab","pmids":["27589564"],"is_preprint":false},{"year":2016,"finding":"LY6E is required for TGFβ signaling and proliferation in breast cancer cells, contributing to phosphorylation of Smad1/5 and Smad2/3. LY6E also promotes cytokine-induced PDL1 expression and modulates NK cell binding to cancer cells, and promotes drug resistance.","method":"LY6E knockdown in breast cancer cell lines, TGFβ/Smad phosphorylation assays, PDL1 expression assays, NK cell co-culture assays, drug resistance assays","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple pathway readouts with loss-of-function, single lab","pmids":["27197181"],"is_preprint":false},{"year":1995,"finding":"TSA-1/Sca-2 (murine LY6E ortholog) is a GPI-anchored protein that modulates TCR-mediated signaling. Anti-TSA-1 inhibits IL-2 production from T cells stimulated with anti-CD3, reducing CD3 zeta-chain tyrosine phosphorylation. This inhibitory function does not require the GPI anchor, as a transmembrane form of TSA-1 retains inhibitory activity.","method":"Anti-TSA-1 antibody treatment of normal T cells and T cell hybridomas, transfection of Jurkat cells with GPI-anchored and transmembrane TSA-1 constructs, IL-2 assay, tyrosine phosphorylation of CD3 zeta by Western blot","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple cell systems, GPI-independent mechanism established by chimeric construct, functional and biochemical readouts","pmids":["7499840"],"is_preprint":false},{"year":1994,"finding":"Cross-linking of Ly-6E on T lymphocytes inhibits anti-CD3-induced IL-2 production. Both GPI-anchored and transmembrane forms of Ly-6E (chimeric construct with H-2Db transmembrane/cytoplasmic domain) mediate inhibition of IL-2 production, indicating the inhibitory signaling depends on the extracellular domain and not the GPI anchor. The Ly-6 inhibitory pathway is operative in human cells (Jurkat).","method":"Transfection of EL-4J cells with Ly-6 proteins, GPI-to-transmembrane chimeric Ly-6E construct, IL-2 production assays, cross-species functional assay in Jurkat cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — chimeric construct approach is rigorous, functional assay replicated in human cells, single lab","pmids":["8051400"],"is_preprint":false},{"year":1989,"finding":"LY6E (Ly-6E/A) is a GPI-anchored cell surface protein. Deletion of 12 or 20 C-terminal residues abolishes GPI modification and results in secretion of the protein. Addition of the LFA-3 cytoplasmic tail to the C-terminus partially inhibits GPI addition. Mutation of an Asn residue at the hypothetical cleavage site alters GPI attachment site usage. Two C-terminal regions act as necessary signals for GPI biosynthesis.","method":"C-terminal deletion mutagenesis, site-directed mutagenesis, COS cell transient transfection, radiolabeling, SDS-PAGE analysis of secretion vs. membrane retention","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — reconstitution-level mutagenesis defining GPI signal sequences, multiple mutants tested, single lab","pmids":["2796989"],"is_preprint":false},{"year":2024,"finding":"NAT10-mediated ac4C (N4-acetylcytidine) modification of LY6E mRNA at its 3'-UTR is required for LY6E mRNA stability and efficient translation during alphavirus (Sindbis virus) infection. NAT10 is upregulated after alphavirus infection, and loss of NAT10 or inhibition of its acetyltransferase activity reduces alphavirus replication by destabilizing LY6E mRNA.","method":"NAT10 knockdown/inhibition, ac4C modification mapping (acRIP-seq or similar), mRNA stability assays, LY6E overexpression rescue, SINV replication assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epitranscriptomic modification site mapped, functional rescue performed, single lab","pmids":["38169284"],"is_preprint":false},{"year":2025,"finding":"GPI biosynthesis pathway acts as a conserved host restriction mechanism against multiple coronaviruses (SARS-CoV-2, HCoV-OC43, PEDV) by disrupting spike protein-mediated membrane fusion at both endosomal and plasma membranes. Focused CRISPR KO screen of 193 GPI-anchored proteins identified LY6E as the key downstream effector of GPI biosynthesis antiviral activity.","method":"Genome-wide CRISPR KO screens with three coronaviruses, focused CRISPR KO screen of 193 GPI-APs, fusion assays","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — systematic CRISPR screens across three viruses plus focused GPI-AP screen, identifies LY6E as key effector, multiple orthogonal approaches","pmids":["40901862"],"is_preprint":false},{"year":2022,"finding":"LY6E associates with α5-nAChR and mediates TGF-β1/Smad signaling (specifically pSmad3) and EMT marker expression in non-small cell lung cancer. Silencing both α5-nAChR and LY6E inhibits cell migration more effectively than silencing either alone. α5-nAChR mediates LY6E expression as well as Zeb1, N-cadherin and vimentin expression.","method":"siRNA knockdown of LY6E and α5-nAChR, Western blot for pSmad3 and EMT markers, cell migration assays, CAM model, mouse xenograft","journal":"Carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — loss-of-function with pathway readouts in vitro and in vivo, single lab, interaction between α5-nAChR and LY6E inferred but not directly demonstrated by co-IP","pmids":["34994389"],"is_preprint":false},{"year":1986,"finding":"The murine Ly-6E.1 protein is a ~17-18 kDa cell surface antigen with intrachain but not interchain disulfide bonds, does not carry N-linked carbohydrate (tunicamycin-insensitive), and exists as two polypeptide forms. The native molecule behaves as a single polypeptide chain rather than a dimer. In the presence of deoxycholate it elutes as ~31 kDa on gel filtration, consistent with detergent association.","method":"Immunoprecipitation from biosynthetically radiolabeled cells, SDS-PAGE (reduced and non-reduced), tunicamycin treatment, pulse-chase, gel filtration, isoelectric focusing","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — biochemical characterization with multiple methods, single lab, foundational structural description","pmids":["3941270"],"is_preprint":false},{"year":2022,"finding":"LY6E facilitates AAV-PHP.eB crossing of the human blood-brain barrier in vitro. RNAi knockdown of LY6E and capsid protein binding assays demonstrated that AAV-PHP.eB delivery across the BBB is mediated by LY6E.","method":"Biomimetic BBB chip model, RNAi knockdown of LY6E, virus capsid protein binding assay, AAV crossing efficiency assay","journal":"Lab on a chip","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — knockdown and binding assay in in vitro BBB model, consistent with computational prediction, single lab","pmids":["36165190"],"is_preprint":false},{"year":2025,"finding":"LY6E regulates IFN-α- and immune complex-induced production of mature IL-1β in macrophages. LY6E modulates NLRP3 inflammasome activation, caspase-1 activation, STING pathway, mitochondrial ROS generation, and CMPK2 activation. LY6E also modulates foam cell formation. LY6E colocalizes with macrophage marker in kidneys from lupus-prone mice and lupus nephritis patients.","method":"Bone marrow-derived macrophage culture with LY6E manipulation, NLRP3/caspase-1 activation assays, mtDNA release assay, mtROS measurement, STING pathway assays, CMPK2 activity assay, foam cell assay, immunofluorescence colocalization in kidney tissue","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — multiple pathway readouts in primary macrophages, single lab, mechanistic complexity supports multiple functional links","pmids":["40114200"],"is_preprint":false},{"year":2025,"finding":"Nuclear PD-L1 transcriptionally activates LY6E expression by binding to RNA polymerase II subunit POLR2A, forming a transcriptional complex that directly drives LY6E promoter activity. This nuclear PD-L1/POLR2A-LY6E axis promotes IFN-γ-driven lung metastasis of triple-negative breast cancer.","method":"CRISPR/Cas9 PD-L1 ablation, RNA-seq, ChIP-seq (nuclear PD-L1 binding), co-immunoprecipitation of PD-L1 and POLR2A, in vivo metastasis assays","journal":"Breast cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and Co-IP identify PD-L1/POLR2A complex at LY6E locus, functional rescue in vivo, single lab","pmids":["41388312"],"is_preprint":false},{"year":2003,"finding":"Chicken LY6E (SCA2/TSA1) specifically interacts with MDV protein US10, as identified in a bacterial two-hybrid screen and confirmed by in vitro protein-binding assay. LY6E was significantly associated with Marek's disease resistance traits in a commercial chicken population.","method":"E. coli two-hybrid screen, in vitro protein-binding assay, linkage analysis in MD resource population","journal":"Cytogenetic and genome research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — in vitro binding assay only (no mammalian cell confirmation), single lab, avian ortholog","pmids":["14970721"],"is_preprint":false},{"year":1994,"finding":"Mouse Sca-2 (Ly6E ortholog) is a member of the Ly-6 family anchored in the membrane by a GPI moiety, as determined from full-length cDNA sequence from thymocytes.","method":"cDNA cloning and sequence analysis, GPI anchor prediction","journal":"PNAS","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — direct sequence determination establishing GPI anchor structure, foundational structural paper","pmids":["8202484"],"is_preprint":false},{"year":1996,"finding":"High-level IFN-gamma-induced expression of the Ly-6E.1 gene in hematopoietic cells requires a 3' chromatin-dependent region containing DNase I hypersensitive sites at +8.7 and +8.9 kb, which contains a consensus gamma-IFN-responsive element. Both 5' and 3' hypersensitive sites are rapidly induced with IFN-gamma.","method":"Deletion constructs of Ly-6E.1 flanking regions, transfection in hematopoietic cells, IFN-gamma induction assays, DNase I hypersensitive site mapping","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — deletion analysis and chromatin mapping identifying regulatory element, functional expression assays, single lab","pmids":["8639891"],"is_preprint":false},{"year":1999,"finding":"IFN-mediated regulation of the Ly-6E gene in T cells requires multiple regulatory regions including the G region needed for both IFN-alpha/beta and IFN-gamma responses. Multiple transcription factors including Oct-1, Oct-2, and HMGI(Y) bind to regulatory elements in the G region. Inhibition of HMG protein expression by antisense HMGI-C RNA abolishes IFN-alpha/beta and IFN-gamma inducibility of the endogenous Ly-6 gene.","method":"Promoter deletion analysis, DNA mobility shift assays (EMSA), antisense RNA inhibition of HMGI-C, IFN-induction assays in EL4 cells","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA binding and antisense functional validation, multiple factors identified, single lab","pmids":["10395674"],"is_preprint":false},{"year":1990,"finding":"PKC (protein kinase C) or a related kinase is required for IFN-mediated Ly-6E induction. PKC inhibitors (H-7, phloretin) block Ly-6E induction by both IFN-gamma and IFN-alpha/beta at mRNA and protein levels. PKC activators (PMA, mezerein) enhance IFN-gamma-mediated but only marginally affect IFN-alpha/beta-mediated Ly-6E induction, indicating IFN-gamma and IFN-alpha/beta utilize overlapping but distinct intracellular pathways.","method":"PKC inhibitors and activators applied to YAC T cell lymphoma, Ly-6E mRNA and surface protein measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pharmacological dissection with multiple agents and two readout levels, single lab","pmids":["1692061"],"is_preprint":false}],"current_model":"LY6E is an interferon-stimulated, GPI-anchored cell surface protein that dually modulates viral infection: it restricts coronaviruses and (in low-CD4 contexts) HIV-1 by blocking spike/envelope-mediated membrane fusion, while paradoxically enhancing entry of influenza A virus, HIV-1 in high-CD4 cells, and alphaviruses by facilitating post-endosomal uncoating or fusion; mechanistically, it serves as the receptor for the fusogenic retroviral protein Syncytin-A in placental syncytiotrophoblast formation, downregulates CD14 via a LY6E-PHB1-TRIM21 ubiquitin-proteasome axis to dampen LPS responses, modulates TCR signaling by reducing CD3 zeta-chain phosphorylation, and promotes tumor growth through the PTEN/PI3K/Akt/HIF-1 axis; its antiviral activity is downstream of GPI biosynthesis and its mRNA stability is regulated by NAT10-mediated ac4C modification."},"narrative":{"mechanistic_narrative":"LY6E is an interferon-inducible, GPI-anchored cell-surface protein of the Ly-6 family that acts as a bidirectional modulator of viral entry by targeting the membrane fusion step [PMID:30190477, PMID:32704094, PMID:32511345, PMID:40901862]. Against coronaviruses it is a potent restriction factor, blocking spike protein-mediated membrane fusion at both endosomal and plasma membranes through a mechanism distinct from IFITM3, and was identified by focused CRISPR screening as the key GPI-anchored effector of the GPI-biosynthesis antiviral pathway [PMID:32704094, PMID:32511345, PMID:32641482, PMID:40901862]. Conditional knockout across multiple lineages established Ly6e as a pan-coronavirus restriction factor that protects respiratory epithelial and immune cells in vivo [PMID:37443277]. Conversely, LY6E enhances entry of influenza A virus, yellow fever virus, alphaviruses and HIV-1 by promoting post-endosomal uncoating or membrane fusion, with a single loop residue required for the enhancing activity [PMID:30190477, PMID:28130445]; its effect on HIV-1 is CD4-level-dependent, restricting entry in low-CD4 cells by driving CD4 internalization while enhancing fusion when CD4 is abundant [PMID:28130445, PMID:30674630]. Beyond virology, LY6E serves as the receptor for the retroviral fusogen Syncytin-A and is essential for syncytiotrophoblast layer I cell-cell fusion in the placenta, its loss causing embryonic lethality of placental origin [PMID:28679758, PMID:29500366]. LY6E also dampens innate and adaptive immune signaling: it downregulates CD14 to limit LPS responsiveness via a LY6E-PHB1-TRIM21 ubiquitin-proteasome axis [PMID:25225669, PMID:37250795], inhibits TCR-induced IL-2 production by reducing CD3 zeta-chain phosphorylation through its extracellular domain independently of the GPI anchor [PMID:7499840, PMID:8051400], and modulates NLRP3 inflammasome and STING-dependent IL-1β production in macrophages [PMID:40114200]. In cancer, LY6E promotes tumor growth and angiogenesis through a PTEN/PI3K/Akt/HIF-1 axis and supports TGFβ/Smad signaling and EMT [PMID:27589564, PMID:27197181, PMID:34994389]. Its expression is IFN-driven through defined chromatin regulatory elements and is post-transcriptionally stabilized by NAT10-mediated ac4C modification of its mRNA during alphavirus infection [PMID:38169284, PMID:8639891, PMID:10395674].","teleology":[{"year":1986,"claim":"Established the basic biochemical identity of the protein as a small, disulfide-bonded, non-N-glycosylated cell-surface antigen, providing the structural baseline before any functional role was known.","evidence":"Immunoprecipitation, SDS-PAGE, tunicamycin treatment and gel filtration of radiolabeled murine Ly-6E.1","pmids":["3941270"],"confidence":"Medium","gaps":["No functional activity assigned","GPI anchor not yet demonstrated","Single ortholog characterized"]},{"year":1989,"claim":"Defined how LY6E is targeted to the membrane, showing two C-terminal signal regions are necessary for GPI biosynthesis and attachment.","evidence":"C-terminal deletion and site-directed mutagenesis in COS cells with secretion versus membrane-retention readouts","pmids":["2796989"],"confidence":"High","gaps":["Functional consequence of GPI anchoring not addressed","No link to downstream signaling or viral roles"]},{"year":1995,"claim":"Resolved that LY6E modulates TCR signaling through its extracellular domain rather than its GPI anchor, by reducing CD3 zeta-chain phosphorylation and IL-2 production.","evidence":"Anti-TSA-1 antibody treatment and GPI-versus-transmembrane chimeric constructs in T cells and Jurkat, with IL-2 and phospho-zeta readouts (also #14)","pmids":["7499840","8051400"],"confidence":"High","gaps":["Direct binding partner transducing the inhibitory signal not identified","Physiological relevance to T-cell responses in vivo not established"]},{"year":1996,"claim":"Mapped the cis-regulatory architecture and trans-acting factors driving IFN-inducible LY6E expression, explaining why it behaves as an interferon-stimulated gene.","evidence":"Promoter/enhancer deletion constructs, DNase I hypersensitive site mapping, EMSA and antisense HMGI-C inhibition with IFN induction assays (also #26, #27)","pmids":["8639891","10395674","1692061"],"confidence":"Medium","gaps":["Human regulatory elements not directly mapped","Connection between IFN induction and antiviral function not yet made"]},{"year":2017,"claim":"Identified LY6E as the cellular receptor for the retroviral fusogen Syncytin-A, linking the protein to physiological cell-cell fusion.","evidence":"cDNA library functional screen, siRNA knockdown and soluble-ectodomain competition in cell-cell fusion assays","pmids":["28679758"],"confidence":"High","gaps":["Structural basis of the LY6E-SynA interaction not defined","Whether the same surface mediates viral entry enhancement unknown"]},{"year":2017,"claim":"Demonstrated that LY6E enhances HIV-1 infection at the membrane fusion step and additionally boosts LTR-driven gene expression, framing it as a proviral factor.","evidence":"RNAi knockdown across PBMCs, SupT1 and THP-1, fusion assays, LTR-reporter and replication assays","pmids":["28130445"],"confidence":"High","gaps":["Molecular mechanism of fusion enhancement not defined","Reconciliation with restrictive contexts not yet established"]},{"year":2018,"claim":"Showed LY6E enhances diverse RNA virus infections by acting after endosomal escape at the uncoating step, and pinpointed a single loop residue essential for enhancement, defining its proviral mechanism.","evidence":"Ectopic expression, influenza A uncoating assays, structure-function mutagenesis and ortholog testing","pmids":["30190477"],"confidence":"High","gaps":["Direct molecular target during uncoating unidentified","How a surface GPI protein acts post-endosomally is unresolved"]},{"year":2018,"claim":"Established the physiological essentiality of LY6E in placental syncytiotrophoblast layer I fusion, with tissue-specific knockouts localizing embryonic lethality to the placenta.","evidence":"Global, epiblast-specific and placenta-specific Ly6e knockout mice with histological analysis (also #8)","pmids":["29500366","23830620"],"confidence":"High","gaps":["Mechanism connecting receptor engagement to fusion machinery not detailed","Human placental requirement not directly tested"]},{"year":2019,"claim":"Reconciled LY6E's opposing effects on HIV-1 by showing they are CD4-level-dependent: in low-CD4 cells it restricts entry by internalizing CD4, whereas in high-CD4 cells it enhances fusion.","evidence":"Knockdown/overexpression in Jurkat and MDMs, CD4 colocalization and internalization assays, and CD4 manipulation","pmids":["30674630"],"confidence":"High","gaps":["How LY6E triggers CD4 internalization mechanistically unclear","Generalizability to primary infection settings not fully tested"]},{"year":2020,"claim":"Defined LY6E as a potent coronavirus restriction factor that blocks spike-mediated fusion, distinct from IFITM3, and demonstrated in vivo protection using conditional knockout mice.","evidence":"Gain/loss-of-function in multiple cell lines, spike fusion assays, IFITM3 comparison, and conditional KO mice in CoV infection models (also #2)","pmids":["32704094","32511345","32641482"],"confidence":"High","gaps":["Molecular mechanism by which a GPI protein blocks fusion not resolved","Why LY6E restricts CoV but enhances other viruses unexplained"]},{"year":2023,"claim":"Generalized LY6E to a pan-coronavirus respiratory restriction factor and identified the protective cell lineages, showing it shields club and ciliated cells and preserves the lung epithelial transcriptome.","evidence":"Seven conditional Ly6e knockout mouse lines with murine CoV and SARS-CoV-2 infection plus lung transcriptomics","pmids":["37443277"],"confidence":"High","gaps":["Cell-intrinsic fusion-blocking mechanism still undefined","Relative contribution of each lineage to overall protection not quantified"]},{"year":2023,"claim":"Elucidated the molecular machinery of LY6E-mediated CD14 downregulation, identifying a LY6E-PHB1-TRIM21 ubiquitin-proteasome assembly.","evidence":"Interactome MS, co-immunoprecipitation, proteasome inhibition and ubiquitination assays with TRIM21 manipulation (also #9)","pmids":["37250795","25225669"],"confidence":"High","gaps":["How a surface GPI protein nucleates a cytoplasmic E3 ligase complex unclear","Breadth of LY6E-PHB1-TRIM21 substrates beyond CD14 unknown"]},{"year":2024,"claim":"Identified post-transcriptional control of LY6E, showing NAT10-mediated ac4C of its 3'-UTR stabilizes the mRNA and supports translation during alphavirus infection.","evidence":"NAT10 knockdown/inhibition, ac4C mapping, mRNA stability assays and LY6E rescue in SINV replication","pmids":["38169284"],"confidence":"Medium","gaps":["Whether ac4C regulation operates in other infection contexts untested","Single lab, epitranscriptomic site mapping not orthogonally confirmed"]},{"year":2025,"claim":"Positioned LY6E as the key downstream effector of a conserved GPI-biosynthesis antiviral pathway against multiple coronaviruses, unifying genetic screen and fusion-block findings.","evidence":"Genome-wide and focused CRISPR KO screens of 193 GPI-APs across three coronaviruses with fusion assays","pmids":["40901862"],"confidence":"High","gaps":["Direct biochemical step of fusion inhibition still not defined","Why only LY6E among GPI-APs is the effector not fully explained"]},{"year":2025,"claim":"Extended LY6E into inflammasome and metastasis biology, showing it modulates NLRP3/STING-driven IL-1β in macrophages and is transcriptionally activated by a nuclear PD-L1/POLR2A complex driving TNBC metastasis.","evidence":"Primary macrophage pathway assays with kidney colocalization (#21) and CRISPR PD-L1 ablation with ChIP-seq, Co-IP and in vivo metastasis (#22)","pmids":["40114200","41388312"],"confidence":"Medium","gaps":["Direct molecular link between LY6E and inflammasome components not defined","Single-lab findings without independent replication"]},{"year":null,"claim":"The unifying biochemical mechanism explaining how a single GPI-anchored protein both blocks coronavirus fusion and enhances fusion/uncoating of other enveloped viruses remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No structure of LY6E or its viral-protein interfaces","Direct molecular partners at the fusion membrane unidentified","Determinants dictating restriction versus enhancement undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0001618","term_label":"virus receptor activity","supporting_discovery_ids":[6,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5,9,13,14]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0,1,17]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,5,15,19]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,3,9,21]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,4,17]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[11,12,13]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[6,7]}],"complexes":["LY6E-PHB1-TRIM21 assembly"],"partners":["SYNCYTIN-A","CD4","PHB1","TRIM21","CD14","POLR2A","CHRNA5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q16553","full_name":"Lymphocyte antigen 6E","aliases":["Retinoic acid-induced gene E protein","RIG-E","Stem cell antigen 2","SCA-2","Thymic shared antigen 1","TSA-1"],"length_aa":131,"mass_kda":13.5,"function":"GPI-anchored cell surface protein that regulates T-lymphocytes proliferation, differentiation, and activation. Regulates the T-cell receptor (TCR) signaling by interacting with component CD3Z/CD247 at the plasma membrane, leading to CD3Z/CD247 phosphorylation modulation (By similarity). Restricts the entry of human coronaviruses, including SARS-CoV, MERS-CoV and SARS-CoV-2, by interfering with spike protein-mediated membrane fusion (PubMed:32641482). Also plays an essential role in placenta formation by acting as the main receptor for syncytin-A (SynA). Therefore, participates in the normal fusion of syncytiotrophoblast layer I (SynT-I) and in the proper morphogenesis of both fetal and maternal vasculatures within the placenta. May also act as a modulator of nicotinic acetylcholine receptors (nAChRs) activity (By similarity) (Microbial infection) Promotes entry, likely through an enhanced virus-cell fusion process, of various viruses including HIV-1, West Nile virus, dengue virus and Zika virus (PubMed:28130445). In contrast, the paramyxovirus PIV5, which enters at the plasma membrane, does not require LY6E (PubMed:28130445, PubMed:29610346). Mechanistically, adopts a microtubule-like organization upon viral infection and enhances viral uncoating after endosomal escape (PubMed:28130445, PubMed:30190477)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q16553/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LY6E","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/LY6E","total_profiled":1310},"omim":[{"mim_id":"603625","title":"LYMPHOCYTE ANTIGEN 6 COMPLEX, LOCUS H; LY6H","url":"https://www.omim.org/entry/603625"},{"mim_id":"601384","title":"LYMPHOCYTE ANTIGEN 6 COMPLEX, LOCUS E; LY6E","url":"https://www.omim.org/entry/601384"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"liver","ntpm":616.3}],"url":"https://www.proteinatlas.org/search/LY6E"},"hgnc":{"alias_symbol":["TSA-1","RIG-E","SCA-2"],"prev_symbol":[]},"alphafold":{"accession":"Q16553","domains":[{"cath_id":"2.10.60.10","chopping":"20-100","consensus_level":"medium","plddt":84.1405,"start":20,"end":100}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16553","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q16553-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q16553-F1-predicted_aligned_error_v6.png","plddt_mean":77.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LY6E","jax_strain_url":"https://www.jax.org/strain/search?query=LY6E"},"sequence":{"accession":"Q16553","fasta_url":"https://rest.uniprot.org/uniprotkb/Q16553.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q16553/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q16553"}},"corpus_meta":[{"pmid":"32704094","id":"PMC_32704094","title":"LY6E 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GPI-anchored, IFN-inducible cell surface protein that enhances infection by multiple RNA viruses (influenza A, HIV, yellow fever virus) by promoting viral entry. Using influenza A virus as a model, the enhancing effect was narrowed to uncoating after endosomal escape. Structure-function analyses identified a single amino acid in a predicted loop region essential for viral enhancement. Diverse mammalian orthologs also enhance viral infectivity, indicating evolutionary conservation.\",\n      \"method\": \"Ectopic expression in multiple cell lines, influenza A virus uncoating assays, structure-function mutagenesis, ortholog testing\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (cell-based assays, mutagenesis, mechanistic dissection to uncoating step), replicated across cell backgrounds and orthologs\",\n      \"pmids\": [\"30190477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LY6E potently restricts infection by multiple coronaviruses (SARS-CoV, SARS-CoV-2, MERS-CoV) by interfering with spike protein-mediated membrane fusion during viral entry. Mice lacking Ly6e in immune cells were highly susceptible to murine CoV (MHV), with loss of hepatic immune cells, higher splenic viral burden, and reduction in global antiviral gene pathways. Constitutive Ly6e directly protects primary B cells from murine CoV infection.\",\n      \"method\": \"Ectopic expression/knockdown assays, spike protein-mediated fusion assays, conditional knockout mice (Ly6e deleted in hematopoietic cells), in vivo murine CoV infection model\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mechanistic fusion assay plus in vivo KO mouse model, replicated across multiple CoV strains, confirmed by two independent publications (PMID:32704094 and preprint PMID:32511345)\",\n      \"pmids\": [\"32704094\", \"32511345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LY6E restricts HCoV-OC43 entry and the entry mediated by spike proteins of other human coronaviruses including SARS-CoV-2. Overexpression of TMPRSS2 or amphotericin treatment (which overcomes IFITM3 restriction) did not compromise LY6E's effect on CoV entry, indicating a mechanism distinct from IFITM3.\",\n      \"method\": \"Ectopic expression in HEK293, C3A, and A549 cells; LY6E knockdown in HepG2; spike-pseudovirus entry assays; comparison with TMPRSS2 overexpression and amphotericin treatment\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell lines, gain- and loss-of-function, mechanistic distinction from IFITM3 pathway established\",\n      \"pmids\": [\"32641482\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ly6e is a pan-coronavirus restriction factor in the respiratory tract. Using conditional Ly6e knockout mice (seven different Cre lines), Ly6e expression in Lyz2-expressing cells, radioresistant Vav1-expressing cells, and non-haematopoietic cells conferred control of murine coronavirus and SARS-CoV-2. Ly6e protected secretory club and ciliated cells from SARS-CoV-2 infection and prevented virus-induced loss of an epithelial cell transcriptomic signature in the lung.\",\n      \"method\": \"Panel of seven conditional Ly6e knockout mouse lines, murine coronavirus and SARS-CoV-2 infection models, transcriptomic profiling of lung\",\n      \"journal\": \"Nature microbiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic conditional KO across seven cell lineages, in vivo infection models with transcriptomic readout, multiple cell-type-specific conclusions\",\n      \"pmids\": [\"37443277\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LY6E promotes HIV-1 infection by enhancing viral membrane fusion at the entry step. Additionally, LY6E enhances LTR-driven HIV-1 gene expression. Knockdown of LY6E in PBMCs, SupT1, and THP-1 cells diminishes HIV-1 replication. HIV-1 infection itself induces LY6E expression concomitant with type I IFN production.\",\n      \"method\": \"LY6E knockdown (RNAi) in multiple cell lines, virion-cell and cell-cell fusion assays, LTR-reporter assay, HIV-1 replication assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell lines, both fusion assay and gene expression assay, gain- and loss-of-function\",\n      \"pmids\": [\"28130445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"In low-CD4-expressing cells (Jurkat, MDMs), LY6E inhibits HIV-1 entry and spread by downregulating cell surface CD4 via enhanced CD4 internalization. LY6E colocalizes with CD4 on the plasma membrane. Artificially raising CD4 in Jurkat cells overcomes LY6E inhibition; blocking CD4 in SupT1 eliminates LY6E enhancement. Thus LY6E's effect on HIV-1 entry is CD4-level-dependent.\",\n      \"method\": \"LY6E knockdown and overexpression in Jurkat and MDMs, colocalization by microscopy, CD4 internalization assay, CD4 manipulation (overexpression and neutralizing antibody), HIV-1 entry assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (colocalization, internalization, CD4 manipulation), mechanistic model fully validated in two cell types\",\n      \"pmids\": [\"30674630\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"LY6E (Ly6e) is identified as the receptor for mouse endogenous retroviral fusogenic protein Syncytin-A (SynA). Cell-cell fusion assay with cDNA library screening identified Ly6e as a GPI-anchored membrane protein sufficient to mediate SynA-induced cell fusion. siRNA knockdown of Ly6e greatly reduced SynA-induced fusion. Competition with soluble ectodomain of Ly6e confirmed direct interaction. No cross-reactive fusion with Syncytin-B was detected.\",\n      \"method\": \"Cell-cell fusion assay combined with cDNA library screening, transfection rescue, siRNA knockdown, competition assay with soluble Ly6e ectodomain\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — receptor identification by functional screen, confirmed by three independent methods (gain-of-function, siRNA, competition/decoy assay)\",\n      \"pmids\": [\"28679758\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Ly6e is essential for syncytiotrophoblast layer I (ST-I) fusion in the mouse placenta. Ly6e knockout causes embryonic lethality due to failure of syncytiotrophoblast layer I cell-cell fusion and defects in both fetal and maternal vasculature morphogenesis. Epiblast-specific (but not placenta-specific) Ly6e inactivation is compatible with embryonic development, indicating lethality is placental in origin.\",\n      \"method\": \"Ly6e global knockout mice, epiblast-specific and placenta-specific conditional Ly6e knockout, histological and morphological analysis of placenta\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with tissue-specific rescue clearly localizes the functional requirement to the placenta, consistent with receptor identification paper\",\n      \"pmids\": [\"29500366\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Ly6e mRNA is expressed in syncytiotrophoblast cells of the mouse placenta labyrinth, with expression correlating spatially with Syncytin-A. LY6E+ cells express Syncytin-A at higher levels than LY6E- cells. Expression increases with trophoblast differentiation.\",\n      \"method\": \"mRNA in situ hybridization, Northern blot, FACS isolation of LY6E+ cells, RT-PCR\",\n      \"journal\": \"Placenta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization with cell-type fractionation, two orthogonal methods, but no functional manipulation\",\n      \"pmids\": [\"23830620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"LY6E in monocytes negatively modulates CD14 expression and dampens responsiveness to LPS stimulation. In the setting of chronic HIV infection, upregulation of LY6E correlates with reduced CD14 levels on monocytes, but the immunosuppressive effect is insufficient to remedy hyperactivation.\",\n      \"method\": \"LY6E knockdown/overexpression in monocytic cells, LPS stimulation assays, CD14 expression measurement, correlation with chronic HIV patient samples\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — in vitro gain- and loss-of-function with functional LPS response readout, single lab\",\n      \"pmids\": [\"25225669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LY6E downregulates CD14 via ubiquitin-dependent proteasomal degradation. The LY6E protein interactome identified PHB1, which interacts with CD14 in a LY6E-dependent manner. TRIM21 was identified as the major ubiquitin E3 ligase mediating LY6E-dependent ubiquitination of CD14, forming a LY6E-PHB1-TRIM21 assembly.\",\n      \"method\": \"Proteasome inhibitor assays, LY6E interactome profiling (MS), co-immunoprecipitation, TRIM21 knockdown/overexpression, ubiquitination assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — mechanistic dissection with interactome MS, co-IP, ubiquitination assay, and E3 ligase identification; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"37250795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LY6E activates HIF-1 transcription principally at the transcriptional level, leading to upregulation of VEGFA and PDGFB. This occurs through decreased PTEN mRNA expression and subsequent activation of the PI3K/Akt pathway. The LY6E-HIF-1 axis increases tumor blood vessel density and promotes tumor growth in immunodeficient mice.\",\n      \"method\": \"LY6E overexpression/knockdown, HIF-1α reporter and mRNA analysis, PTEN/PI3K/Akt pathway analysis, in vivo xenograft tumor growth and angiogenesis assay\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — pathway dissection with multiple molecular readouts and in vivo model, single lab\",\n      \"pmids\": [\"27589564\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"LY6E is required for TGFβ signaling and proliferation in breast cancer cells, contributing to phosphorylation of Smad1/5 and Smad2/3. LY6E also promotes cytokine-induced PDL1 expression and modulates NK cell binding to cancer cells, and promotes drug resistance.\",\n      \"method\": \"LY6E knockdown in breast cancer cell lines, TGFβ/Smad phosphorylation assays, PDL1 expression assays, NK cell co-culture assays, drug resistance assays\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple pathway readouts with loss-of-function, single lab\",\n      \"pmids\": [\"27197181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"TSA-1/Sca-2 (murine LY6E ortholog) is a GPI-anchored protein that modulates TCR-mediated signaling. Anti-TSA-1 inhibits IL-2 production from T cells stimulated with anti-CD3, reducing CD3 zeta-chain tyrosine phosphorylation. This inhibitory function does not require the GPI anchor, as a transmembrane form of TSA-1 retains inhibitory activity.\",\n      \"method\": \"Anti-TSA-1 antibody treatment of normal T cells and T cell hybridomas, transfection of Jurkat cells with GPI-anchored and transmembrane TSA-1 constructs, IL-2 assay, tyrosine phosphorylation of CD3 zeta by Western blot\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple cell systems, GPI-independent mechanism established by chimeric construct, functional and biochemical readouts\",\n      \"pmids\": [\"7499840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Cross-linking of Ly-6E on T lymphocytes inhibits anti-CD3-induced IL-2 production. Both GPI-anchored and transmembrane forms of Ly-6E (chimeric construct with H-2Db transmembrane/cytoplasmic domain) mediate inhibition of IL-2 production, indicating the inhibitory signaling depends on the extracellular domain and not the GPI anchor. The Ly-6 inhibitory pathway is operative in human cells (Jurkat).\",\n      \"method\": \"Transfection of EL-4J cells with Ly-6 proteins, GPI-to-transmembrane chimeric Ly-6E construct, IL-2 production assays, cross-species functional assay in Jurkat cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — chimeric construct approach is rigorous, functional assay replicated in human cells, single lab\",\n      \"pmids\": [\"8051400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1989,\n      \"finding\": \"LY6E (Ly-6E/A) is a GPI-anchored cell surface protein. Deletion of 12 or 20 C-terminal residues abolishes GPI modification and results in secretion of the protein. Addition of the LFA-3 cytoplasmic tail to the C-terminus partially inhibits GPI addition. Mutation of an Asn residue at the hypothetical cleavage site alters GPI attachment site usage. Two C-terminal regions act as necessary signals for GPI biosynthesis.\",\n      \"method\": \"C-terminal deletion mutagenesis, site-directed mutagenesis, COS cell transient transfection, radiolabeling, SDS-PAGE analysis of secretion vs. membrane retention\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — reconstitution-level mutagenesis defining GPI signal sequences, multiple mutants tested, single lab\",\n      \"pmids\": [\"2796989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"NAT10-mediated ac4C (N4-acetylcytidine) modification of LY6E mRNA at its 3'-UTR is required for LY6E mRNA stability and efficient translation during alphavirus (Sindbis virus) infection. NAT10 is upregulated after alphavirus infection, and loss of NAT10 or inhibition of its acetyltransferase activity reduces alphavirus replication by destabilizing LY6E mRNA.\",\n      \"method\": \"NAT10 knockdown/inhibition, ac4C modification mapping (acRIP-seq or similar), mRNA stability assays, LY6E overexpression rescue, SINV replication assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epitranscriptomic modification site mapped, functional rescue performed, single lab\",\n      \"pmids\": [\"38169284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"GPI biosynthesis pathway acts as a conserved host restriction mechanism against multiple coronaviruses (SARS-CoV-2, HCoV-OC43, PEDV) by disrupting spike protein-mediated membrane fusion at both endosomal and plasma membranes. Focused CRISPR KO screen of 193 GPI-anchored proteins identified LY6E as the key downstream effector of GPI biosynthesis antiviral activity.\",\n      \"method\": \"Genome-wide CRISPR KO screens with three coronaviruses, focused CRISPR KO screen of 193 GPI-APs, fusion assays\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — systematic CRISPR screens across three viruses plus focused GPI-AP screen, identifies LY6E as key effector, multiple orthogonal approaches\",\n      \"pmids\": [\"40901862\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LY6E associates with α5-nAChR and mediates TGF-β1/Smad signaling (specifically pSmad3) and EMT marker expression in non-small cell lung cancer. Silencing both α5-nAChR and LY6E inhibits cell migration more effectively than silencing either alone. α5-nAChR mediates LY6E expression as well as Zeb1, N-cadherin and vimentin expression.\",\n      \"method\": \"siRNA knockdown of LY6E and α5-nAChR, Western blot for pSmad3 and EMT markers, cell migration assays, CAM model, mouse xenograft\",\n      \"journal\": \"Carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — loss-of-function with pathway readouts in vitro and in vivo, single lab, interaction between α5-nAChR and LY6E inferred but not directly demonstrated by co-IP\",\n      \"pmids\": [\"34994389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1986,\n      \"finding\": \"The murine Ly-6E.1 protein is a ~17-18 kDa cell surface antigen with intrachain but not interchain disulfide bonds, does not carry N-linked carbohydrate (tunicamycin-insensitive), and exists as two polypeptide forms. The native molecule behaves as a single polypeptide chain rather than a dimer. In the presence of deoxycholate it elutes as ~31 kDa on gel filtration, consistent with detergent association.\",\n      \"method\": \"Immunoprecipitation from biosynthetically radiolabeled cells, SDS-PAGE (reduced and non-reduced), tunicamycin treatment, pulse-chase, gel filtration, isoelectric focusing\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical characterization with multiple methods, single lab, foundational structural description\",\n      \"pmids\": [\"3941270\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"LY6E facilitates AAV-PHP.eB crossing of the human blood-brain barrier in vitro. RNAi knockdown of LY6E and capsid protein binding assays demonstrated that AAV-PHP.eB delivery across the BBB is mediated by LY6E.\",\n      \"method\": \"Biomimetic BBB chip model, RNAi knockdown of LY6E, virus capsid protein binding assay, AAV crossing efficiency assay\",\n      \"journal\": \"Lab on a chip\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — knockdown and binding assay in in vitro BBB model, consistent with computational prediction, single lab\",\n      \"pmids\": [\"36165190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LY6E regulates IFN-α- and immune complex-induced production of mature IL-1β in macrophages. LY6E modulates NLRP3 inflammasome activation, caspase-1 activation, STING pathway, mitochondrial ROS generation, and CMPK2 activation. LY6E also modulates foam cell formation. LY6E colocalizes with macrophage marker in kidneys from lupus-prone mice and lupus nephritis patients.\",\n      \"method\": \"Bone marrow-derived macrophage culture with LY6E manipulation, NLRP3/caspase-1 activation assays, mtDNA release assay, mtROS measurement, STING pathway assays, CMPK2 activity assay, foam cell assay, immunofluorescence colocalization in kidney tissue\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — multiple pathway readouts in primary macrophages, single lab, mechanistic complexity supports multiple functional links\",\n      \"pmids\": [\"40114200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Nuclear PD-L1 transcriptionally activates LY6E expression by binding to RNA polymerase II subunit POLR2A, forming a transcriptional complex that directly drives LY6E promoter activity. This nuclear PD-L1/POLR2A-LY6E axis promotes IFN-γ-driven lung metastasis of triple-negative breast cancer.\",\n      \"method\": \"CRISPR/Cas9 PD-L1 ablation, RNA-seq, ChIP-seq (nuclear PD-L1 binding), co-immunoprecipitation of PD-L1 and POLR2A, in vivo metastasis assays\",\n      \"journal\": \"Breast cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and Co-IP identify PD-L1/POLR2A complex at LY6E locus, functional rescue in vivo, single lab\",\n      \"pmids\": [\"41388312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Chicken LY6E (SCA2/TSA1) specifically interacts with MDV protein US10, as identified in a bacterial two-hybrid screen and confirmed by in vitro protein-binding assay. LY6E was significantly associated with Marek's disease resistance traits in a commercial chicken population.\",\n      \"method\": \"E. coli two-hybrid screen, in vitro protein-binding assay, linkage analysis in MD resource population\",\n      \"journal\": \"Cytogenetic and genome research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — in vitro binding assay only (no mammalian cell confirmation), single lab, avian ortholog\",\n      \"pmids\": [\"14970721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Mouse Sca-2 (Ly6E ortholog) is a member of the Ly-6 family anchored in the membrane by a GPI moiety, as determined from full-length cDNA sequence from thymocytes.\",\n      \"method\": \"cDNA cloning and sequence analysis, GPI anchor prediction\",\n      \"journal\": \"PNAS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — direct sequence determination establishing GPI anchor structure, foundational structural paper\",\n      \"pmids\": [\"8202484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"High-level IFN-gamma-induced expression of the Ly-6E.1 gene in hematopoietic cells requires a 3' chromatin-dependent region containing DNase I hypersensitive sites at +8.7 and +8.9 kb, which contains a consensus gamma-IFN-responsive element. Both 5' and 3' hypersensitive sites are rapidly induced with IFN-gamma.\",\n      \"method\": \"Deletion constructs of Ly-6E.1 flanking regions, transfection in hematopoietic cells, IFN-gamma induction assays, DNase I hypersensitive site mapping\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — deletion analysis and chromatin mapping identifying regulatory element, functional expression assays, single lab\",\n      \"pmids\": [\"8639891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"IFN-mediated regulation of the Ly-6E gene in T cells requires multiple regulatory regions including the G region needed for both IFN-alpha/beta and IFN-gamma responses. Multiple transcription factors including Oct-1, Oct-2, and HMGI(Y) bind to regulatory elements in the G region. Inhibition of HMG protein expression by antisense HMGI-C RNA abolishes IFN-alpha/beta and IFN-gamma inducibility of the endogenous Ly-6 gene.\",\n      \"method\": \"Promoter deletion analysis, DNA mobility shift assays (EMSA), antisense RNA inhibition of HMGI-C, IFN-induction assays in EL4 cells\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA binding and antisense functional validation, multiple factors identified, single lab\",\n      \"pmids\": [\"10395674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1990,\n      \"finding\": \"PKC (protein kinase C) or a related kinase is required for IFN-mediated Ly-6E induction. PKC inhibitors (H-7, phloretin) block Ly-6E induction by both IFN-gamma and IFN-alpha/beta at mRNA and protein levels. PKC activators (PMA, mezerein) enhance IFN-gamma-mediated but only marginally affect IFN-alpha/beta-mediated Ly-6E induction, indicating IFN-gamma and IFN-alpha/beta utilize overlapping but distinct intracellular pathways.\",\n      \"method\": \"PKC inhibitors and activators applied to YAC T cell lymphoma, Ly-6E mRNA and surface protein measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pharmacological dissection with multiple agents and two readout levels, single lab\",\n      \"pmids\": [\"1692061\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LY6E is an interferon-stimulated, GPI-anchored cell surface protein that dually modulates viral infection: it restricts coronaviruses and (in low-CD4 contexts) HIV-1 by blocking spike/envelope-mediated membrane fusion, while paradoxically enhancing entry of influenza A virus, HIV-1 in high-CD4 cells, and alphaviruses by facilitating post-endosomal uncoating or fusion; mechanistically, it serves as the receptor for the fusogenic retroviral protein Syncytin-A in placental syncytiotrophoblast formation, downregulates CD14 via a LY6E-PHB1-TRIM21 ubiquitin-proteasome axis to dampen LPS responses, modulates TCR signaling by reducing CD3 zeta-chain phosphorylation, and promotes tumor growth through the PTEN/PI3K/Akt/HIF-1 axis; its antiviral activity is downstream of GPI biosynthesis and its mRNA stability is regulated by NAT10-mediated ac4C modification.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LY6E is an interferon-inducible, GPI-anchored cell-surface protein of the Ly-6 family that acts as a bidirectional modulator of viral entry by targeting the membrane fusion step [#0, #1, #17]. Against coronaviruses it is a potent restriction factor, blocking spike protein-mediated membrane fusion at both endosomal and plasma membranes through a mechanism distinct from IFITM3, and was identified by focused CRISPR screening as the key GPI-anchored effector of the GPI-biosynthesis antiviral pathway [#1, #2, #17]. Conditional knockout across multiple lineages established Ly6e as a pan-coronavirus restriction factor that protects respiratory epithelial and immune cells in vivo [#3]. Conversely, LY6E enhances entry of influenza A virus, yellow fever virus, alphaviruses and HIV-1 by promoting post-endosomal uncoating or membrane fusion, with a single loop residue required for the enhancing activity [#0, #4]; its effect on HIV-1 is CD4-level-dependent, restricting entry in low-CD4 cells by driving CD4 internalization while enhancing fusion when CD4 is abundant [#4, #5]. Beyond virology, LY6E serves as the receptor for the retroviral fusogen Syncytin-A and is essential for syncytiotrophoblast layer I cell-cell fusion in the placenta, its loss causing embryonic lethality of placental origin [#6, #7]. LY6E also dampens innate and adaptive immune signaling: it downregulates CD14 to limit LPS responsiveness via a LY6E-PHB1-TRIM21 ubiquitin-proteasome axis [#9, #10], inhibits TCR-induced IL-2 production by reducing CD3 zeta-chain phosphorylation through its extracellular domain independently of the GPI anchor [#13, #14], and modulates NLRP3 inflammasome and STING-dependent IL-1\\u03b2 production in macrophages [#21]. In cancer, LY6E promotes tumor growth and angiogenesis through a PTEN/PI3K/Akt/HIF-1 axis and supports TGF\\u03b2/Smad signaling and EMT [#11, #12, #18]. Its expression is IFN-driven through defined chromatin regulatory elements and is post-transcriptionally stabilized by NAT10-mediated ac4C modification of its mRNA during alphavirus infection [#16, #25, #26].\",\n  \"teleology\": [\n    {\n      \"year\": 1986,\n      \"claim\": \"Established the basic biochemical identity of the protein as a small, disulfide-bonded, non-N-glycosylated cell-surface antigen, providing the structural baseline before any functional role was known.\",\n      \"evidence\": \"Immunoprecipitation, SDS-PAGE, tunicamycin treatment and gel filtration of radiolabeled murine Ly-6E.1\",\n      \"pmids\": [\"3941270\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional activity assigned\", \"GPI anchor not yet demonstrated\", \"Single ortholog characterized\"]\n    },\n    {\n      \"year\": 1989,\n      \"claim\": \"Defined how LY6E is targeted to the membrane, showing two C-terminal signal regions are necessary for GPI biosynthesis and attachment.\",\n      \"evidence\": \"C-terminal deletion and site-directed mutagenesis in COS cells with secretion versus membrane-retention readouts\",\n      \"pmids\": [\"2796989\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of GPI anchoring not addressed\", \"No link to downstream signaling or viral roles\"]\n    },\n    {\n      \"year\": 1995,\n      \"claim\": \"Resolved that LY6E modulates TCR signaling through its extracellular domain rather than its GPI anchor, by reducing CD3 zeta-chain phosphorylation and IL-2 production.\",\n      \"evidence\": \"Anti-TSA-1 antibody treatment and GPI-versus-transmembrane chimeric constructs in T cells and Jurkat, with IL-2 and phospho-zeta readouts (also #14)\",\n      \"pmids\": [\"7499840\", \"8051400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct binding partner transducing the inhibitory signal not identified\", \"Physiological relevance to T-cell responses in vivo not established\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Mapped the cis-regulatory architecture and trans-acting factors driving IFN-inducible LY6E expression, explaining why it behaves as an interferon-stimulated gene.\",\n      \"evidence\": \"Promoter/enhancer deletion constructs, DNase I hypersensitive site mapping, EMSA and antisense HMGI-C inhibition with IFN induction assays (also #26, #27)\",\n      \"pmids\": [\"8639891\", \"10395674\", \"1692061\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human regulatory elements not directly mapped\", \"Connection between IFN induction and antiviral function not yet made\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified LY6E as the cellular receptor for the retroviral fusogen Syncytin-A, linking the protein to physiological cell-cell fusion.\",\n      \"evidence\": \"cDNA library functional screen, siRNA knockdown and soluble-ectodomain competition in cell-cell fusion assays\",\n      \"pmids\": [\"28679758\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the LY6E-SynA interaction not defined\", \"Whether the same surface mediates viral entry enhancement unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstrated that LY6E enhances HIV-1 infection at the membrane fusion step and additionally boosts LTR-driven gene expression, framing it as a proviral factor.\",\n      \"evidence\": \"RNAi knockdown across PBMCs, SupT1 and THP-1, fusion assays, LTR-reporter and replication assays\",\n      \"pmids\": [\"28130445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism of fusion enhancement not defined\", \"Reconciliation with restrictive contexts not yet established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed LY6E enhances diverse RNA virus infections by acting after endosomal escape at the uncoating step, and pinpointed a single loop residue essential for enhancement, defining its proviral mechanism.\",\n      \"evidence\": \"Ectopic expression, influenza A uncoating assays, structure-function mutagenesis and ortholog testing\",\n      \"pmids\": [\"30190477\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct molecular target during uncoating unidentified\", \"How a surface GPI protein acts post-endosomally is unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Established the physiological essentiality of LY6E in placental syncytiotrophoblast layer I fusion, with tissue-specific knockouts localizing embryonic lethality to the placenta.\",\n      \"evidence\": \"Global, epiblast-specific and placenta-specific Ly6e knockout mice with histological analysis (also #8)\",\n      \"pmids\": [\"29500366\", \"23830620\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism connecting receptor engagement to fusion machinery not detailed\", \"Human placental requirement not directly tested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Reconciled LY6E's opposing effects on HIV-1 by showing they are CD4-level-dependent: in low-CD4 cells it restricts entry by internalizing CD4, whereas in high-CD4 cells it enhances fusion.\",\n      \"evidence\": \"Knockdown/overexpression in Jurkat and MDMs, CD4 colocalization and internalization assays, and CD4 manipulation\",\n      \"pmids\": [\"30674630\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How LY6E triggers CD4 internalization mechanistically unclear\", \"Generalizability to primary infection settings not fully tested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined LY6E as a potent coronavirus restriction factor that blocks spike-mediated fusion, distinct from IFITM3, and demonstrated in vivo protection using conditional knockout mice.\",\n      \"evidence\": \"Gain/loss-of-function in multiple cell lines, spike fusion assays, IFITM3 comparison, and conditional KO mice in CoV infection models (also #2)\",\n      \"pmids\": [\"32704094\", \"32511345\", \"32641482\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism by which a GPI protein blocks fusion not resolved\", \"Why LY6E restricts CoV but enhances other viruses unexplained\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Generalized LY6E to a pan-coronavirus respiratory restriction factor and identified the protective cell lineages, showing it shields club and ciliated cells and preserves the lung epithelial transcriptome.\",\n      \"evidence\": \"Seven conditional Ly6e knockout mouse lines with murine CoV and SARS-CoV-2 infection plus lung transcriptomics\",\n      \"pmids\": [\"37443277\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-intrinsic fusion-blocking mechanism still undefined\", \"Relative contribution of each lineage to overall protection not quantified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Elucidated the molecular machinery of LY6E-mediated CD14 downregulation, identifying a LY6E-PHB1-TRIM21 ubiquitin-proteasome assembly.\",\n      \"evidence\": \"Interactome MS, co-immunoprecipitation, proteasome inhibition and ubiquitination assays with TRIM21 manipulation (also #9)\",\n      \"pmids\": [\"37250795\", \"25225669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a surface GPI protein nucleates a cytoplasmic E3 ligase complex unclear\", \"Breadth of LY6E-PHB1-TRIM21 substrates beyond CD14 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified post-transcriptional control of LY6E, showing NAT10-mediated ac4C of its 3'-UTR stabilizes the mRNA and supports translation during alphavirus infection.\",\n      \"evidence\": \"NAT10 knockdown/inhibition, ac4C mapping, mRNA stability assays and LY6E rescue in SINV replication\",\n      \"pmids\": [\"38169284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ac4C regulation operates in other infection contexts untested\", \"Single lab, epitranscriptomic site mapping not orthogonally confirmed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Positioned LY6E as the key downstream effector of a conserved GPI-biosynthesis antiviral pathway against multiple coronaviruses, unifying genetic screen and fusion-block findings.\",\n      \"evidence\": \"Genome-wide and focused CRISPR KO screens of 193 GPI-APs across three coronaviruses with fusion assays\",\n      \"pmids\": [\"40901862\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical step of fusion inhibition still not defined\", \"Why only LY6E among GPI-APs is the effector not fully explained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended LY6E into inflammasome and metastasis biology, showing it modulates NLRP3/STING-driven IL-1\\u03b2 in macrophages and is transcriptionally activated by a nuclear PD-L1/POLR2A complex driving TNBC metastasis.\",\n      \"evidence\": \"Primary macrophage pathway assays with kidney colocalization (#21) and CRISPR PD-L1 ablation with ChIP-seq, Co-IP and in vivo metastasis (#22)\",\n      \"pmids\": [\"40114200\", \"41388312\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link between LY6E and inflammasome components not defined\", \"Single-lab findings without independent replication\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The unifying biochemical mechanism explaining how a single GPI-anchored protein both blocks coronavirus fusion and enhances fusion/uncoating of other enveloped viruses remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of LY6E or its viral-protein interfaces\", \"Direct molecular partners at the fusion membrane unidentified\", \"Determinants dictating restriction versus enhancement undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": [6, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5, 9, 13, 14]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0, 1, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 5, 15, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 3, 9, 21]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 4, 17]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [11, 12, 13]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"complexes\": [\"LY6E-PHB1-TRIM21 assembly\"],\n    \"partners\": [\"Syncytin-A\", \"CD4\", \"PHB1\", \"TRIM21\", \"CD14\", \"POLR2A\", \"CHRNA5\"]\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}