{"gene":"TMEM259","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2020,"finding":"TMEM259/Membralin is a component of an ER membrane ERAD complex together with the ubiquitin ligase RNF185 and ubiquitin-like domain proteins TMUB1/2; this complex cooperates with cytosolic ubiquitin ligase UBE3C and p97 ATPase to degrade a subset of misfolded ER membrane proteins.","method":"CRISPR-Cas9 genome-wide screen, biochemical fractionation, mass spectrometry, Co-IP","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genome-wide functional screen identified the branch, reciprocal biochemical and MS approaches defined the complex composition, multiple orthogonal methods in a single rigorous study","pmids":["32738194"],"is_preprint":false},{"year":2023,"finding":"TMEM259/Membralin (as part of the RNF185/MBRL ERAD branch) acts upstream of UBE3C in degrading misfolded CFTR; UBE3C knockdown stabilised misfolded CFTR and ΔY490-ABCB1 even in the absence of RNF185/RNF5, indicating UBE3C can function independently of the Membralin complex for some substrates.","method":"siRNA knockdown, flow cytometry, immunoblot, functional channel assay","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple substrates tested, single lab","pmids":["38067172"],"is_preprint":false},{"year":2002,"finding":"Membralin (C19orf6/TMEM259) is a novel multi-transmembrane protein encoded on human chromosome 19p13.3 with multiple splice variants; it is conserved from nematodes and Drosophila to mammals and has no closely related paralogues, indicating it represents the sole member of a unique protein family.","method":"cDNA cloning, sequence analysis, in situ hybridization","journal":"Brain research. Gene expression patterns","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct molecular characterization of the gene/protein, replicated across species by sequence analysis, but no functional assay","pmids":["12638133"],"is_preprint":false},{"year":2025,"finding":"TMEM259/Membralin acts as a non-canonical ER-phagy receptor: its luminal loop recruits MAN1B1 (an α-mannosidase that trims high-mannose N-glycans), its cytoplasmic loop engages VCP/p97, and its cytoplasmic tail contains a functional LC3-interacting region (LIR). This Membralin-MAN1B1-VCP axis directs viral class I fusion glycoproteins (SARS-CoV-2 spike, Ebola GP, influenza HA, HIV-1 Env) to lysosomes via ER-to-lysosome-associated degradation (ERLAD) independently of polyubiquitination; loss of Membralin or MAN1B1 markedly increased pseudoviral infectivity.","method":"Co-IP, domain mutagenesis (LIR mutation), autophagy flux assays, pseudovirus infectivity assay, KO cell lines","journal":"Advanced science (Weinheim, Baden-Wurttemberg, Germany)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (Co-IP, domain mutagenesis, functional infectivity readout, KO rescue), multiple viral substrates tested, mechanistic dissection of distinct protein domains","pmids":["41324484"],"is_preprint":false},{"year":2025,"finding":"TMEM259/Membralin selectively recognises densely glycosylated viral substrates over misfolded host glycoproteins, suggesting MAN1B1 functions as a glycan-density sensor within the Membralin ERLAD complex; misfolded host glycoproteins are instead degraded through canonical ERAD or FAM134B-dependent ERLAD pathways.","method":"Co-IP, ER-phagy reporter assays, comparative substrate degradation assays (viral vs. host misfolded glycoproteins)","journal":"Research square (preprint) / Autophagy reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mechanistic claim supported by comparative substrate experiments in two related publications (preprint + peer-reviewed commentary), single lab","pmids":["40678220","41799849"],"is_preprint":false}],"current_model":"TMEM259/Membralin is a multi-pass ER membrane protein that functions both as a component of the RNF185-containing ERAD complex (with TMUB1/2, UBE3C, and p97) for quality control of misfolded ER membrane proteins, and as a non-canonical ER-phagy receptor that assembles a MAN1B1-VCP/p97 complex and uses a cytoplasmic LIR motif to direct densely glycosylated viral class I fusion glycoproteins to lysosomes via a ubiquitin-independent ERLAD pathway, thereby contributing to intrinsic antiviral defense."},"narrative":{"mechanistic_narrative":"TMEM259/Membralin is a multi-pass ER membrane protein that operates in two distinct ER protein quality-control routes [PMID:32738194, PMID:41324484]. As a component of an ER membrane ERAD complex with the ubiquitin ligase RNF185 and the ubiquitin-like proteins TMUB1/2, it cooperates with the cytosolic ligase UBE3C and the p97 ATPase to degrade a subset of misfolded ER membrane proteins, including misfolded CFTR, acting upstream of UBE3C in this branch [PMID:32738194, PMID:38067172]. Independently, Membralin functions as a non-canonical ER-phagy receptor whose luminal loop recruits the α-mannosidase MAN1B1, whose cytoplasmic loop engages VCP/p97, and whose cytoplasmic tail carries a functional LC3-interacting region (LIR); through this Membralin–MAN1B1–VCP axis it directs densely glycosylated viral class I fusion glycoproteins (SARS-CoV-2 spike, Ebola GP, influenza HA, HIV-1 Env) to lysosomes via ubiquitin-independent ER-to-lysosome-associated degradation (ERLAD), and its loss increases pseudoviral infectivity [PMID:41324484]. Substrate selection is biased toward heavily glycosylated viral targets over misfolded host glycoproteins, consistent with MAN1B1 acting as a glycan-density sensor within the complex [PMID:40678220, PMID:41799849]. Membralin is the sole member of a conserved, multi-transmembrane protein family with no close paralogues [PMID:12638133].","teleology":[{"year":2002,"claim":"Establishing the molecular identity of the gene was the first step: defining whether C19orf6 encoded a distinct protein and how broadly it was conserved.","evidence":"cDNA cloning, sequence analysis and in situ hybridization across species","pmids":["12638133"],"confidence":"Medium","gaps":["No functional assay performed","Membrane topology not experimentally resolved","No interaction partners or pathway assigned"]},{"year":2020,"claim":"A genome-wide functional screen answered what Membralin does, placing it in a defined ERAD complex for misfolded ER membrane proteins.","evidence":"CRISPR-Cas9 genome-wide screen with biochemical fractionation, mass spectrometry and Co-IP","pmids":["32738194"],"confidence":"High","gaps":["Full substrate range of the RNF185/Membralin branch not enumerated","Structural basis of complex assembly unresolved","Membralin's specific biochemical contribution within the complex undefined"]},{"year":2023,"claim":"Dissecting the hierarchy of the ERAD branch showed UBE3C acts downstream of and partly independently from the Membralin/RNF185 complex on physiological substrates such as misfolded CFTR.","evidence":"siRNA knockdown, flow cytometry, immunoblot and functional channel assay across multiple substrates","pmids":["38067172"],"confidence":"Medium","gaps":["Single-lab study","Direct catalytic role of Membralin in CFTR turnover not defined","Extent of substrate overlap between Membralin-dependent and -independent UBE3C activity unclear"]},{"year":2025,"claim":"Domain-level dissection revealed a second, mechanistically distinct role: Membralin is a non-canonical ER-phagy receptor that routes glycosylated viral fusion glycoproteins to lysosomes via ubiquitin-independent ERLAD.","evidence":"Co-IP, LIR-motif domain mutagenesis, autophagy flux assays, pseudovirus infectivity readout and KO/rescue cell lines across four viral substrates","pmids":["41324484"],"confidence":"High","gaps":["How the luminal MAN1B1 signal is relayed to the cytoplasmic LIR is unresolved","Structure of the Membralin-MAN1B1-VCP complex not determined","In vivo antiviral relevance not established"]},{"year":2025,"claim":"Comparative substrate experiments addressed how the receptor discriminates targets, indicating glycan density rather than misfolding selects viral substrates, with MAN1B1 as a candidate sensor.","evidence":"Co-IP, ER-phagy reporter assays and comparative degradation of viral versus host misfolded glycoproteins","pmids":["40678220","41799849"],"confidence":"Medium","gaps":["Glycan-density sensing mechanism inferred rather than biochemically reconstituted","Single lab across linked publications including a preprint","Quantitative glycan threshold for substrate selection undefined"]},{"year":null,"claim":"How the two roles of Membralin — ubiquitin-dependent ERAD and ubiquitin-independent ERLAD ER-phagy — are coordinated or partitioned within the same protein remains open.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model integrating ERAD and ERLAD functions","Determinants switching Membralin between the two pathways unknown","Physiological and antiviral consequences of loss in vivo not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0038024","term_label":"cargo receptor activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,2,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[3]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[3]}],"complexes":["RNF185-TMUB1/2 ERAD complex","Membralin-MAN1B1-VCP ERLAD complex"],"partners":["RNF185","TMUB1","TMUB2","UBE3C","VCP","MAN1B1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q4ZIN3","full_name":"Membralin","aliases":["Transmembrane protein 259"],"length_aa":620,"mass_kda":67.9,"function":"May have a role in the ERAD pathway required for clearance of misfolded proteins in the endoplasmic reticulum (ER). Promotes survival of motor neurons, probably by protecting against ER stress","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/Q4ZIN3/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM259","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM259","total_profiled":1310},"omim":[{"mim_id":"620096","title":"RING FINGER PROTEIN 185; RNF185","url":"https://www.omim.org/entry/620096"},{"mim_id":"613297","title":"MEMBRANE-ASSOCIATED RING-CH FINGER PROTEIN 6; MARCHF6","url":"https://www.omim.org/entry/613297"},{"mim_id":"611011","title":"TRANSMEMBRANE PROTEIN 259; TMEM259","url":"https://www.omim.org/entry/611011"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Endoplasmic reticulum","reliability":"Approved"},{"location":"Nuclear speckles","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM259"},"hgnc":{"alias_symbol":["MGC4022","ASBABP1","MBRL"],"prev_symbol":["C19orf6"]},"alphafold":{"accession":"Q4ZIN3","domains":[{"cath_id":"-","chopping":"64-90_301-464","consensus_level":"high","plddt":84.8043,"start":64,"end":464},{"cath_id":"-","chopping":"96-128_206-297","consensus_level":"medium","plddt":80.1555,"start":96,"end":297}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4ZIN3","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q4ZIN3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q4ZIN3-F1-predicted_aligned_error_v6.png","plddt_mean":63.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM259","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM259"},"sequence":{"accession":"Q4ZIN3","fasta_url":"https://rest.uniprot.org/uniprotkb/Q4ZIN3.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q4ZIN3/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q4ZIN3"}},"corpus_meta":[{"pmid":"34963663","id":"PMC_34963663","title":"Meta-analysis of human and mouse ALS astrocytes reveals multi-omic signatures of inflammatory reactive states.","date":"2021","source":"Genome research","url":"https://pubmed.ncbi.nlm.nih.gov/34963663","citation_count":77,"is_preprint":false},{"pmid":"30466389","id":"PMC_30466389","title":"Multi-drug resistant Enterobacter bugandensis species isolated from the International Space Station and comparative genomic analyses with human pathogenic strains.","date":"2018","source":"BMC microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/30466389","citation_count":68,"is_preprint":false},{"pmid":"32738194","id":"PMC_32738194","title":"Quality Control of ER Membrane Proteins by the RNF185/Membralin Ubiquitin Ligase Complex.","date":"2020","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/32738194","citation_count":53,"is_preprint":false},{"pmid":"3258791","id":"PMC_3258791","title":"Immunoconjugate generation between the ribosome inactivating protein restrictocin and an anti-human breast carcinoma MAB.","date":"1988","source":"Cancer immunology, immunotherapy : CII","url":"https://pubmed.ncbi.nlm.nih.gov/3258791","citation_count":38,"is_preprint":false},{"pmid":"15722182","id":"PMC_15722182","title":"Cloning and expression of the human NMDA receptor subunit NR3B in the adult human hippocampus.","date":"2004","source":"Neuroscience letters","url":"https://pubmed.ncbi.nlm.nih.gov/15722182","citation_count":29,"is_preprint":false},{"pmid":"29262357","id":"PMC_29262357","title":"Myoglobin and α-Lactalbumin Form Smaller Complexes with the Biosurfactant Rhamnolipid Than with SDS.","date":"2017","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/29262357","citation_count":26,"is_preprint":false},{"pmid":"27247891","id":"PMC_27247891","title":"Keratinolytic activities of alkaliphilic Bacillus sp. 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this complex cooperates with cytosolic ubiquitin ligase UBE3C and p97 ATPase to degrade a subset of misfolded ER membrane proteins.\",\n      \"method\": \"CRISPR-Cas9 genome-wide screen, biochemical fractionation, mass spectrometry, Co-IP\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genome-wide functional screen identified the branch, reciprocal biochemical and MS approaches defined the complex composition, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"32738194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TMEM259/Membralin (as part of the RNF185/MBRL ERAD branch) acts upstream of UBE3C in degrading misfolded CFTR; UBE3C knockdown stabilised misfolded CFTR and ΔY490-ABCB1 even in the absence of RNF185/RNF5, indicating UBE3C can function independently of the Membralin complex for some substrates.\",\n      \"method\": \"siRNA knockdown, flow cytometry, immunoblot, functional channel assay\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with defined cellular phenotype, multiple substrates tested, single lab\",\n      \"pmids\": [\"38067172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Membralin (C19orf6/TMEM259) is a novel multi-transmembrane protein encoded on human chromosome 19p13.3 with multiple splice variants; it is conserved from nematodes and Drosophila to mammals and has no closely related paralogues, indicating it represents the sole member of a unique protein family.\",\n      \"method\": \"cDNA cloning, sequence analysis, in situ hybridization\",\n      \"journal\": \"Brain research. Gene expression patterns\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct molecular characterization of the gene/protein, replicated across species by sequence analysis, but no functional assay\",\n      \"pmids\": [\"12638133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM259/Membralin acts as a non-canonical ER-phagy receptor: its luminal loop recruits MAN1B1 (an α-mannosidase that trims high-mannose N-glycans), its cytoplasmic loop engages VCP/p97, and its cytoplasmic tail contains a functional LC3-interacting region (LIR). This Membralin-MAN1B1-VCP axis directs viral class I fusion glycoproteins (SARS-CoV-2 spike, Ebola GP, influenza HA, HIV-1 Env) to lysosomes via ER-to-lysosome-associated degradation (ERLAD) independently of polyubiquitination; loss of Membralin or MAN1B1 markedly increased pseudoviral infectivity.\",\n      \"method\": \"Co-IP, domain mutagenesis (LIR mutation), autophagy flux assays, pseudovirus infectivity assay, KO cell lines\",\n      \"journal\": \"Advanced science (Weinheim, Baden-Wurttemberg, Germany)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (Co-IP, domain mutagenesis, functional infectivity readout, KO rescue), multiple viral substrates tested, mechanistic dissection of distinct protein domains\",\n      \"pmids\": [\"41324484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM259/Membralin selectively recognises densely glycosylated viral substrates over misfolded host glycoproteins, suggesting MAN1B1 functions as a glycan-density sensor within the Membralin ERLAD complex; misfolded host glycoproteins are instead degraded through canonical ERAD or FAM134B-dependent ERLAD pathways.\",\n      \"method\": \"Co-IP, ER-phagy reporter assays, comparative substrate degradation assays (viral vs. host misfolded glycoproteins)\",\n      \"journal\": \"Research square (preprint) / Autophagy reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mechanistic claim supported by comparative substrate experiments in two related publications (preprint + peer-reviewed commentary), single lab\",\n      \"pmids\": [\"40678220\", \"41799849\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM259/Membralin is a multi-pass ER membrane protein that functions both as a component of the RNF185-containing ERAD complex (with TMUB1/2, UBE3C, and p97) for quality control of misfolded ER membrane proteins, and as a non-canonical ER-phagy receptor that assembles a MAN1B1-VCP/p97 complex and uses a cytoplasmic LIR motif to direct densely glycosylated viral class I fusion glycoproteins to lysosomes via a ubiquitin-independent ERLAD pathway, thereby contributing to intrinsic antiviral defense.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM259/Membralin is a multi-pass ER membrane protein that operates in two distinct ER protein quality-control routes [#0, #3]. As a component of an ER membrane ERAD complex with the ubiquitin ligase RNF185 and the ubiquitin-like proteins TMUB1/2, it cooperates with the cytosolic ligase UBE3C and the p97 ATPase to degrade a subset of misfolded ER membrane proteins, including misfolded CFTR, acting upstream of UBE3C in this branch [#0, #1]. Independently, Membralin functions as a non-canonical ER-phagy receptor whose luminal loop recruits the α-mannosidase MAN1B1, whose cytoplasmic loop engages VCP/p97, and whose cytoplasmic tail carries a functional LC3-interacting region (LIR); through this Membralin–MAN1B1–VCP axis it directs densely glycosylated viral class I fusion glycoproteins (SARS-CoV-2 spike, Ebola GP, influenza HA, HIV-1 Env) to lysosomes via ubiquitin-independent ER-to-lysosome-associated degradation (ERLAD), and its loss increases pseudoviral infectivity [#3]. Substrate selection is biased toward heavily glycosylated viral targets over misfolded host glycoproteins, consistent with MAN1B1 acting as a glycan-density sensor within the complex [#4]. Membralin is the sole member of a conserved, multi-transmembrane protein family with no close paralogues [#2].\"\n  ,\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Establishing the molecular identity of the gene was the first step: defining whether C19orf6 encoded a distinct protein and how broadly it was conserved.\",\n      \"evidence\": \"cDNA cloning, sequence analysis and in situ hybridization across species\",\n      \"pmids\": [\"12638133\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No functional assay performed\",\n        \"Membrane topology not experimentally resolved\",\n        \"No interaction partners or pathway assigned\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A genome-wide functional screen answered what Membralin does, placing it in a defined ERAD complex for misfolded ER membrane proteins.\",\n      \"evidence\": \"CRISPR-Cas9 genome-wide screen with biochemical fractionation, mass spectrometry and Co-IP\",\n      \"pmids\": [\"32738194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Full substrate range of the RNF185/Membralin branch not enumerated\",\n        \"Structural basis of complex assembly unresolved\",\n        \"Membralin's specific biochemical contribution within the complex undefined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Dissecting the hierarchy of the ERAD branch showed UBE3C acts downstream of and partly independently from the Membralin/RNF185 complex on physiological substrates such as misfolded CFTR.\",\n      \"evidence\": \"siRNA knockdown, flow cytometry, immunoblot and functional channel assay across multiple substrates\",\n      \"pmids\": [\"38067172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study\",\n        \"Direct catalytic role of Membralin in CFTR turnover not defined\",\n        \"Extent of substrate overlap between Membralin-dependent and -independent UBE3C activity unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Domain-level dissection revealed a second, mechanistically distinct role: Membralin is a non-canonical ER-phagy receptor that routes glycosylated viral fusion glycoproteins to lysosomes via ubiquitin-independent ERLAD.\",\n      \"evidence\": \"Co-IP, LIR-motif domain mutagenesis, autophagy flux assays, pseudovirus infectivity readout and KO/rescue cell lines across four viral substrates\",\n      \"pmids\": [\"41324484\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How the luminal MAN1B1 signal is relayed to the cytoplasmic LIR is unresolved\",\n        \"Structure of the Membralin-MAN1B1-VCP complex not determined\",\n        \"In vivo antiviral relevance not established\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Comparative substrate experiments addressed how the receptor discriminates targets, indicating glycan density rather than misfolding selects viral substrates, with MAN1B1 as a candidate sensor.\",\n      \"evidence\": \"Co-IP, ER-phagy reporter assays and comparative degradation of viral versus host misfolded glycoproteins\",\n      \"pmids\": [\"40678220\", \"41799849\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Glycan-density sensing mechanism inferred rather than biochemically reconstituted\",\n        \"Single lab across linked publications including a preprint\",\n        \"Quantitative glycan threshold for substrate selection undefined\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the two roles of Membralin — ubiquitin-dependent ERAD and ubiquitin-independent ERLAD ER-phagy — are coordinated or partitioned within the same protein remains open.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No structural model integrating ERAD and ERLAD functions\",\n        \"Determinants switching Membralin between the two pathways unknown\",\n        \"Physiological and antiviral consequences of loss in vivo not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0038024\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 2, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [\n      \"RNF185-TMUB1/2 ERAD complex\",\n      \"Membralin-MAN1B1-VCP ERLAD complex\"\n    ],\n    \"partners\": [\n      \"RNF185\",\n      \"TMUB1\",\n      \"TMUB2\",\n      \"UBE3C\",\n      \"VCP\",\n      \"MAN1B1\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}