{"gene":"MAN1B1","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2011,"finding":"MAN1B1 encodes an alpha-1,2-mannosidase; missense mutations (p.Glu397Lys and p.Arg334Cys) at conserved residues either reduce kcat by ~1300-fold or disrupt stable protein expression in mammalian cells, establishing that catalytic activity is required for normal function.","method":"Sanger sequencing, biochemical kinetic assay, protein expression analysis in mammalian cells","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — enzymatic kcat measurement and expression assay, single lab, two orthogonal methods","pmids":["21763484"],"is_preprint":false},{"year":2011,"finding":"Endogenous human ERManI (MAN1B1) predominantly resides in the Golgi complex (not the ER), where it is subjected to O-glycosylation. Appending a COPI-binding motif to partially redistribute ERManI to the ER accelerated N-glycan trimming of misfolded alpha1-antitrypsin NHK but did not accelerate NHK degradation, implicating the Golgi as the site where the glycoprotein ERAD substrate tagging signal is generated.","method":"Subcellular fractionation, immunofluorescence localization, O-glycosylation biochemical analysis, COPI-binding motif fusion redistribution experiment, metabolic pulse-chase degradation assay","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (localization, glycosylation biochemistry, engineered redistribution, pulse-chase) in a single rigorous study","pmids":["21697506"],"is_preprint":false},{"year":2013,"finding":"Golgi-localized ERManI (MAN1B1) is confirmed in human cells; loss of MAN1B1 function causes altered Golgi morphology (dilatation and fragmentation) in patient-derived cells, and MAN1B1 mutations result in accumulation of hybrid-type N-glycans consistent with deficient mannosidase activity.","method":"Exome sequencing, patient fibroblast immunofluorescence (Golgi morphology), glycan analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — patient cell-based localization and Golgi morphology phenotype, glycan biochemistry, two methods","pmids":["24348268"],"is_preprint":false},{"year":2014,"finding":"MAN1B1 plays a non-enzymatic, catalysis-independent gatekeeper role in Golgi-based protein quality control: neither the mannosidase activity nor the catalytic domain is essential for retention or degradation of misfolded ERAD substrate Null Hong Kong (NHK). Instead, a conserved vertebrate-specific non-enzymatic decapeptide sequence in the luminal stem domain controls the fate of misfolded NHK.","method":"Catalytic site mutagenesis, domain deletion/truncation constructs, ERAD substrate (NHK) degradation assays, multiple biochemical reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis combined with domain-truncation experiments and multiple orthogonal ERAD readouts in one study","pmids":["24627495"],"is_preprint":false},{"year":2015,"finding":"ERManI (MAN1B1) is required for HIV-1 envelope glycoprotein degradation via ERAD: ectopic ERManI inhibits HIV-1 Env expression in a dose-dependent manner; CRISPR/Cas9 knockout of MAN1B1 disrupts TSPO-mediated Env degradation; HIV-1 Env physically interacts with ERManI; the ERManI catalytic domain is critical for the Env-ERManI interaction; inactivation of the catalytic site by mutagenesis disrupts ERManI activity.","method":"Ectopic expression, CRISPR/Cas9 knockout, co-immunoprecipitation, domain-mapping constructs, site-directed mutagenesis of catalytic site, biochemical degradation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — CRISPR KO, co-IP, domain mapping, and catalytic site mutagenesis all in one study with multiple orthogonal methods","pmids":["26205822"],"is_preprint":false},{"year":2020,"finding":"MAN1B1 has a functional dichotomy in ERAD: (1) a conventional catalysis-dependent system requiring an intact active site in the luminal domain to accelerate proteasomal degradation of misfolded N-glycosylated alpha1-antitrypsin variants NHK and ATZ; (2) an unconventional catalysis-independent system controlled by an evolutionarily extended N-terminal cytoplasmic tail that accelerates degradation independently of N-glycans on the misfolded substrate.","method":"Man1b1 knockout HEK293T cells, transfection of mutated/truncated Man1b1 constructs, metabolic pulse-chase labeling, proteasome inhibitor assays, N-glycan site mutagenesis on ERAD substrates","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — KO cells + reconstitution with mutant/truncated constructs + pulse-chase + multiple orthogonal substrate tests in one rigorous study","pmids":["32958677"],"is_preprint":false},{"year":2013,"finding":"ERManI (MAN1B1) is a target of miR-125b via a conserved motif in its 3'UTR; knockdown of endogenous ERManI in hepatoma cells inhibits proliferation, migration, and invasion without altering global glycoprotein secretion or ER-stress status, indicating a role in hepatocellular carcinoma independent of its glycoprotein quality control function.","method":"3'UTR reporter assay (miR-125b target validation), RNAi knockdown, cell proliferation/migration/invasion assays, global glycoprotein secretion assay, ER stress markers","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — RNAi phenotype with multiple orthogonal functional readouts plus 3'UTR reporter, single lab","pmids":["23940818"],"is_preprint":false},{"year":2025,"finding":"Membralin (TMEM259) recruits MAN1B1 through its luminal loop and VCP/p97 through its cytoplasmic loop to assemble a selective ERLAD complex. This Membralin-MAN1B1-VCP axis targets viral class I fusion glycoproteins (SARS-CoV-2 spike, Ebola GP, influenza HA, HIV-1 Env) for lysosomal degradation via a ubiquitin-independent, LC3/autophagy-dependent pathway, while misfolded host glycoproteins are cleared via canonical ERAD. The complex selectively recognizes densely glycosylated substrates. Loss of MAN1B1 markedly enhances pseudoviral infectivity.","method":"Co-immunoprecipitation (Membralin-MAN1B1-VCP complex), domain-mapping (luminal loop responsible for MAN1B1 recruitment), MAN1B1 knockout, pseudoviral infectivity assay, lysosomal degradation assay, LC3-LIR functional analysis","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, KO phenotype, functional viral assays; single lab, newly published","pmids":["41324484"],"is_preprint":false},{"year":2025,"finding":"ERK activation stabilizes MAN1B1 protein by regulating the interaction between MAN1B1 and the E3 ubiquitin ligase HRD1; abnormally activated ERK prevents HRD1-mediated ubiquitination/degradation of MAN1B1, resulting in elevated MAN1B1 levels that glycosylate CD47 and enhance its interaction with SIRPα, facilitating tumor immune evasion.","method":"Western blotting, co-immunoprecipitation (MAN1B1-HRD1 interaction), MAN1B1 knockout (in vitro and murine model), ERK inhibition, phagocytosis assays, patient-derived tumor-like cell clusters","journal":"Cancer communications (London, England)","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP of MAN1B1-HRD1, KO phenotype in vitro and in vivo, functional phagocytosis readout, single lab","pmids":["40493414"],"is_preprint":false},{"year":2025,"finding":"A short luminal juxtamembrane peptide with a specific helical charge distribution at the transmembrane-luminal interface determines ERManI (MAN1B1) localization to quality control vesicles (QCVs) versus Golgi. Site-directed mutagenesis disrupting the charge pattern or altering helical register shifts localization from QCVs to Golgi; grafting this peptide onto an unrelated transmembrane protein (beta-1,3-galactosyltransferase) redirected it from Golgi to QCVs.","method":"Site-directed mutagenesis of luminal juxtamembrane charged residues, alanine insertion mutagenesis (helical register shift), domain-grafting experiment, live-cell immunofluorescence localization, structural prediction","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutagenesis plus domain-grafting experiment with localization readout; preprint, single lab, not yet peer-reviewed","pmids":["bio_10.1101_2025.11.12.688035"],"is_preprint":true}],"current_model":"MAN1B1 encodes a Golgi-localized (not ER-resident) alpha-1,2-mannosidase that functions in N-glycoprotein quality control via two distinct mechanisms: a conventional catalysis-dependent pathway requiring active-site integrity to generate a mannose-trimmed ERAD signal on misfolded N-glycoproteins, and an unconventional catalysis-independent pathway governed by its N-terminal cytoplasmic tail (and a luminal stem decapeptide) that retains and routes misfolded glycoproteins for proteasomal degradation without requiring glycan trimming; additionally, MAN1B1 is recruited by the ER-phagy receptor Membralin into a MAN1B1-VCP complex that selectively degrades densely glycosylated viral envelope glycoproteins via lysosomes, and its protein stability is regulated by ERK-dependent modulation of its interaction with the E3 ubiquitin ligase HRD1."},"narrative":{"mechanistic_narrative":"MAN1B1 encodes a Golgi-localized alpha-1,2-mannosidase (ERManI) that functions in N-glycoprotein quality control and endoplasmic-reticulum-associated degradation (ERAD) [PMID:21763484, PMID:21697506]. Endogenous human ERManI resides predominantly in the Golgi rather than the ER, where it is O-glycosylated and generates the mannose-trimmed glycan signal that tags misfolded N-glycoproteins for proteasomal degradation; redistributing it toward the ER accelerates glycan trimming of misfolded alpha1-antitrypsin but not substrate degradation, placing the tagging step in the Golgi [PMID:21697506]. MAN1B1 acts through two mechanistically distinct routes: a conventional catalysis-dependent system requiring an intact luminal active site to accelerate degradation of misfolded alpha1-antitrypsin variants NHK and ATZ, and an unconventional catalysis-independent gatekeeper function in which an extended N-terminal cytoplasmic tail and a conserved luminal stem decapeptide route misfolded substrates for degradation without glycan trimming [PMID:24627495, PMID:32958677]. Beyond host quality control, MAN1B1 is recruited by the ER-phagy receptor Membralin into a Membralin-MAN1B1-VCP complex that selectively directs densely glycosylated viral envelope glycoproteins to lysosomal degradation via a ubiquitin-independent, LC3-dependent pathway, and its loss enhances pseudoviral infectivity [PMID:41324484]; consistent with a direct antiviral role, ERManI physically interacts with and is required for ERAD of HIV-1 envelope glycoprotein [PMID:26205822]. MAN1B1 protein stability is set by ERK-dependent control of its interaction with the E3 ubiquitin ligase HRD1, and elevated MAN1B1 promotes CD47 glycosylation and tumor immune evasion [PMID:40493414]. Loss-of-function mutations at conserved catalytic residues cause altered Golgi morphology and accumulation of hybrid-type N-glycans in patient cells, defining a congenital disorder of glycosylation [PMID:21763484, PMID:24348268].","teleology":[{"year":2011,"claim":"Establishing that MAN1B1 is an alpha-1,2-mannosidase whose catalytic activity is required for normal function answered whether the gene's disease relevance is enzymatic.","evidence":"Sanger sequencing of patients plus kinetic and expression assays of missense mutants in mammalian cells","pmids":["21763484"],"confidence":"Medium","gaps":["Did not localize the enzyme or define which substrates it acts on","Does not separate loss of catalysis from loss of protein stability as the disease driver"]},{"year":2011,"claim":"Localizing endogenous ERManI to the Golgi rather than the ER reassigned where the ERAD glycan-tagging signal is generated, overturning the assumption of ER residence.","evidence":"Subcellular fractionation, immunofluorescence, O-glycosylation analysis, COPI-motif redistribution, and pulse-chase degradation in human cells","pmids":["21697506"],"confidence":"High","gaps":["Mechanism coupling Golgi trimming to downstream proteasomal delivery not defined","Did not address catalysis-independent functions"]},{"year":2013,"claim":"Patient-derived cells linked MAN1B1 loss to altered Golgi morphology and hybrid-type N-glycan accumulation, connecting the enzyme defect to a cellular and glycomic phenotype.","evidence":"Exome sequencing, fibroblast immunofluorescence, and glycan analysis","pmids":["24348268"],"confidence":"Medium","gaps":["Causality between Golgi dilatation and mannosidase loss not mechanistically resolved"]},{"year":2013,"claim":"Identification of MAN1B1 as a miR-125b target with proliferation/migration/invasion phenotypes raised a quality-control-independent role in hepatocellular carcinoma.","evidence":"3'UTR reporter, RNAi knockdown, and functional cell assays in hepatoma cells","pmids":["23940818"],"confidence":"Medium","gaps":["Molecular basis of the cancer phenotype distinct from glycoprotein QC not defined","Single cell-type context"]},{"year":2014,"claim":"Demonstrating that neither catalysis nor the catalytic domain is required for retention/degradation of misfolded NHK revealed a non-enzymatic gatekeeper function localized to a luminal stem decapeptide.","evidence":"Active-site mutagenesis, domain truncations, and ERAD reporter assays","pmids":["24627495"],"confidence":"High","gaps":["Binding partners executing the non-enzymatic routing not identified","How the decapeptide selects substrates unknown"]},{"year":2015,"claim":"Showing ERManI is required for HIV-1 Env ERAD and physically interacts with Env via its catalytic domain extended MAN1B1 function to viral glycoprotein clearance.","evidence":"Ectopic expression, CRISPR knockout, co-IP, domain mapping, and catalytic-site mutagenesis","pmids":["26205822"],"confidence":"High","gaps":["Degradation route (proteasome vs lysosome) for Env not resolved here","Relationship to the non-enzymatic pathway unclear"]},{"year":2020,"claim":"Resolving the functional dichotomy distinguished a luminal catalysis-dependent ERAD system from an N-terminal cytoplasmic-tail-driven catalysis- and glycan-independent system.","evidence":"Knockout HEK293T reconstitution with mutant/truncated constructs, pulse-chase, proteasome inhibition, and substrate N-glycan-site mutagenesis","pmids":["32958677"],"confidence":"High","gaps":["Effectors recruited by the cytoplasmic tail not identified","Structural basis for dual mechanism not defined"]},{"year":2025,"claim":"Defining the Membralin-MAN1B1-VCP complex established a ubiquitin-independent, LC3-dependent ERLAD route that selectively degrades densely glycosylated viral fusion glycoproteins.","evidence":"Reciprocal co-IP with domain mapping, MAN1B1 knockout, pseudoviral infectivity, and lysosomal/LC3-LIR functional assays","pmids":["41324484"],"confidence":"Medium","gaps":["Single lab, newly published","How dense glycosylation is sensed mechanistically not resolved","Stoichiometry and assembly order of the complex unknown"]},{"year":2025,"claim":"Linking ERK to HRD1-mediated MAN1B1 turnover explained how MAN1B1 levels are set and connected its stabilization to CD47 glycosylation and tumor immune evasion.","evidence":"Western blotting, MAN1B1-HRD1 co-IP, MAN1B1 knockout in vitro and in mice, ERK inhibition, and phagocytosis assays","pmids":["40493414"],"confidence":"Medium","gaps":["Whether MAN1B1 directly glycosylates CD47 vs acts indirectly not fully resolved","Single lab"]},{"year":2025,"claim":"A luminal juxtamembrane helical charge motif was shown to partition ERManI between quality-control vesicles and the Golgi, identifying a sorting determinant for its localization.","evidence":"Charge/helical-register mutagenesis, domain grafting onto an unrelated transmembrane protein, and live-cell localization (preprint)","pmids":["bio_10.1101_2025.11.12.688035"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Identity of the trafficking machinery reading this motif unknown","Functional consequence of QCV vs Golgi residence for ERAD not established"]},{"year":null,"claim":"How the catalytic, non-enzymatic cytoplasmic-tail, ERLAD, and trafficking activities are integrated and coordinated on individual substrates remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model coupling the dual mechanisms","Cytoplasmic-tail effectors and ERLAD assembly factors not fully mapped","Substrate selection rules for each pathway undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,5]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]},{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[3,5]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,3,5]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,2]}],"complexes":["Membralin-MAN1B1-VCP ERLAD complex"],"partners":["TMEM259","VCP","HRD1","HIV-1 ENV"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKM7","full_name":"Endoplasmic reticulum mannosyl-oligosaccharide 1,2-alpha-mannosidase","aliases":["ER alpha-1,2-mannosidase","ER mannosidase 1","ERMan1","Man9GlcNAc2-specific-processing alpha-mannosidase","Mannosidase alpha class 1B member 1"],"length_aa":699,"mass_kda":79.6,"function":"Involved in glycoprotein quality control targeting of misfolded glycoproteins for degradation. It primarily trims a single alpha-1,2-linked mannose residue from Man(9)GlcNAc(2) to produce Man(8)GlcNAc(2), but at high enzyme concentrations, as found in the ER quality control compartment (ERQC), it further trims the carbohydrates to Man(5-6)GlcNAc(2)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q9UKM7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MAN1B1","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":[],"url":"https://opencell.sf.czbiohub.org/search/MAN1B1","total_profiled":1310},"omim":[{"mim_id":"614202","title":"RAFIQ SYNDROME; RAFQS","url":"https://www.omim.org/entry/614202"},{"mim_id":"607673","title":"ENDOPLASMIC RETICULUM DEGRADATION-ENHANCING ALPHA-MANNOSIDASE-LIKE PROTEIN 1; EDEM1","url":"https://www.omim.org/entry/607673"},{"mim_id":"604346","title":"MANNOSIDASE, ALPHA, CLASS 1B, MEMBER 1; MAN1B1","url":"https://www.omim.org/entry/604346"},{"mim_id":"600119","title":"SARCOGLYCAN, ALPHA; SGCA","url":"https://www.omim.org/entry/600119"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Vesicles","reliability":"Uncertain"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MAN1B1"},"hgnc":{"alias_symbol":["MANA-ER","MRT15","ERManI","ERMan1"],"prev_symbol":[]},"alphafold":{"accession":"Q9UKM7","domains":[{"cath_id":"1.50.10.10","chopping":"249-695","consensus_level":"medium","plddt":98.3145,"start":249,"end":695}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKM7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKM7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKM7-F1-predicted_aligned_error_v6.png","plddt_mean":80.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MAN1B1","jax_strain_url":"https://www.jax.org/strain/search?query=MAN1B1"},"sequence":{"accession":"Q9UKM7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKM7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKM7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKM7"}},"corpus_meta":[{"pmid":"21763484","id":"PMC_21763484","title":"Mutations in the alpha 1,2-mannosidase gene, MAN1B1, cause autosomal-recessive intellectual disability.","date":"2011","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21763484","citation_count":70,"is_preprint":false},{"pmid":"24348268","id":"PMC_24348268","title":"MAN1B1 deficiency: an unexpected CDG-II.","date":"2013","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24348268","citation_count":65,"is_preprint":false},{"pmid":"21697506","id":"PMC_21697506","title":"Golgi localization of ERManI defines spatial separation of the mammalian glycoprotein quality control system.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/21697506","citation_count":55,"is_preprint":false},{"pmid":"24566669","id":"PMC_24566669","title":"Diagnostic serum glycosylation profile in patients with intellectual disability as a result of MAN1B1 deficiency.","date":"2014","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/24566669","citation_count":45,"is_preprint":false},{"pmid":"26205822","id":"PMC_26205822","title":"ERManI (Endoplasmic Reticulum Class I α-Mannosidase) Is Required for HIV-1 Envelope Glycoprotein Degradation via Endoplasmic Reticulum-associated Protein Degradation Pathway.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26205822","citation_count":34,"is_preprint":false},{"pmid":"24627495","id":"PMC_24627495","title":"A Golgi-localized mannosidase (MAN1B1) plays a non-enzymatic gatekeeper role in protein biosynthetic quality control.","date":"2014","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24627495","citation_count":29,"is_preprint":false},{"pmid":"26401844","id":"PMC_26401844","title":"N-Glycosylation of Serum IgG and Total Glycoproteins in MAN1B1 Deficiency.","date":"2015","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/26401844","citation_count":28,"is_preprint":false},{"pmid":"36635499","id":"PMC_36635499","title":"Hepatitis B virus X protein promotes MAN1B1 expression by enhancing stability of GRP78 via TRIM25 to facilitate hepatocarcinogenesis.","date":"2023","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36635499","citation_count":24,"is_preprint":false},{"pmid":"23940818","id":"PMC_23940818","title":"ERManI is a target of miR-125b and promotes transformation phenotypes in hepatocellular carcinoma (HCC).","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23940818","citation_count":20,"is_preprint":false},{"pmid":"27148587","id":"PMC_27148587","title":"Somatic overgrowth associated with homozygous mutations in both MAN1B1 and SEC23A.","date":"2016","source":"Cold Spring Harbor molecular case 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localization","date":"2025-11-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.12.688035","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13498,"output_tokens":3059,"usd":0.043189,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10420,"output_tokens":3592,"usd":0.07095,"stage2_stop_reason":"end_turn"},"total_usd":0.114139,"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\": 2011,\n      \"finding\": \"MAN1B1 encodes an alpha-1,2-mannosidase; missense mutations (p.Glu397Lys and p.Arg334Cys) at conserved residues either reduce kcat by ~1300-fold or disrupt stable protein expression in mammalian cells, establishing that catalytic activity is required for normal function.\",\n      \"method\": \"Sanger sequencing, biochemical kinetic assay, protein expression analysis in mammalian cells\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — enzymatic kcat measurement and expression assay, single lab, two orthogonal methods\",\n      \"pmids\": [\"21763484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Endogenous human ERManI (MAN1B1) predominantly resides in the Golgi complex (not the ER), where it is subjected to O-glycosylation. Appending a COPI-binding motif to partially redistribute ERManI to the ER accelerated N-glycan trimming of misfolded alpha1-antitrypsin NHK but did not accelerate NHK degradation, implicating the Golgi as the site where the glycoprotein ERAD substrate tagging signal is generated.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence localization, O-glycosylation biochemical analysis, COPI-binding motif fusion redistribution experiment, metabolic pulse-chase degradation assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (localization, glycosylation biochemistry, engineered redistribution, pulse-chase) in a single rigorous study\",\n      \"pmids\": [\"21697506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Golgi-localized ERManI (MAN1B1) is confirmed in human cells; loss of MAN1B1 function causes altered Golgi morphology (dilatation and fragmentation) in patient-derived cells, and MAN1B1 mutations result in accumulation of hybrid-type N-glycans consistent with deficient mannosidase activity.\",\n      \"method\": \"Exome sequencing, patient fibroblast immunofluorescence (Golgi morphology), glycan analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — patient cell-based localization and Golgi morphology phenotype, glycan biochemistry, two methods\",\n      \"pmids\": [\"24348268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAN1B1 plays a non-enzymatic, catalysis-independent gatekeeper role in Golgi-based protein quality control: neither the mannosidase activity nor the catalytic domain is essential for retention or degradation of misfolded ERAD substrate Null Hong Kong (NHK). Instead, a conserved vertebrate-specific non-enzymatic decapeptide sequence in the luminal stem domain controls the fate of misfolded NHK.\",\n      \"method\": \"Catalytic site mutagenesis, domain deletion/truncation constructs, ERAD substrate (NHK) degradation assays, multiple biochemical reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis combined with domain-truncation experiments and multiple orthogonal ERAD readouts in one study\",\n      \"pmids\": [\"24627495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERManI (MAN1B1) is required for HIV-1 envelope glycoprotein degradation via ERAD: ectopic ERManI inhibits HIV-1 Env expression in a dose-dependent manner; CRISPR/Cas9 knockout of MAN1B1 disrupts TSPO-mediated Env degradation; HIV-1 Env physically interacts with ERManI; the ERManI catalytic domain is critical for the Env-ERManI interaction; inactivation of the catalytic site by mutagenesis disrupts ERManI activity.\",\n      \"method\": \"Ectopic expression, CRISPR/Cas9 knockout, co-immunoprecipitation, domain-mapping constructs, site-directed mutagenesis of catalytic site, biochemical degradation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — CRISPR KO, co-IP, domain mapping, and catalytic site mutagenesis all in one study with multiple orthogonal methods\",\n      \"pmids\": [\"26205822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAN1B1 has a functional dichotomy in ERAD: (1) a conventional catalysis-dependent system requiring an intact active site in the luminal domain to accelerate proteasomal degradation of misfolded N-glycosylated alpha1-antitrypsin variants NHK and ATZ; (2) an unconventional catalysis-independent system controlled by an evolutionarily extended N-terminal cytoplasmic tail that accelerates degradation independently of N-glycans on the misfolded substrate.\",\n      \"method\": \"Man1b1 knockout HEK293T cells, transfection of mutated/truncated Man1b1 constructs, metabolic pulse-chase labeling, proteasome inhibitor assays, N-glycan site mutagenesis on ERAD substrates\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — KO cells + reconstitution with mutant/truncated constructs + pulse-chase + multiple orthogonal substrate tests in one rigorous study\",\n      \"pmids\": [\"32958677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ERManI (MAN1B1) is a target of miR-125b via a conserved motif in its 3'UTR; knockdown of endogenous ERManI in hepatoma cells inhibits proliferation, migration, and invasion without altering global glycoprotein secretion or ER-stress status, indicating a role in hepatocellular carcinoma independent of its glycoprotein quality control function.\",\n      \"method\": \"3'UTR reporter assay (miR-125b target validation), RNAi knockdown, cell proliferation/migration/invasion assays, global glycoprotein secretion assay, ER stress markers\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — RNAi phenotype with multiple orthogonal functional readouts plus 3'UTR reporter, single lab\",\n      \"pmids\": [\"23940818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Membralin (TMEM259) recruits MAN1B1 through its luminal loop and VCP/p97 through its cytoplasmic loop to assemble a selective ERLAD complex. This Membralin-MAN1B1-VCP axis targets viral class I fusion glycoproteins (SARS-CoV-2 spike, Ebola GP, influenza HA, HIV-1 Env) for lysosomal degradation via a ubiquitin-independent, LC3/autophagy-dependent pathway, while misfolded host glycoproteins are cleared via canonical ERAD. The complex selectively recognizes densely glycosylated substrates. Loss of MAN1B1 markedly enhances pseudoviral infectivity.\",\n      \"method\": \"Co-immunoprecipitation (Membralin-MAN1B1-VCP complex), domain-mapping (luminal loop responsible for MAN1B1 recruitment), MAN1B1 knockout, pseudoviral infectivity assay, lysosomal degradation assay, LC3-LIR functional analysis\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping, KO phenotype, functional viral assays; single lab, newly published\",\n      \"pmids\": [\"41324484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ERK activation stabilizes MAN1B1 protein by regulating the interaction between MAN1B1 and the E3 ubiquitin ligase HRD1; abnormally activated ERK prevents HRD1-mediated ubiquitination/degradation of MAN1B1, resulting in elevated MAN1B1 levels that glycosylate CD47 and enhance its interaction with SIRPα, facilitating tumor immune evasion.\",\n      \"method\": \"Western blotting, co-immunoprecipitation (MAN1B1-HRD1 interaction), MAN1B1 knockout (in vitro and murine model), ERK inhibition, phagocytosis assays, patient-derived tumor-like cell clusters\",\n      \"journal\": \"Cancer communications (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP of MAN1B1-HRD1, KO phenotype in vitro and in vivo, functional phagocytosis readout, single lab\",\n      \"pmids\": [\"40493414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A short luminal juxtamembrane peptide with a specific helical charge distribution at the transmembrane-luminal interface determines ERManI (MAN1B1) localization to quality control vesicles (QCVs) versus Golgi. Site-directed mutagenesis disrupting the charge pattern or altering helical register shifts localization from QCVs to Golgi; grafting this peptide onto an unrelated transmembrane protein (beta-1,3-galactosyltransferase) redirected it from Golgi to QCVs.\",\n      \"method\": \"Site-directed mutagenesis of luminal juxtamembrane charged residues, alanine insertion mutagenesis (helical register shift), domain-grafting experiment, live-cell immunofluorescence localization, structural prediction\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutagenesis plus domain-grafting experiment with localization readout; preprint, single lab, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.11.12.688035\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MAN1B1 encodes a Golgi-localized (not ER-resident) alpha-1,2-mannosidase that functions in N-glycoprotein quality control via two distinct mechanisms: a conventional catalysis-dependent pathway requiring active-site integrity to generate a mannose-trimmed ERAD signal on misfolded N-glycoproteins, and an unconventional catalysis-independent pathway governed by its N-terminal cytoplasmic tail (and a luminal stem decapeptide) that retains and routes misfolded glycoproteins for proteasomal degradation without requiring glycan trimming; additionally, MAN1B1 is recruited by the ER-phagy receptor Membralin into a MAN1B1-VCP complex that selectively degrades densely glycosylated viral envelope glycoproteins via lysosomes, and its protein stability is regulated by ERK-dependent modulation of its interaction with the E3 ubiquitin ligase HRD1.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MAN1B1 encodes a Golgi-localized alpha-1,2-mannosidase (ERManI) that functions in N-glycoprotein quality control and endoplasmic-reticulum-associated degradation (ERAD) [#0, #1]. Endogenous human ERManI resides predominantly in the Golgi rather than the ER, where it is O-glycosylated and generates the mannose-trimmed glycan signal that tags misfolded N-glycoproteins for proteasomal degradation; redistributing it toward the ER accelerates glycan trimming of misfolded alpha1-antitrypsin but not substrate degradation, placing the tagging step in the Golgi [#1]. MAN1B1 acts through two mechanistically distinct routes: a conventional catalysis-dependent system requiring an intact luminal active site to accelerate degradation of misfolded alpha1-antitrypsin variants NHK and ATZ, and an unconventional catalysis-independent gatekeeper function in which an extended N-terminal cytoplasmic tail and a conserved luminal stem decapeptide route misfolded substrates for degradation without glycan trimming [#3, #5]. Beyond host quality control, MAN1B1 is recruited by the ER-phagy receptor Membralin into a Membralin-MAN1B1-VCP complex that selectively directs densely glycosylated viral envelope glycoproteins to lysosomal degradation via a ubiquitin-independent, LC3-dependent pathway, and its loss enhances pseudoviral infectivity [#7]; consistent with a direct antiviral role, ERManI physically interacts with and is required for ERAD of HIV-1 envelope glycoprotein [#4]. MAN1B1 protein stability is set by ERK-dependent control of its interaction with the E3 ubiquitin ligase HRD1, and elevated MAN1B1 promotes CD47 glycosylation and tumor immune evasion [#8]. Loss-of-function mutations at conserved catalytic residues cause altered Golgi morphology and accumulation of hybrid-type N-glycans in patient cells, defining a congenital disorder of glycosylation [#0, #2].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that MAN1B1 is an alpha-1,2-mannosidase whose catalytic activity is required for normal function answered whether the gene's disease relevance is enzymatic.\",\n      \"evidence\": \"Sanger sequencing of patients plus kinetic and expression assays of missense mutants in mammalian cells\",\n      \"pmids\": [\"21763484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not localize the enzyme or define which substrates it acts on\", \"Does not separate loss of catalysis from loss of protein stability as the disease driver\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Localizing endogenous ERManI to the Golgi rather than the ER reassigned where the ERAD glycan-tagging signal is generated, overturning the assumption of ER residence.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, O-glycosylation analysis, COPI-motif redistribution, and pulse-chase degradation in human cells\",\n      \"pmids\": [\"21697506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism coupling Golgi trimming to downstream proteasomal delivery not defined\", \"Did not address catalysis-independent functions\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Patient-derived cells linked MAN1B1 loss to altered Golgi morphology and hybrid-type N-glycan accumulation, connecting the enzyme defect to a cellular and glycomic phenotype.\",\n      \"evidence\": \"Exome sequencing, fibroblast immunofluorescence, and glycan analysis\",\n      \"pmids\": [\"24348268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between Golgi dilatation and mannosidase loss not mechanistically resolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identification of MAN1B1 as a miR-125b target with proliferation/migration/invasion phenotypes raised a quality-control-independent role in hepatocellular carcinoma.\",\n      \"evidence\": \"3'UTR reporter, RNAi knockdown, and functional cell assays in hepatoma cells\",\n      \"pmids\": [\"23940818\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of the cancer phenotype distinct from glycoprotein QC not defined\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Demonstrating that neither catalysis nor the catalytic domain is required for retention/degradation of misfolded NHK revealed a non-enzymatic gatekeeper function localized to a luminal stem decapeptide.\",\n      \"evidence\": \"Active-site mutagenesis, domain truncations, and ERAD reporter assays\",\n      \"pmids\": [\"24627495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding partners executing the non-enzymatic routing not identified\", \"How the decapeptide selects substrates unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing ERManI is required for HIV-1 Env ERAD and physically interacts with Env via its catalytic domain extended MAN1B1 function to viral glycoprotein clearance.\",\n      \"evidence\": \"Ectopic expression, CRISPR knockout, co-IP, domain mapping, and catalytic-site mutagenesis\",\n      \"pmids\": [\"26205822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Degradation route (proteasome vs lysosome) for Env not resolved here\", \"Relationship to the non-enzymatic pathway unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolving the functional dichotomy distinguished a luminal catalysis-dependent ERAD system from an N-terminal cytoplasmic-tail-driven catalysis- and glycan-independent system.\",\n      \"evidence\": \"Knockout HEK293T reconstitution with mutant/truncated constructs, pulse-chase, proteasome inhibition, and substrate N-glycan-site mutagenesis\",\n      \"pmids\": [\"32958677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Effectors recruited by the cytoplasmic tail not identified\", \"Structural basis for dual mechanism not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defining the Membralin-MAN1B1-VCP complex established a ubiquitin-independent, LC3-dependent ERLAD route that selectively degrades densely glycosylated viral fusion glycoproteins.\",\n      \"evidence\": \"Reciprocal co-IP with domain mapping, MAN1B1 knockout, pseudoviral infectivity, and lysosomal/LC3-LIR functional assays\",\n      \"pmids\": [\"41324484\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, newly published\", \"How dense glycosylation is sensed mechanistically not resolved\", \"Stoichiometry and assembly order of the complex unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linking ERK to HRD1-mediated MAN1B1 turnover explained how MAN1B1 levels are set and connected its stabilization to CD47 glycosylation and tumor immune evasion.\",\n      \"evidence\": \"Western blotting, MAN1B1-HRD1 co-IP, MAN1B1 knockout in vitro and in mice, ERK inhibition, and phagocytosis assays\",\n      \"pmids\": [\"40493414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether MAN1B1 directly glycosylates CD47 vs acts indirectly not fully resolved\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A luminal juxtamembrane helical charge motif was shown to partition ERManI between quality-control vesicles and the Golgi, identifying a sorting determinant for its localization.\",\n      \"evidence\": \"Charge/helical-register mutagenesis, domain grafting onto an unrelated transmembrane protein, and live-cell localization (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.11.12.688035\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Identity of the trafficking machinery reading this motif unknown\", \"Functional consequence of QCV vs Golgi residence for ERAD not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the catalytic, non-enzymatic cytoplasmic-tail, ERLAD, and trafficking activities are integrated and coordinated on individual substrates remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model coupling the dual mechanisms\", \"Cytoplasmic-tail effectors and ERLAD assembly factors not fully mapped\", \"Substrate selection rules for each pathway undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 3, 5]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"complexes\": [\"Membralin-MAN1B1-VCP ERLAD complex\"],\n    \"partners\": [\"TMEM259\", \"VCP\", \"HRD1\", \"HIV-1 Env\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}