{"gene":"MAN1B1","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2011,"finding":"MAN1B1 encodes an alpha 1,2-mannosidase whose missense mutations (p.Glu397Lys and p.Arg334Cys) either reduce kcat by ~1300-fold or disrupt stable protein expression in mammalian cells, establishing enzymatic activity as essential for its function in N-glycoprotein processing.","method":"Sanger sequencing, enzymatic activity assays, mammalian cell expression studies with disease-associated missense mutations","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 — in vitro enzymatic assay with quantified kcat reduction plus cell-based expression disruption; replicated across multiple families","pmids":["21763484"],"is_preprint":false},{"year":2011,"finding":"Endogenous human MAN1B1 (ERManI) predominantly localizes to the Golgi complex (not the ER), where it is subjected to O-glycosylation; appending a COPI-binding motif to redirect it back to the ER accelerated mannose trimming of misfolded alpha1-antitrypsin NHK glycans but did not accelerate NHK degradation, implicating the Golgi as the site for ERAD substrate tagging.","method":"Subcellular fractionation, immunofluorescence localization, O-glycosylation analysis, COPI-motif chimera construction, metabolic pulse-chase degradation assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (localization, glycan analysis, chimeric protein with functional readout) in a single rigorous study","pmids":["21697506"],"is_preprint":false},{"year":2013,"finding":"MAN1B1 deficiency causes altered Golgi morphology (marked dilatation and fragmentation) in patient cells, and the endogenous protein localizes to the Golgi complex rather than the ER, confirming a Golgi-based role in glycoprotein quality control.","method":"Exome sequencing for gene identification; patient-derived cell immunofluorescence and electron microscopy for Golgi morphology; subcellular localization studies","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — localization confirmed by imaging in patient cells with functional Golgi morphology phenotype; single lab","pmids":["24348268"],"is_preprint":false},{"year":2014,"finding":"Golgi-localized MAN1B1 plays a non-enzymatic gatekeeper role in protein quality control: neither mannosidase activity nor the catalytic domain is required for retention or degradation of the misfolded ERAD substrate Null Hong Kong (NHK); instead, a highly conserved vertebrate-specific non-enzymatic decapeptide sequence in the luminal stem domain controls the fate of misfolded NHK.","method":"Active-site mutagenesis, catalytic domain deletion constructs, overexpression of domain mutants with pulse-chase and degradation assays in human cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — active-site mutagenesis combined with domain deletion analysis and functional degradation assays; multiple orthogonal lines of evidence","pmids":["24627495"],"is_preprint":false},{"year":2014,"finding":"MAN1B1 deficiency results in accumulation of hybrid-type N-glycans (detectable on transferrin, IgG, and alpha1-antitrypsin), consistent with deficient alpha-mannosidase activity trimming the terminal mannose from the middle branch of N-glycans in the Golgi.","method":"High-resolution mass spectrometry glycoprofiling of intact plasma transferrin and serum proteins from 12 MAN1B1-CDG patients with confirmed MAN1B1 mutations","journal":"Brain : a journal of neurology","confidence":"High","confidence_rationale":"Tier 1-2 — biochemical glycan analysis in multiple patients with genetically confirmed mutations; replicated across large cohort","pmids":["24566669"],"is_preprint":false},{"year":2015,"finding":"ERManI/MAN1B1 is required for TSPO-mediated HIV-1 envelope glycoprotein degradation via ERAD; MAN1B1 knockout (CRISPR/Cas9) disrupts this degradation, HIV-1 Env interacts with ERManI, and the catalytic domain is critical for this interaction; active-site mutagenesis inactivates ERManI enzymatic and functional activity.","method":"CRISPR/Cas9 knockout, Co-immunoprecipitation, domain deletion/chimera analysis, site-directed mutagenesis of catalytic sites, ectopic expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — genetic KO with defined phenotype, direct protein interaction (Co-IP), domain mapping, and active-site mutagenesis in a single study","pmids":["26205822"],"is_preprint":false},{"year":2020,"finding":"MAN1B1 contributes to ERAD through two distinct mechanisms: (1) a conventional catalytic system requiring an intact active site in the luminal domain that trims alpha-linked mannose to generate an N-glycan-based ERAD signal, and (2) an unconventional, catalysis-independent system controlled by the evolutionarily extended N-terminal cytoplasmic tail that accelerates proteasomal degradation of misfolded AAT variants (NHK and ATZ) independently of N-glycans.","method":"Man1b1 knockout HEK293T cells, transfection of mutated/truncated Man1b1 constructs, metabolic pulse-chase labeling, proteasome inhibitor studies","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — KO cells with domain-specific rescue constructs, pulse-chase kinetics, multiple substrates; orthogonal functional readouts","pmids":["32958677"],"is_preprint":false},{"year":2025,"finding":"Membralin (TMEM259) assembles a MAN1B1-VCP complex that directs viral class I fusion glycoproteins (SARS-CoV-2 spike, Ebola GP, influenza HA, HIV-1 Env) to lysosomes via an ER-to-lysosome-associated degradation (ERLAD) pathway; Membralin recruits MAN1B1 through its luminal loop, and the complex recognizes densely glycosylated viral substrates (likely via clustered N-glycans); loss of MAN1B1 markedly enhances pseudoviral infectivity.","method":"Co-immunoprecipitation, domain mapping of Membralin-MAN1B1 interaction, MAN1B1 knockout, pseudoviral infectivity assay, LC3-interaction region (LIR) mutagenesis, lysosomal delivery tracking","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, domain mapping, KO with functional infectivity readout, multiple viral substrates tested","pmids":["41324484"],"is_preprint":false},{"year":2025,"finding":"ERK activation stabilizes MAN1B1 protein by promoting its interaction with the E3 ubiquitin ligase HRD1, which normally targets MAN1B1 for ubiquitin-mediated degradation; stabilized MAN1B1 glycosylates CD47, enhancing CD47-SIRPα interaction and tumor immune evasion in bladder cancer.","method":"Western blotting for protein stability, Co-immunoprecipitation of MAN1B1-HRD1 interaction, MAN1B1 knockout in vitro and in vivo, phagocytosis assays, ERK pathway inhibition","journal":"Cancer communications (London, England)","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP for interaction, KO with functional phagocytosis phenotype; single lab, mechanism not fully reconstituted in vitro","pmids":["40493414"],"is_preprint":false},{"year":2022,"finding":"Knockdown of Man1b1 in mouse excitatory neurons disrupted axon growth, dendrite formation, and spine maturation, and in utero electroporation experiments showed Man1b1 knockdown impaired neural stem cell proliferation, differentiation, and cortical neuron migration in the murine cortex.","method":"shRNA knockdown in primary cultured neurons, in utero electroporation in mouse cortex, morphometric analysis of axons/dendrites/spines","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in neurons with specific morphological readouts; single lab, no rescue with wild-type","pmids":["40869158"],"is_preprint":false},{"year":2025,"finding":"A short luminal juxtamembrane peptide with a conserved helical charge pattern at the transmembrane-luminal interface determines subcellular localization of ERManI/MAN1B1 to quality control vesicles (QCVs); site-directed mutagenesis disrupting this charge pattern or altering its helical register shifted localization between QCVs and the Golgi, and grafting this peptide onto an unrelated transmembrane protein redirected it to QCVs.","method":"Site-directed mutagenesis, alanine insertion to alter helical register, chimeric protein construction, immunofluorescence localization, structural prediction","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 1 — mutagenesis with localization readout and domain transfer experiment; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.11.12.688035"],"is_preprint":true},{"year":2025,"finding":"Downregulation of MAN1B1 in POMT-deficient cells contributes to impaired N-glycosylation and trafficking of integrin β1; overexpression of MAN1B1 rescues the integrin β1 maturation defect, demonstrating that MAN1B1 activity links O-mannosylation and N-glycan processing pathways.","method":"MAN1B1 knockdown and overexpression in POMT-deficient cells, flow cytometry for integrin β1 surface expression, N-glycan analysis","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — rescue overexpression experiment; preprint, single lab, indirect mechanistic link","pmids":["bio_10.1101_2025.06.18.660317"],"is_preprint":true}],"current_model":"MAN1B1 encodes a Golgi-resident alpha-1,2-mannosidase that trims terminal mannose from N-glycans to generate ERAD signals for misfolded glycoproteins, but also operates through a second, catalysis-independent mechanism controlled by its N-terminal cytoplasmic tail; it is recruited by Membralin (TMEM259) into a MAN1B1-VCP complex that selectively targets densely glycosylated viral envelope proteins for lysosomal degradation, and its stability is regulated post-translationally through ERK-dependent modulation of HRD1-mediated ubiquitination."},"narrative":{"teleology":[{"year":2011,"claim":"Establishing that MAN1B1 is an enzymatically active alpha-1,2-mannosidase whose catalytic function is essential, as disease-associated missense mutations either collapsed kcat by ~1300-fold or abolished stable protein expression, linking enzymatic loss to congenital glycosylation defects.","evidence":"Sanger sequencing of patient families, recombinant enzyme kinetic assays, and mammalian cell expression of disease mutants","pmids":["21763484"],"confidence":"High","gaps":["Physiological substrates in vivo not identified","Whether catalytic-dead protein retains any non-enzymatic function was not tested"]},{"year":2011,"claim":"Revising the assumed ER localization, this work showed endogenous MAN1B1 predominantly resides in the Golgi where it undergoes O-glycosylation, establishing the Golgi rather than the ER as the compartment where ERAD substrate tagging by mannose trimming occurs.","evidence":"Subcellular fractionation, immunofluorescence, O-glycosylation analysis, and COPI-motif chimera pulse-chase assays in human cells","pmids":["21697506"],"confidence":"High","gaps":["Mechanism of Golgi retention was undefined","Whether a minor ER pool contributes to function was not excluded"]},{"year":2013,"claim":"Patient cell analysis confirmed Golgi localization and revealed that MAN1B1 deficiency causes Golgi dilatation and fragmentation, demonstrating a structural role of the enzyme in maintaining Golgi integrity.","evidence":"Immunofluorescence and electron microscopy in patient-derived fibroblasts with confirmed MAN1B1 mutations","pmids":["24348268"],"confidence":"Medium","gaps":["Whether Golgi disruption is a direct effect or secondary to glycan processing defects was not resolved","Molecular mechanism of Golgi fragmentation unknown"]},{"year":2014,"claim":"Systematic domain dissection revealed that MAN1B1 possesses a catalysis-independent quality control function: neither mannosidase activity nor the catalytic domain was required for retention and degradation of misfolded NHK, with a conserved luminal stem decapeptide controlling substrate fate, fundamentally expanding the protein's role beyond its enzymatic activity.","evidence":"Active-site mutagenesis, catalytic domain deletions, and pulse-chase degradation assays in human cells","pmids":["24627495"],"confidence":"High","gaps":["Binding partners of the non-enzymatic decapeptide not identified","Whether the dual mechanism operates on the same or distinct substrate pools was unclear"]},{"year":2014,"claim":"Mass spectrometry glycoprofiling of a large patient cohort defined the in vivo enzymatic product of MAN1B1 deficiency as accumulation of hybrid-type N-glycans, pinpointing the enzyme's activity to trimming the terminal mannose from the middle branch of N-glycans in the Golgi.","evidence":"High-resolution mass spectrometry of intact plasma transferrin and serum glycoproteins from 12 MAN1B1-CDG patients","pmids":["24566669"],"confidence":"High","gaps":["Whether all hybrid glycan species are direct substrates versus secondary effects was not distinguished"]},{"year":2015,"claim":"MAN1B1 was placed in the ERAD pathway for HIV-1 envelope glycoprotein, showing that TSPO-mediated Env degradation requires MAN1B1 and that the catalytic domain mediates direct Env interaction, extending its quality control role to viral glycoprotein disposal.","evidence":"CRISPR/Cas9 MAN1B1 knockout, Co-IP, domain deletion/chimera, and active-site mutagenesis in human cells with HIV-1 Env","pmids":["26205822"],"confidence":"High","gaps":["Mechanism by which TSPO and MAN1B1 cooperate was not resolved","Whether catalytic trimming or lectin-like binding mediates Env recognition was unclear"]},{"year":2020,"claim":"The dual mechanism of MAN1B1 was formally delineated: a conventional catalytic pathway generating N-glycan ERAD signals, and an unconventional pathway driven by the N-terminal cytoplasmic tail that accelerates proteasomal degradation independently of N-glycans, with each system operating on overlapping ERAD substrates.","evidence":"MAN1B1 knockout HEK293T cells with domain-specific rescue constructs, pulse-chase labeling, and proteasome inhibitor studies across multiple AAT variants","pmids":["32958677"],"confidence":"High","gaps":["Cytoplasmic interactors mediating the non-catalytic pathway not identified","Relative physiological contribution of each pathway unclear"]},{"year":2022,"claim":"MAN1B1 function was extended to neuronal development: knockdown in mouse neurons disrupted axon growth, dendrite formation, and spine maturation, while in utero electroporation revealed impaired neural stem cell proliferation and cortical neuron migration, providing a cellular basis for intellectual disability in MAN1B1-CDG patients.","evidence":"shRNA knockdown in cultured mouse excitatory neurons and in utero electroporation in mouse cortex with morphometric analysis","pmids":["40869158"],"confidence":"Medium","gaps":["No rescue with wild-type MAN1B1 was performed","Whether neuronal phenotypes are glycan-dependent or mediated by the non-catalytic arm is unknown","Specific neuronal substrates not identified"]},{"year":2025,"claim":"Membralin (TMEM259) was identified as the adaptor that recruits MAN1B1 into a MAN1B1–VCP complex, directing densely glycosylated viral class I fusion proteins (SARS-CoV-2 spike, Ebola GP, influenza HA, HIV-1 Env) to lysosomes via ERLAD, establishing MAN1B1 as a broad innate antiviral effector.","evidence":"Reciprocal Co-IP, domain mapping, MAN1B1 knockout, pseudoviral infectivity assays, LIR mutagenesis, and lysosomal delivery tracking across multiple viral glycoproteins","pmids":["41324484"],"confidence":"High","gaps":["Whether catalytic activity or lectin-like recognition drives viral substrate selection is unresolved","Structural basis of the Membralin–MAN1B1–VCP complex unknown"]},{"year":2025,"claim":"Post-translational regulation of MAN1B1 was uncovered: ERK activation stabilizes MAN1B1 by modulating its interaction with the E3 ligase HRD1 that normally ubiquitinates MAN1B1 for degradation, linking MAPK signaling to glycoprotein quality control capacity and, in bladder cancer, to CD47-mediated immune evasion.","evidence":"Co-IP of MAN1B1–HRD1 interaction, MAN1B1 knockout in vitro and in vivo, phagocytosis assays, ERK pathway inhibition in bladder cancer cells","pmids":["40493414"],"confidence":"Medium","gaps":["Direct ERK phosphorylation site on MAN1B1 or HRD1 not mapped","Mechanism not reconstituted with purified components","Whether HRD1-mediated turnover occurs in non-cancer contexts is untested"]},{"year":null,"claim":"Key unresolved questions include the structural basis of the MAN1B1 dual mechanism, the identity of cytoplasmic interactors of the N-terminal tail, the molecular determinants distinguishing substrates routed to proteasomal ERAD versus lysosomal ERLAD, and the precise localization determinant that partitions MAN1B1 between the Golgi and quality control vesicles.","evidence":"","pmids":[],"confidence":"Low","gaps":["No crystal or cryo-EM structure of MAN1B1","Cytoplasmic tail interactome unmapped","ERAD versus ERLAD substrate sorting logic unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,4,5,6]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,6]}],"localization":[{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[1,2,4]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[6,7]}],"pathway":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,3,4,6]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[7]}],"complexes":["MAN1B1–Membralin–VCP complex"],"partners":["TMEM259","VCP","HRD1","TSPO"],"other_free_text":[]},"mechanistic_narrative":"MAN1B1 is a Golgi-resident alpha-1,2-mannosidase that functions as a glycoprotein quality control gatekeeper through both catalytic and non-catalytic mechanisms. Its enzymatic activity trims terminal mannose residues from N-glycans to generate ERAD signals for misfolded glycoproteins such as alpha1-antitrypsin NHK, while a separate catalysis-independent mechanism controlled by its evolutionarily extended N-terminal cytoplasmic tail accelerates proteasomal degradation of misfolded substrates independently of N-glycans [PMID:32958677, PMID:24627495]. MAN1B1 is recruited by Membralin (TMEM259) into a MAN1B1–VCP complex that directs densely glycosylated viral envelope proteins to lysosomes via ER-to-lysosome-associated degradation, and its loss markedly enhances pseudoviral infectivity [PMID:41324484]. Biallelic loss-of-function mutations cause a congenital disorder of glycosylation (MAN1B1-CDG) characterized by accumulation of hybrid-type N-glycans, Golgi fragmentation, and intellectual disability [PMID:21763484, PMID:24566669, PMID:24348268]."},"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":64,"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":32,"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":23,"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 studies","url":"https://pubmed.ncbi.nlm.nih.gov/27148587","citation_count":19,"is_preprint":false},{"pmid":"26279649","id":"PMC_26279649","title":"MAN1B1 Mutation Leads to a Recognizable Phenotype: A Case Report and Future Prospects.","date":"2015","source":"Molecular syndromology","url":"https://pubmed.ncbi.nlm.nih.gov/26279649","citation_count":14,"is_preprint":false},{"pmid":"32958677","id":"PMC_32958677","title":"The cytoplasmic tail of human mannosidase Man1b1 contributes to catalysis-independent quality control of misfolded alpha1-antitrypsin.","date":"2020","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/32958677","citation_count":13,"is_preprint":false},{"pmid":"29947113","id":"PMC_29947113","title":"Use of Endoglycosidase H as a diagnostic tool for MAN1B1-CDG patients.","date":"2018","source":"Electrophoresis","url":"https://pubmed.ncbi.nlm.nih.gov/29947113","citation_count":11,"is_preprint":false},{"pmid":"34162022","id":"PMC_34162022","title":"MAN1B1-CDG: novel patients and novel variant.","date":"2021","source":"Journal of pediatric endocrinology & metabolism : JPEM","url":"https://pubmed.ncbi.nlm.nih.gov/34162022","citation_count":8,"is_preprint":false},{"pmid":"40493414","id":"PMC_40493414","title":"Targeting MAN1B1 potently enhances bladder cancer antitumor immunity via deglycosylation of CD47.","date":"2025","source":"Cancer communications (London, England)","url":"https://pubmed.ncbi.nlm.nih.gov/40493414","citation_count":6,"is_preprint":false},{"pmid":"34258140","id":"PMC_34258140","title":"Translational balancing questioned: Unaltered glycosylation during disulfiram treatment in mannosyl-oligosaccharide alpha-1,2-mannnosidase-congenital disorders of glycosylation (MAN1B1-CDG).","date":"2021","source":"JIMD reports","url":"https://pubmed.ncbi.nlm.nih.gov/34258140","citation_count":6,"is_preprint":false},{"pmid":"36016584","id":"PMC_36016584","title":"Identification of MAN1B1 as a Novel Marker for Bladder Cancer and Its Relationship with Immune Cell Infiltration.","date":"2022","source":"Journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/36016584","citation_count":4,"is_preprint":false},{"pmid":"39840888","id":"PMC_39840888","title":"A Case of Rafiq Syndrome (MAN1B1-CDG) in a Palestinian Child, With Brief Literature Review of 44 Cases.","date":"2025","source":"Journal of investigative medicine high impact case reports","url":"https://pubmed.ncbi.nlm.nih.gov/39840888","citation_count":3,"is_preprint":false},{"pmid":"36142510","id":"PMC_36142510","title":"Case Report: Compound Heterozygous Variants of the MAN1B1 Gene in a Russian Patient with Rafiq Syndrome.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36142510","citation_count":3,"is_preprint":false},{"pmid":"41324484","id":"PMC_41324484","title":"Membralin Assembles a MAN1B1-VCP Complex to Target Foreign Glycoproteins from the Endoplasmic Reticulum to Lysosomes for Degradation.","date":"2025","source":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/41324484","citation_count":2,"is_preprint":false},{"pmid":"39896699","id":"PMC_39896699","title":"Rafiq Syndrome: Old Variant in MAN1B1 Gene and Some New Phenotypic Features.","date":"2025","source":"Iranian journal of child neurology","url":"https://pubmed.ncbi.nlm.nih.gov/39896699","citation_count":1,"is_preprint":false},{"pmid":"40869158","id":"PMC_40869158","title":"Bi-Allelic Loss-of-Function Variant in MAN1B1 Cause Rafiq Syndrome and Developmental Delay.","date":"2025","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40869158","citation_count":1,"is_preprint":false},{"pmid":"41799849","id":"PMC_41799849","title":"TMEM259/MEMBRALIN is a non-canonical ER-phagy receptor that associates with MAN1B1 and VCP to eliminate viral glycoproteins.","date":"2026","source":"Autophagy reports","url":"https://pubmed.ncbi.nlm.nih.gov/41799849","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.11.12.688035","title":"Helical charge distribution at the transmembrane-luminal interface determines subcellular localization","date":"2025-11-13","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.12.688035","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.06.18.660317","title":"POMT-dependent <i>O</i> -mannosylation regulates integrin β1 maturation via <i>N</i> -glycan processing","date":"2025-06-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.18.660317","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13148,"output_tokens":3174,"usd":0.043527},"stage2":{"model":"claude-opus-4-6","input_tokens":6531,"output_tokens":2899,"usd":0.157695},"total_usd":0.201222,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","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 whose missense mutations (p.Glu397Lys and p.Arg334Cys) either reduce kcat by ~1300-fold or disrupt stable protein expression in mammalian cells, establishing enzymatic activity as essential for its function in N-glycoprotein processing.\",\n      \"method\": \"Sanger sequencing, enzymatic activity assays, mammalian cell expression studies with disease-associated missense mutations\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro enzymatic assay with quantified kcat reduction plus cell-based expression disruption; replicated across multiple families\",\n      \"pmids\": [\"21763484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Endogenous human MAN1B1 (ERManI) predominantly localizes to the Golgi complex (not the ER), where it is subjected to O-glycosylation; appending a COPI-binding motif to redirect it back to the ER accelerated mannose trimming of misfolded alpha1-antitrypsin NHK glycans but did not accelerate NHK degradation, implicating the Golgi as the site for ERAD substrate tagging.\",\n      \"method\": \"Subcellular fractionation, immunofluorescence localization, O-glycosylation analysis, COPI-motif chimera construction, metabolic pulse-chase degradation assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (localization, glycan analysis, chimeric protein with functional readout) in a single rigorous study\",\n      \"pmids\": [\"21697506\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"MAN1B1 deficiency causes altered Golgi morphology (marked dilatation and fragmentation) in patient cells, and the endogenous protein localizes to the Golgi complex rather than the ER, confirming a Golgi-based role in glycoprotein quality control.\",\n      \"method\": \"Exome sequencing for gene identification; patient-derived cell immunofluorescence and electron microscopy for Golgi morphology; subcellular localization studies\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — localization confirmed by imaging in patient cells with functional Golgi morphology phenotype; single lab\",\n      \"pmids\": [\"24348268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Golgi-localized MAN1B1 plays a non-enzymatic gatekeeper role in protein quality control: neither mannosidase activity nor the catalytic domain is required for retention or degradation of the misfolded ERAD substrate Null Hong Kong (NHK); instead, a highly conserved vertebrate-specific non-enzymatic decapeptide sequence in the luminal stem domain controls the fate of misfolded NHK.\",\n      \"method\": \"Active-site mutagenesis, catalytic domain deletion constructs, overexpression of domain mutants with pulse-chase and degradation assays in human cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis combined with domain deletion analysis and functional degradation assays; multiple orthogonal lines of evidence\",\n      \"pmids\": [\"24627495\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"MAN1B1 deficiency results in accumulation of hybrid-type N-glycans (detectable on transferrin, IgG, and alpha1-antitrypsin), consistent with deficient alpha-mannosidase activity trimming the terminal mannose from the middle branch of N-glycans in the Golgi.\",\n      \"method\": \"High-resolution mass spectrometry glycoprofiling of intact plasma transferrin and serum proteins from 12 MAN1B1-CDG patients with confirmed MAN1B1 mutations\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — biochemical glycan analysis in multiple patients with genetically confirmed mutations; replicated across large cohort\",\n      \"pmids\": [\"24566669\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ERManI/MAN1B1 is required for TSPO-mediated HIV-1 envelope glycoprotein degradation via ERAD; MAN1B1 knockout (CRISPR/Cas9) disrupts this degradation, HIV-1 Env interacts with ERManI, and the catalytic domain is critical for this interaction; active-site mutagenesis inactivates ERManI enzymatic and functional activity.\",\n      \"method\": \"CRISPR/Cas9 knockout, Co-immunoprecipitation, domain deletion/chimera analysis, site-directed mutagenesis of catalytic sites, ectopic expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — genetic KO with defined phenotype, direct protein interaction (Co-IP), domain mapping, and active-site mutagenesis in a single study\",\n      \"pmids\": [\"26205822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"MAN1B1 contributes to ERAD through two distinct mechanisms: (1) a conventional catalytic system requiring an intact active site in the luminal domain that trims alpha-linked mannose to generate an N-glycan-based ERAD signal, and (2) an unconventional, catalysis-independent system controlled by the evolutionarily extended N-terminal cytoplasmic tail that accelerates proteasomal degradation of misfolded AAT variants (NHK and ATZ) independently of N-glycans.\",\n      \"method\": \"Man1b1 knockout HEK293T cells, transfection of mutated/truncated Man1b1 constructs, metabolic pulse-chase labeling, proteasome inhibitor studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — KO cells with domain-specific rescue constructs, pulse-chase kinetics, multiple substrates; orthogonal functional readouts\",\n      \"pmids\": [\"32958677\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Membralin (TMEM259) assembles a MAN1B1-VCP complex that directs viral class I fusion glycoproteins (SARS-CoV-2 spike, Ebola GP, influenza HA, HIV-1 Env) to lysosomes via an ER-to-lysosome-associated degradation (ERLAD) pathway; Membralin recruits MAN1B1 through its luminal loop, and the complex recognizes densely glycosylated viral substrates (likely via clustered N-glycans); loss of MAN1B1 markedly enhances pseudoviral infectivity.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping of Membralin-MAN1B1 interaction, MAN1B1 knockout, pseudoviral infectivity assay, LC3-interaction region (LIR) mutagenesis, lysosomal delivery tracking\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, domain mapping, KO with functional infectivity readout, multiple viral substrates tested\",\n      \"pmids\": [\"41324484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"ERK activation stabilizes MAN1B1 protein by promoting its interaction with the E3 ubiquitin ligase HRD1, which normally targets MAN1B1 for ubiquitin-mediated degradation; stabilized MAN1B1 glycosylates CD47, enhancing CD47-SIRPα interaction and tumor immune evasion in bladder cancer.\",\n      \"method\": \"Western blotting for protein stability, Co-immunoprecipitation of MAN1B1-HRD1 interaction, MAN1B1 knockout in vitro and in vivo, phagocytosis assays, ERK pathway inhibition\",\n      \"journal\": \"Cancer communications (London, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP for interaction, KO with functional phagocytosis phenotype; single lab, mechanism not fully reconstituted in vitro\",\n      \"pmids\": [\"40493414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Knockdown of Man1b1 in mouse excitatory neurons disrupted axon growth, dendrite formation, and spine maturation, and in utero electroporation experiments showed Man1b1 knockdown impaired neural stem cell proliferation, differentiation, and cortical neuron migration in the murine cortex.\",\n      \"method\": \"shRNA knockdown in primary cultured neurons, in utero electroporation in mouse cortex, morphometric analysis of axons/dendrites/spines\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in neurons with specific morphological readouts; single lab, no rescue with wild-type\",\n      \"pmids\": [\"40869158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A short luminal juxtamembrane peptide with a conserved helical charge pattern at the transmembrane-luminal interface determines subcellular localization of ERManI/MAN1B1 to quality control vesicles (QCVs); site-directed mutagenesis disrupting this charge pattern or altering its helical register shifted localization between QCVs and the Golgi, and grafting this peptide onto an unrelated transmembrane protein redirected it to QCVs.\",\n      \"method\": \"Site-directed mutagenesis, alanine insertion to alter helical register, chimeric protein construction, immunofluorescence localization, structural prediction\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis with localization readout and domain transfer experiment; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.11.12.688035\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Downregulation of MAN1B1 in POMT-deficient cells contributes to impaired N-glycosylation and trafficking of integrin β1; overexpression of MAN1B1 rescues the integrin β1 maturation defect, demonstrating that MAN1B1 activity links O-mannosylation and N-glycan processing pathways.\",\n      \"method\": \"MAN1B1 knockdown and overexpression in POMT-deficient cells, flow cytometry for integrin β1 surface expression, N-glycan analysis\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — rescue overexpression experiment; preprint, single lab, indirect mechanistic link\",\n      \"pmids\": [\"bio_10.1101_2025.06.18.660317\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"MAN1B1 encodes a Golgi-resident alpha-1,2-mannosidase that trims terminal mannose from N-glycans to generate ERAD signals for misfolded glycoproteins, but also operates through a second, catalysis-independent mechanism controlled by its N-terminal cytoplasmic tail; it is recruited by Membralin (TMEM259) into a MAN1B1-VCP complex that selectively targets densely glycosylated viral envelope proteins for lysosomal degradation, and its stability is regulated post-translationally through ERK-dependent modulation of HRD1-mediated ubiquitination.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MAN1B1 is a Golgi-resident alpha-1,2-mannosidase that functions as a glycoprotein quality control gatekeeper through both catalytic and non-catalytic mechanisms. Its enzymatic activity trims terminal mannose residues from N-glycans to generate ERAD signals for misfolded glycoproteins such as alpha1-antitrypsin NHK, while a separate catalysis-independent mechanism controlled by its evolutionarily extended N-terminal cytoplasmic tail accelerates proteasomal degradation of misfolded substrates independently of N-glycans [PMID:32958677, PMID:24627495]. MAN1B1 is recruited by Membralin (TMEM259) into a MAN1B1–VCP complex that directs densely glycosylated viral envelope proteins to lysosomes via ER-to-lysosome-associated degradation, and its loss markedly enhances pseudoviral infectivity [PMID:41324484]. Biallelic loss-of-function mutations cause a congenital disorder of glycosylation (MAN1B1-CDG) characterized by accumulation of hybrid-type N-glycans, Golgi fragmentation, and intellectual disability [PMID:21763484, PMID:24566669, PMID:24348268].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that MAN1B1 is an enzymatically active alpha-1,2-mannosidase whose catalytic function is essential, as disease-associated missense mutations either collapsed kcat by ~1300-fold or abolished stable protein expression, linking enzymatic loss to congenital glycosylation defects.\",\n      \"evidence\": \"Sanger sequencing of patient families, recombinant enzyme kinetic assays, and mammalian cell expression of disease mutants\",\n      \"pmids\": [\"21763484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates in vivo not identified\", \"Whether catalytic-dead protein retains any non-enzymatic function was not tested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revising the assumed ER localization, this work showed endogenous MAN1B1 predominantly resides in the Golgi where it undergoes O-glycosylation, establishing the Golgi rather than the ER as the compartment where ERAD substrate tagging by mannose trimming occurs.\",\n      \"evidence\": \"Subcellular fractionation, immunofluorescence, O-glycosylation analysis, and COPI-motif chimera pulse-chase assays in human cells\",\n      \"pmids\": [\"21697506\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of Golgi retention was undefined\", \"Whether a minor ER pool contributes to function was not excluded\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Patient cell analysis confirmed Golgi localization and revealed that MAN1B1 deficiency causes Golgi dilatation and fragmentation, demonstrating a structural role of the enzyme in maintaining Golgi integrity.\",\n      \"evidence\": \"Immunofluorescence and electron microscopy in patient-derived fibroblasts with confirmed MAN1B1 mutations\",\n      \"pmids\": [\"24348268\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether Golgi disruption is a direct effect or secondary to glycan processing defects was not resolved\", \"Molecular mechanism of Golgi fragmentation unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Systematic domain dissection revealed that MAN1B1 possesses a catalysis-independent quality control function: neither mannosidase activity nor the catalytic domain was required for retention and degradation of misfolded NHK, with a conserved luminal stem decapeptide controlling substrate fate, fundamentally expanding the protein's role beyond its enzymatic activity.\",\n      \"evidence\": \"Active-site mutagenesis, catalytic domain deletions, and pulse-chase degradation assays in human cells\",\n      \"pmids\": [\"24627495\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding partners of the non-enzymatic decapeptide not identified\", \"Whether the dual mechanism operates on the same or distinct substrate pools was unclear\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Mass spectrometry glycoprofiling of a large patient cohort defined the in vivo enzymatic product of MAN1B1 deficiency as accumulation of hybrid-type N-glycans, pinpointing the enzyme's activity to trimming the terminal mannose from the middle branch of N-glycans in the Golgi.\",\n      \"evidence\": \"High-resolution mass spectrometry of intact plasma transferrin and serum glycoproteins from 12 MAN1B1-CDG patients\",\n      \"pmids\": [\"24566669\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether all hybrid glycan species are direct substrates versus secondary effects was not distinguished\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"MAN1B1 was placed in the ERAD pathway for HIV-1 envelope glycoprotein, showing that TSPO-mediated Env degradation requires MAN1B1 and that the catalytic domain mediates direct Env interaction, extending its quality control role to viral glycoprotein disposal.\",\n      \"evidence\": \"CRISPR/Cas9 MAN1B1 knockout, Co-IP, domain deletion/chimera, and active-site mutagenesis in human cells with HIV-1 Env\",\n      \"pmids\": [\"26205822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which TSPO and MAN1B1 cooperate was not resolved\", \"Whether catalytic trimming or lectin-like binding mediates Env recognition was unclear\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"The dual mechanism of MAN1B1 was formally delineated: a conventional catalytic pathway generating N-glycan ERAD signals, and an unconventional pathway driven by the N-terminal cytoplasmic tail that accelerates proteasomal degradation independently of N-glycans, with each system operating on overlapping ERAD substrates.\",\n      \"evidence\": \"MAN1B1 knockout HEK293T cells with domain-specific rescue constructs, pulse-chase labeling, and proteasome inhibitor studies across multiple AAT variants\",\n      \"pmids\": [\"32958677\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cytoplasmic interactors mediating the non-catalytic pathway not identified\", \"Relative physiological contribution of each pathway unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"MAN1B1 function was extended to neuronal development: knockdown in mouse neurons disrupted axon growth, dendrite formation, and spine maturation, while in utero electroporation revealed impaired neural stem cell proliferation and cortical neuron migration, providing a cellular basis for intellectual disability in MAN1B1-CDG patients.\",\n      \"evidence\": \"shRNA knockdown in cultured mouse excitatory neurons and in utero electroporation in mouse cortex with morphometric analysis\",\n      \"pmids\": [\"40869158\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No rescue with wild-type MAN1B1 was performed\", \"Whether neuronal phenotypes are glycan-dependent or mediated by the non-catalytic arm is unknown\", \"Specific neuronal substrates not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Membralin (TMEM259) was identified as the adaptor that recruits MAN1B1 into a MAN1B1–VCP complex, directing densely glycosylated viral class I fusion proteins (SARS-CoV-2 spike, Ebola GP, influenza HA, HIV-1 Env) to lysosomes via ERLAD, establishing MAN1B1 as a broad innate antiviral effector.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mapping, MAN1B1 knockout, pseudoviral infectivity assays, LIR mutagenesis, and lysosomal delivery tracking across multiple viral glycoproteins\",\n      \"pmids\": [\"41324484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether catalytic activity or lectin-like recognition drives viral substrate selection is unresolved\", \"Structural basis of the Membralin–MAN1B1–VCP complex unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Post-translational regulation of MAN1B1 was uncovered: ERK activation stabilizes MAN1B1 by modulating its interaction with the E3 ligase HRD1 that normally ubiquitinates MAN1B1 for degradation, linking MAPK signaling to glycoprotein quality control capacity and, in bladder cancer, to CD47-mediated immune evasion.\",\n      \"evidence\": \"Co-IP of MAN1B1–HRD1 interaction, MAN1B1 knockout in vitro and in vivo, phagocytosis assays, ERK pathway inhibition in bladder cancer cells\",\n      \"pmids\": [\"40493414\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ERK phosphorylation site on MAN1B1 or HRD1 not mapped\", \"Mechanism not reconstituted with purified components\", \"Whether HRD1-mediated turnover occurs in non-cancer contexts is untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis of the MAN1B1 dual mechanism, the identity of cytoplasmic interactors of the N-terminal tail, the molecular determinants distinguishing substrates routed to proteasomal ERAD versus lysosomal ERLAD, and the precise localization determinant that partitions MAN1B1 between the Golgi and quality control vesicles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No crystal or cryo-EM structure of MAN1B1\", \"Cytoplasmic tail interactome unmapped\", \"ERAD versus ERLAD substrate sorting logic unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 4, 5, 6]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [6, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 3, 4, 6]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"MAN1B1–Membralin–VCP complex\"\n    ],\n    \"partners\": [\n      \"TMEM259\",\n      \"VCP\",\n      \"HRD1\",\n      \"TSPO\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}