{"gene":"LMAN2L","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2003,"finding":"VIPL (LMAN2L) is a non-cycling resident protein of the ER, unlike VIP36 and ERGIC-53 which cycle in the early secretory pathway. ER retention of VIPL involves a di-arginine (RKR) signal in its cytoplasmic tail, as demonstrated by mutagenesis experiments.","method":"Mutagenesis, subcellular localization (cell culture expression), pulse-chase analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus localization experiments, replicated independently by two separate labs in the same year (PMIDs 12609988 and 12878160)","pmids":["12609988","12878160"],"is_preprint":false},{"year":2003,"finding":"Overexpression of VIPL (LMAN2L) redistributed ERGIC-53 to the ER without affecting the cycling of the KDEL-receptor or overall early secretory pathway morphology, suggesting VIPL functions as a regulator of ERGIC-53.","method":"Overexpression in cell culture with immunofluorescence localization of ERGIC-53","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — single overexpression experiment with localization readout, but independently consistent with the ER-retention finding","pmids":["12609988"],"is_preprint":false},{"year":2003,"finding":"Knockdown of VIPL (LMAN2L) mRNA by siRNA significantly slowed the secretion of two glycoproteins (Mr 35 and 250 kDa), supporting a role for VIPL as an ER export receptor for glycoproteins.","method":"siRNA knockdown with secretion assay (pulse-chase/medium collection)","journal":"Experimental cell research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — loss-of-function with defined secretory phenotype, single lab, single method","pmids":["12878160"],"is_preprint":false},{"year":2003,"finding":"Mutating the retrograde transport signal KR to AA in the VIPL (LMAN2L) cytoplasmic tail (KRFY motif) resulted in transport of VIPL to the cell surface, confirming that the KR motif mediates ER/ERGIC retrieval.","method":"Site-directed mutagenesis with subcellular localization assay (immunofluorescence, surface expression)","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct mutagenesis with functional localization readout, replicated concept across two independent studies (PMIDs 12609988 and 12878160)","pmids":["12878160","12609988"],"is_preprint":false},{"year":2007,"finding":"VIPL (LMAN2L) has sugar-binding activity specific for high-mannose-type N-glycans, preferentially recognizing the Manα1-2Manα1-2Man sequence (deglucosylated trimannose in the D1 branch). Glucosylation of the outer mannose residue blocks binding. Sugar-binding activity is stronger at neutral pH (ER lumen pH) than under acidic conditions.","method":"Flow cytometry with recombinant soluble VIPL, surface plasmon resonance, competition with high-mannose N-glycans, endoglycosidase H treatment","journal":"Glycobiology","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro binding reconstitution with recombinant protein, multiple orthogonal methods (flow cytometry, SPR, glycan competition), confirmed by frontal affinity chromatography in a second independent study (PMID 18025080)","pmids":["17621594","18025080"],"is_preprint":false},{"year":2007,"finding":"Frontal affinity chromatography revealed that the carbohydrate recognition domain (CRD) of VIPL (LMAN2L) selectively interacts with deglucosylated trimannose in the D1 branch of high-mannose-type oligosaccharides in a Ca2+-dependent manner, with different pH dependence compared to VIP36. Structure-based mutagenesis showed that single amino acid substitutions in the CRD can switch the sugar-binding properties among L-type lectins.","method":"Frontal affinity chromatography with pyridylaminated sugar library, Ca2+-dependence assay, structure-based mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative in vitro biochemical assay with defined sugar library, mutagenesis, replicated and extended findings from PMID 17621594","pmids":["18025080"],"is_preprint":false},{"year":2019,"finding":"A frameshift mutation (c.1073delT) eliminating LMAN2L's ER retention signal causes mislocalization of the protein from the ER to the plasma membrane, establishing that the ER retention signal is required for proper subcellular localization and function in brain development.","method":"Genetic analysis of dominant mutation, protein localization assay demonstrating plasma membrane mistargeting","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional localization consequence demonstrated from a naturally occurring human mutation, single study","pmids":["31020005"],"is_preprint":false},{"year":2024,"finding":"HCMV pUS2 targets LMAN2L for proteasomal degradation via the host E3 ligase TRC8 through the ERAD pathway. LMAN2L loss results in downregulation of integrin alpha-6 (ITGA6) from the cell surface, demonstrating that LMAN2L is required for ITGA6 trafficking.","method":"Proteomics (plasma membrane profiling), genetic knockdown/overexpression of pUS2 and TRC8, co-immunoprecipitation","journal":"The Journal of general virology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — proteomic surface profiling plus E3 ligase dependency established, but single study with limited mechanistic depth for LMAN2L's direct role","pmids":["38687323"],"is_preprint":false},{"year":2026,"finding":"LMAN2L co-localizes and physically interacts with STING, and is essential for STING translocation from the ER to the Golgi upon activation. LMAN2L does not affect STING dimerization or TBK1 recruitment. HCMV pUS2 mediates LMAN2L degradation by recruiting the E3 ubiquitin ligase RNF139 and E2 ubiquitin-conjugating enzyme UBE2G2, directing LMAN2L through the ERAD pathway. LMAN2L knockout diminishes HCMV-induced type I interferon and ISG expression.","method":"Co-immunoprecipitation, co-localization (immunofluorescence), LMAN2L knockout with STING pathway readouts (IFN, ISG expression), ERAD pathway analysis with E3/E2 identification","journal":"PLoS pathogens","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — reciprocal Co-IP with functional STING translocation assay and KO phenotype, single lab study","pmids":["42149942"],"is_preprint":false}],"current_model":"LMAN2L (VIPL) is a Ca2+-dependent L-type lectin and non-cycling ER-resident membrane protein that recognizes the Manα1-2Manα1-2Man sequence of high-mannose N-glycans (with binding abolished by glucosylation) at neutral pH, is retained in the ER via a cytoplasmic di-arginine (RKR/KRFY) signal, facilitates glycoprotein ER export (including ITGA6) and STING translocation from the ER to Golgi, and can be targeted for ERAD-mediated proteasomal degradation by HCMV pUS2 acting through E3 ligases TRC8 or RNF139 with E2 enzyme UBE2G2."},"narrative":{"mechanistic_narrative":"LMAN2L (VIPL) is a Ca2+-dependent L-type lectin and ER-resident membrane protein that functions as a cargo recognition factor for high-mannose glycoproteins in the early secretory pathway [PMID:17621594, PMID:18025080]. Unlike the cycling lectins ERGIC-53 and VIP36, LMAN2L is a non-cycling ER resident retained by a cytoplasmic di-arginine (RKR/KRFY) signal; mutation of this motif sends the protein to the cell surface [PMID:12609988, PMID:12878160]. Its carbohydrate recognition domain selectively binds the deglucosylated Manα1-2Manα1-2Man trimannose of the D1 branch of high-mannose N-glycans in a Ca2+-dependent manner, with binding favored at the neutral pH of the ER lumen and abolished by glucosylation of the outer mannose [PMID:17621594, PMID:18025080]. Functionally, LMAN2L supports ER export and trafficking of glycoproteins, including integrin alpha-6 (ITGA6), and is required for STING translocation from the ER to the Golgi upon activation, with its loss diminishing HCMV-induced type I interferon and ISG responses without affecting STING dimerization or TBK1 recruitment [PMID:12878160, PMID:38687323, PMID:42149942]. LMAN2L is itself a target of HCMV-driven ERAD: viral pUS2 recruits the host E3 ligases TRC8 or RNF139 with the E2 enzyme UBE2G2 to direct LMAN2L for proteasomal degradation [PMID:38687323, PMID:42149942]. A frameshift mutation eliminating the ER retention signal causes plasma-membrane mislocalization and links LMAN2L to brain development [PMID:31020005].","teleology":[{"year":2003,"claim":"Established that LMAN2L is a distinct, non-cycling ER-resident lectin whose localization depends on a cytoplasmic di-arginine retrieval signal, distinguishing it from cycling family members ERGIC-53 and VIP36.","evidence":"Mutagenesis of the cytoplasmic RKR/KRFY motif with subcellular localization and pulse-chase analysis in cultured cells, replicated by two labs","pmids":["12609988","12878160"],"confidence":"High","gaps":["Does not identify the retrograde transport machinery reading the di-arginine signal","Does not define the physiological glycoprotein cargo at this stage"]},{"year":2003,"claim":"Implicated LMAN2L in early-secretory-pathway regulation and glycoprotein ER export, addressing what cellular process it serves.","evidence":"Overexpression redistributing ERGIC-53 to the ER, plus siRNA knockdown slowing secretion of two glycoproteins in cultured cells","pmids":["12609988","12878160"],"confidence":"Medium","gaps":["Secreted glycoprotein cargoes identified only by molecular weight, not molecular identity","Mechanistic relationship to ERGIC-53 not resolved"]},{"year":2007,"claim":"Defined the molecular basis of cargo recognition, showing LMAN2L is a Ca2+-dependent lectin selective for the deglucosylated D1-branch trimannose of high-mannose N-glycans, with pH and glucosylation gating binding.","evidence":"Recombinant soluble LMAN2L analyzed by flow cytometry, SPR, frontal affinity chromatography with a pyridylaminated sugar library, and structure-based CRD mutagenesis","pmids":["17621594","18025080"],"confidence":"High","gaps":["In vitro glycan binding not directly linked to specific endogenous cargo in cells","Crystal structure of LMAN2L itself not reported"]},{"year":2019,"claim":"Connected the ER retention signal to organismal physiology, showing loss of retention causes plasma-membrane mislocalization and links LMAN2L to brain development.","evidence":"Genetic analysis of a dominant frameshift mutation (c.1073delT) with protein localization assay","pmids":["31020005"],"confidence":"Medium","gaps":["Cellular mechanism connecting mislocalization to neurodevelopmental phenotype unresolved","Single study"]},{"year":2024,"claim":"Identified a specific endogenous trafficking cargo and revealed LMAN2L as a viral ERAD target, showing LMAN2L is required for cell-surface ITGA6 and is degraded by HCMV pUS2 via TRC8.","evidence":"Plasma-membrane proteomic profiling, pUS2/TRC8 knockdown and overexpression, and co-immunoprecipitation","pmids":["38687323"],"confidence":"Medium","gaps":["Direct lectin-glycan interaction with ITGA6 not biochemically demonstrated","Single study with limited mechanistic depth"]},{"year":2026,"claim":"Placed LMAN2L in innate antiviral signaling, showing it physically interacts with STING and is essential for STING ER-to-Golgi translocation and downstream interferon responses, and is degraded via pUS2-RNF139-UBE2G2 ERAD.","evidence":"Reciprocal co-immunoprecipitation, co-localization, LMAN2L knockout with STING translocation and IFN/ISG readouts, and E3/E2 identification","pmids":["42149942"],"confidence":"Medium","gaps":["Whether STING engagement is glycan-dependent via the CRD is not established","Single-lab study","Distinction between TRC8 and RNF139 as the operative ligase across contexts unresolved"]},{"year":null,"claim":"It remains unknown how LMAN2L's lectin glycan-recognition activity mechanistically couples to selection of specific cargoes such as ITGA6 and STING and to its neurodevelopmental role.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of LMAN2L CRD bound to physiological cargo","Recruitment/retrieval machinery for the di-arginine signal not identified","Glycan-dependence of STING and ITGA6 handling untested"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,6]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[2,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8]}],"complexes":[],"partners":["STING1","ITGA6","ERGIC-53"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9H0V9","full_name":"VIP36-like protein","aliases":["Lectin mannose-binding 2-like","LMAN2-like protein"],"length_aa":348,"mass_kda":39.7,"function":"May be involved in the regulation of export from the endoplasmic reticulum of a subset of glycoproteins. May function as a regulator of ERGIC-53","subcellular_location":"Endoplasmic reticulum membrane; Golgi apparatus membrane","url":"https://www.uniprot.org/uniprotkb/Q9H0V9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LMAN2L","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CERS6","stoichiometry":4.0},{"gene":"ANKRD46","stoichiometry":0.2},{"gene":"CANX","stoichiometry":0.2},{"gene":"COPE","stoichiometry":0.2},{"gene":"RER1","stoichiometry":0.2},{"gene":"TMED10","stoichiometry":0.2},{"gene":"TMED2","stoichiometry":0.2},{"gene":"YIPF5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/LMAN2L","total_profiled":1310},"omim":[{"mim_id":"617863","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL DOMINANT 69; MRD69","url":"https://www.omim.org/entry/617863"},{"mim_id":"616887","title":"INTELLECTUAL DEVELOPMENTAL DISORDER, AUTOSOMAL RECESSIVE 52; MRT52","url":"https://www.omim.org/entry/616887"},{"mim_id":"609552","title":"LECTIN, MANNOSE-BINDING 2-LIKE; LMAN2L","url":"https://www.omim.org/entry/609552"},{"mim_id":"601567","title":"LECTIN, MANNOSE-BINDING 1; LMAN1","url":"https://www.omim.org/entry/601567"},{"mim_id":"137570","title":"SOLUTE CARRIER FAMILY 20 (PHOSPHATE TRANSPORTER), MEMBER 1; SLC20A1","url":"https://www.omim.org/entry/137570"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/LMAN2L"},"hgnc":{"alias_symbol":["DKFZp564L2423","VIPL"],"prev_symbol":[]},"alphafold":{"accession":"Q9H0V9","domains":[{"cath_id":"2.60.120.200","chopping":"47-293","consensus_level":"high","plddt":93.25,"start":47,"end":293}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0V9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0V9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9H0V9-F1-predicted_aligned_error_v6.png","plddt_mean":84.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LMAN2L","jax_strain_url":"https://www.jax.org/strain/search?query=LMAN2L"},"sequence":{"accession":"Q9H0V9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9H0V9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9H0V9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9H0V9"}},"corpus_meta":[{"pmid":"18025080","id":"PMC_18025080","title":"Molecular basis of sugar recognition by the human L-type lectins ERGIC-53, VIPL, and VIP36.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18025080","citation_count":121,"is_preprint":false},{"pmid":"12609988","id":"PMC_12609988","title":"Profile-based data base scanning for animal L-type lectins and characterization of VIPL, a novel VIP36-like endoplasmic reticulum protein.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12609988","citation_count":59,"is_preprint":false},{"pmid":"12878160","id":"PMC_12878160","title":"VIPL, a VIP36-like membrane protein with a putative function in the export of glycoproteins from the endoplasmic reticulum.","date":"2003","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/12878160","citation_count":50,"is_preprint":false},{"pmid":"24914473","id":"PMC_24914473","title":"Genetic association of LMAN2L gene in schizophrenia and bipolar disorder and its interaction with ANK3 gene polymorphism.","date":"2014","source":"Progress in neuro-psychopharmacology & biological psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/24914473","citation_count":21,"is_preprint":false},{"pmid":"17621594","id":"PMC_17621594","title":"VIPL has sugar-binding activity specific for high-mannose-type N-glycans, and glucosylation of the alpha1,2 mannotriosyl branch blocks its binding.","date":"2007","source":"Glycobiology","url":"https://pubmed.ncbi.nlm.nih.gov/17621594","citation_count":18,"is_preprint":false},{"pmid":"26566883","id":"PMC_26566883","title":"Homozygous missense mutation in the LMAN2L gene segregates with intellectual disability in a large consanguineous Pakistani family.","date":"2015","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26566883","citation_count":14,"is_preprint":false},{"pmid":"33116598","id":"PMC_33116598","title":"Long Non-Coding RNA LINC00662 Regulated Proliferation and Migration by Targeting miR-34a-5p/LMAN2L Axis in Glioma.","date":"2020","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/33116598","citation_count":12,"is_preprint":false},{"pmid":"31020005","id":"PMC_31020005","title":"Dominant LMAN2L mutation causes intellectual disability with remitting epilepsy.","date":"2019","source":"Annals of clinical and translational neurology","url":"https://pubmed.ncbi.nlm.nih.gov/31020005","citation_count":10,"is_preprint":false},{"pmid":"38687323","id":"PMC_38687323","title":"HCMV US2 co-opts TRC8 to degrade the endoplasmic reticulum-resident protein LMAN2L.","date":"2024","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/38687323","citation_count":2,"is_preprint":false},{"pmid":"42149942","id":"PMC_42149942","title":"HCMV-pUS2 Disrupts cGAS-STING Signaling through LMAN2L Degradation.","date":"2026","source":"PLoS pathogens","url":"https://pubmed.ncbi.nlm.nih.gov/42149942","citation_count":0,"is_preprint":false},{"pmid":"40221759","id":"PMC_40221759","title":"Novel compound heterozygous mutations in LMAN2L cause early childhood refractory epilepsy.","date":"2025","source":"Italian journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/40221759","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7796,"output_tokens":2327,"usd":0.029146,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9342,"output_tokens":2550,"usd":0.05523,"stage2_stop_reason":"end_turn"},"total_usd":0.084376,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"VIPL (LMAN2L) is a non-cycling resident protein of the ER, unlike VIP36 and ERGIC-53 which cycle in the early secretory pathway. ER retention of VIPL involves a di-arginine (RKR) signal in its cytoplasmic tail, as demonstrated by mutagenesis experiments.\",\n      \"method\": \"Mutagenesis, subcellular localization (cell culture expression), pulse-chase analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus localization experiments, replicated independently by two separate labs in the same year (PMIDs 12609988 and 12878160)\",\n      \"pmids\": [\"12609988\", \"12878160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Overexpression of VIPL (LMAN2L) redistributed ERGIC-53 to the ER without affecting the cycling of the KDEL-receptor or overall early secretory pathway morphology, suggesting VIPL functions as a regulator of ERGIC-53.\",\n      \"method\": \"Overexpression in cell culture with immunofluorescence localization of ERGIC-53\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single overexpression experiment with localization readout, but independently consistent with the ER-retention finding\",\n      \"pmids\": [\"12609988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Knockdown of VIPL (LMAN2L) mRNA by siRNA significantly slowed the secretion of two glycoproteins (Mr 35 and 250 kDa), supporting a role for VIPL as an ER export receptor for glycoproteins.\",\n      \"method\": \"siRNA knockdown with secretion assay (pulse-chase/medium collection)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — loss-of-function with defined secretory phenotype, single lab, single method\",\n      \"pmids\": [\"12878160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Mutating the retrograde transport signal KR to AA in the VIPL (LMAN2L) cytoplasmic tail (KRFY motif) resulted in transport of VIPL to the cell surface, confirming that the KR motif mediates ER/ERGIC retrieval.\",\n      \"method\": \"Site-directed mutagenesis with subcellular localization assay (immunofluorescence, surface expression)\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct mutagenesis with functional localization readout, replicated concept across two independent studies (PMIDs 12609988 and 12878160)\",\n      \"pmids\": [\"12878160\", \"12609988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"VIPL (LMAN2L) has sugar-binding activity specific for high-mannose-type N-glycans, preferentially recognizing the Manα1-2Manα1-2Man sequence (deglucosylated trimannose in the D1 branch). Glucosylation of the outer mannose residue blocks binding. Sugar-binding activity is stronger at neutral pH (ER lumen pH) than under acidic conditions.\",\n      \"method\": \"Flow cytometry with recombinant soluble VIPL, surface plasmon resonance, competition with high-mannose N-glycans, endoglycosidase H treatment\",\n      \"journal\": \"Glycobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro binding reconstitution with recombinant protein, multiple orthogonal methods (flow cytometry, SPR, glycan competition), confirmed by frontal affinity chromatography in a second independent study (PMID 18025080)\",\n      \"pmids\": [\"17621594\", \"18025080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Frontal affinity chromatography revealed that the carbohydrate recognition domain (CRD) of VIPL (LMAN2L) selectively interacts with deglucosylated trimannose in the D1 branch of high-mannose-type oligosaccharides in a Ca2+-dependent manner, with different pH dependence compared to VIP36. Structure-based mutagenesis showed that single amino acid substitutions in the CRD can switch the sugar-binding properties among L-type lectins.\",\n      \"method\": \"Frontal affinity chromatography with pyridylaminated sugar library, Ca2+-dependence assay, structure-based mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative in vitro biochemical assay with defined sugar library, mutagenesis, replicated and extended findings from PMID 17621594\",\n      \"pmids\": [\"18025080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A frameshift mutation (c.1073delT) eliminating LMAN2L's ER retention signal causes mislocalization of the protein from the ER to the plasma membrane, establishing that the ER retention signal is required for proper subcellular localization and function in brain development.\",\n      \"method\": \"Genetic analysis of dominant mutation, protein localization assay demonstrating plasma membrane mistargeting\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional localization consequence demonstrated from a naturally occurring human mutation, single study\",\n      \"pmids\": [\"31020005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"HCMV pUS2 targets LMAN2L for proteasomal degradation via the host E3 ligase TRC8 through the ERAD pathway. LMAN2L loss results in downregulation of integrin alpha-6 (ITGA6) from the cell surface, demonstrating that LMAN2L is required for ITGA6 trafficking.\",\n      \"method\": \"Proteomics (plasma membrane profiling), genetic knockdown/overexpression of pUS2 and TRC8, co-immunoprecipitation\",\n      \"journal\": \"The Journal of general virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — proteomic surface profiling plus E3 ligase dependency established, but single study with limited mechanistic depth for LMAN2L's direct role\",\n      \"pmids\": [\"38687323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"LMAN2L co-localizes and physically interacts with STING, and is essential for STING translocation from the ER to the Golgi upon activation. LMAN2L does not affect STING dimerization or TBK1 recruitment. HCMV pUS2 mediates LMAN2L degradation by recruiting the E3 ubiquitin ligase RNF139 and E2 ubiquitin-conjugating enzyme UBE2G2, directing LMAN2L through the ERAD pathway. LMAN2L knockout diminishes HCMV-induced type I interferon and ISG expression.\",\n      \"method\": \"Co-immunoprecipitation, co-localization (immunofluorescence), LMAN2L knockout with STING pathway readouts (IFN, ISG expression), ERAD pathway analysis with E3/E2 identification\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — reciprocal Co-IP with functional STING translocation assay and KO phenotype, single lab study\",\n      \"pmids\": [\"42149942\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LMAN2L (VIPL) is a Ca2+-dependent L-type lectin and non-cycling ER-resident membrane protein that recognizes the Manα1-2Manα1-2Man sequence of high-mannose N-glycans (with binding abolished by glucosylation) at neutral pH, is retained in the ER via a cytoplasmic di-arginine (RKR/KRFY) signal, facilitates glycoprotein ER export (including ITGA6) and STING translocation from the ER to Golgi, and can be targeted for ERAD-mediated proteasomal degradation by HCMV pUS2 acting through E3 ligases TRC8 or RNF139 with E2 enzyme UBE2G2.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LMAN2L (VIPL) is a Ca2+-dependent L-type lectin and ER-resident membrane protein that functions as a cargo recognition factor for high-mannose glycoproteins in the early secretory pathway [#4, #5]. Unlike the cycling lectins ERGIC-53 and VIP36, LMAN2L is a non-cycling ER resident retained by a cytoplasmic di-arginine (RKR/KRFY) signal; mutation of this motif sends the protein to the cell surface [#0, #3]. Its carbohydrate recognition domain selectively binds the deglucosylated Manα1-2Manα1-2Man trimannose of the D1 branch of high-mannose N-glycans in a Ca2+-dependent manner, with binding favored at the neutral pH of the ER lumen and abolished by glucosylation of the outer mannose [#4, #5]. Functionally, LMAN2L supports ER export and trafficking of glycoproteins, including integrin alpha-6 (ITGA6), and is required for STING translocation from the ER to the Golgi upon activation, with its loss diminishing HCMV-induced type I interferon and ISG responses without affecting STING dimerization or TBK1 recruitment [#2, #7, #8]. LMAN2L is itself a target of HCMV-driven ERAD: viral pUS2 recruits the host E3 ligases TRC8 or RNF139 with the E2 enzyme UBE2G2 to direct LMAN2L for proteasomal degradation [#7, #8]. A frameshift mutation eliminating the ER retention signal causes plasma-membrane mislocalization and links LMAN2L to brain development [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that LMAN2L is a distinct, non-cycling ER-resident lectin whose localization depends on a cytoplasmic di-arginine retrieval signal, distinguishing it from cycling family members ERGIC-53 and VIP36.\",\n      \"evidence\": \"Mutagenesis of the cytoplasmic RKR/KRFY motif with subcellular localization and pulse-chase analysis in cultured cells, replicated by two labs\",\n      \"pmids\": [\"12609988\", \"12878160\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not identify the retrograde transport machinery reading the di-arginine signal\", \"Does not define the physiological glycoprotein cargo at this stage\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Implicated LMAN2L in early-secretory-pathway regulation and glycoprotein ER export, addressing what cellular process it serves.\",\n      \"evidence\": \"Overexpression redistributing ERGIC-53 to the ER, plus siRNA knockdown slowing secretion of two glycoproteins in cultured cells\",\n      \"pmids\": [\"12609988\", \"12878160\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Secreted glycoprotein cargoes identified only by molecular weight, not molecular identity\", \"Mechanistic relationship to ERGIC-53 not resolved\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defined the molecular basis of cargo recognition, showing LMAN2L is a Ca2+-dependent lectin selective for the deglucosylated D1-branch trimannose of high-mannose N-glycans, with pH and glucosylation gating binding.\",\n      \"evidence\": \"Recombinant soluble LMAN2L analyzed by flow cytometry, SPR, frontal affinity chromatography with a pyridylaminated sugar library, and structure-based CRD mutagenesis\",\n      \"pmids\": [\"17621594\", \"18025080\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vitro glycan binding not directly linked to specific endogenous cargo in cells\", \"Crystal structure of LMAN2L itself not reported\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected the ER retention signal to organismal physiology, showing loss of retention causes plasma-membrane mislocalization and links LMAN2L to brain development.\",\n      \"evidence\": \"Genetic analysis of a dominant frameshift mutation (c.1073delT) with protein localization assay\",\n      \"pmids\": [\"31020005\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cellular mechanism connecting mislocalization to neurodevelopmental phenotype unresolved\", \"Single study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified a specific endogenous trafficking cargo and revealed LMAN2L as a viral ERAD target, showing LMAN2L is required for cell-surface ITGA6 and is degraded by HCMV pUS2 via TRC8.\",\n      \"evidence\": \"Plasma-membrane proteomic profiling, pUS2/TRC8 knockdown and overexpression, and co-immunoprecipitation\",\n      \"pmids\": [\"38687323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct lectin-glycan interaction with ITGA6 not biochemically demonstrated\", \"Single study with limited mechanistic depth\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Placed LMAN2L in innate antiviral signaling, showing it physically interacts with STING and is essential for STING ER-to-Golgi translocation and downstream interferon responses, and is degraded via pUS2-RNF139-UBE2G2 ERAD.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation, co-localization, LMAN2L knockout with STING translocation and IFN/ISG readouts, and E3/E2 identification\",\n      \"pmids\": [\"42149942\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether STING engagement is glycan-dependent via the CRD is not established\", \"Single-lab study\", \"Distinction between TRC8 and RNF139 as the operative ligase across contexts unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how LMAN2L's lectin glycan-recognition activity mechanistically couples to selection of specific cargoes such as ITGA6 and STING and to its neurodevelopmental role.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of LMAN2L CRD bound to physiological cargo\", \"Recruitment/retrieval machinery for the di-arginine signal not identified\", \"Glycan-dependence of STING and ITGA6 handling untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0030246\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [2, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"STING1\", \"ITGA6\", \"ERGIC-53\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}