{"gene":"TMUB2","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2020,"finding":"TMUB2 (along with TMUB1) is a component of an ER membrane ERAD complex that includes the ubiquitin ligase RNF185 and TMEM259/Membralin, which 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, and mass spectrometry to identify complex components; functional ERAD assays with model substrates","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal biochemical and MS approaches identifying complex membership, combined with functional genome-wide screen and mechanistic ERAD assays in a peer-reviewed study","pmids":["32738194"],"is_preprint":false},{"year":2016,"finding":"TMUB2 (transmembrane and ubiquitin-like domain-containing 2) was identified as a binding partner of PRL-1 and PRL-3 oncogenic phosphatases by yeast two-hybrid screening; however, functional confirmation by immunoprecipitation was performed only for other interactors (SELPLG and FKBP8), not for TMUB2 itself.","method":"Yeast two-hybrid screen; NCBI BLAST alignment for protein identification","journal":"Experimental and therapeutic medicine","confidence":"Low","confidence_rationale":"Tier 4 / Weak — yeast two-hybrid only, no biochemical confirmation of TMUB2–PRL interaction was reported in the abstract","pmids":["27882103"],"is_preprint":false}],"current_model":"TMUB2 is a ubiquitin-like domain-containing component of an ER membrane quality-control complex (with RNF185, TMUB1, and Membralin/TMEM259) that cooperates with UBE3C and the p97 ATPase to ubiquitinate and degrade a subset of misfolded ER membrane proteins via the ERAD pathway."},"narrative":{"mechanistic_narrative":"TMUB2 is a ubiquitin-like domain-containing transmembrane protein that functions in endoplasmic reticulum-associated degradation (ERAD) of misfolded ER membrane proteins [PMID:32738194]. It is a component of an ER membrane quality-control complex that includes the ubiquitin ligase RNF185, TMUB1, and TMEM259/Membralin, and that cooperates with the cytosolic ubiquitin ligase UBE3C and the p97 ATPase to ubiquitinate and extract a subset of misfolded ER membrane substrates for degradation [PMID:32738194]. Beyond its membership in this RNF185-Membralin ERAD complex, no further mechanistic detail for TMUB2 has been characterized in the available corpus.","teleology":[{"year":2016,"claim":"An initial interaction screen placed TMUB2 in the candidate interactome of the PRL-1/PRL-3 oncogenic phosphatases, raising the possibility of a role in phosphatase-associated signaling.","evidence":"Yeast two-hybrid screen with BLAST-based identification, in which TMUB2 was recovered as a candidate partner but not validated biochemically","pmids":["27882103"],"confidence":"Low","gaps":["TMUB2-PRL interaction was not confirmed by immunoprecipitation or any independent biochemical method","no functional consequence of a TMUB2-PRL association was demonstrated","yeast two-hybrid hits frequently reflect indirect or spurious binding"]},{"year":2020,"claim":"Defining TMUB2's molecular function, it was established as a subunit of an ER membrane ERAD complex that drives degradation of a subset of misfolded ER membrane proteins, anchoring the gene to protein quality control.","evidence":"Genome-wide CRISPR-Cas9 screen, biochemical fractionation and mass spectrometry for complex membership, plus functional ERAD assays with model substrates","pmids":["32738194"],"confidence":"High","gaps":["the specific contribution of the TMUB2 ubiquitin-like domain to complex assembly or substrate handoff is not resolved","the full substrate repertoire selected by this complex is not defined","no structural model of TMUB2 within the RNF185-Membralin complex is available"]},{"year":null,"claim":"How TMUB2 specifically recognizes or coordinates substrate ubiquitination within the RNF185-Membralin-UBE3C-p97 axis, and whether its earlier reported phosphatase association is biologically relevant, remain unresolved.","evidence":"No experiment in the available corpus addresses TMUB2 substrate selectivity or reconciles its ERAD role with the candidate PRL interaction","pmids":[],"confidence":"Low","gaps":["mechanistic role of the ubiquitin-like domain is uncharacterized","no reconciliation of ERAD function with the 2016 PRL phosphatase screen","no quantitative substrate spectrum or kinetics reported"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0]}],"complexes":["RNF185-Membralin ER membrane ERAD complex"],"partners":["RNF185","TMUB1","TMEM259","UBE3C","VCP"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q71RG4","full_name":"Transmembrane and ubiquitin-like domain-containing protein 2","aliases":[],"length_aa":321,"mass_kda":33.8,"function":"","subcellular_location":"Membrane","url":"https://www.uniprot.org/uniprotkb/Q71RG4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMUB2","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CANX","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TMUB2","total_profiled":1310},"omim":[{"mim_id":"620096","title":"RING FINGER PROTEIN 185; RNF185","url":"https://www.omim.org/entry/620096"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMUB2"},"hgnc":{"alias_symbol":["MGC3123"],"prev_symbol":[]},"alphafold":{"accession":"Q71RG4","domains":[{"cath_id":"3.10.20.90","chopping":"173-241","consensus_level":"high","plddt":90.5845,"start":173,"end":241},{"cath_id":"4.10.860","chopping":"271-319","consensus_level":"high","plddt":75.6159,"start":271,"end":319}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q71RG4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q71RG4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q71RG4-F1-predicted_aligned_error_v6.png","plddt_mean":62.06},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMUB2","jax_strain_url":"https://www.jax.org/strain/search?query=TMUB2"},"sequence":{"accession":"Q71RG4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q71RG4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q71RG4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q71RG4"}},"corpus_meta":[{"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":"27882103","id":"PMC_27882103","title":"Identification of proteins suppressing the functions of oncogenic phosphatase of regenerating liver 1 and 3.","date":"2016","source":"Experimental and therapeutic medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27882103","citation_count":6,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3186,"output_tokens":587,"usd":0.009182,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6912,"output_tokens":1435,"usd":0.035217,"stage2_stop_reason":"end_turn"},"total_usd":0.044399,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"TMUB2 (along with TMUB1) is a component of an ER membrane ERAD complex that includes the ubiquitin ligase RNF185 and TMEM259/Membralin, which 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, and mass spectrometry to identify complex components; functional ERAD assays with model substrates\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal biochemical and MS approaches identifying complex membership, combined with functional genome-wide screen and mechanistic ERAD assays in a peer-reviewed study\",\n      \"pmids\": [\"32738194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TMUB2 (transmembrane and ubiquitin-like domain-containing 2) was identified as a binding partner of PRL-1 and PRL-3 oncogenic phosphatases by yeast two-hybrid screening; however, functional confirmation by immunoprecipitation was performed only for other interactors (SELPLG and FKBP8), not for TMUB2 itself.\",\n      \"method\": \"Yeast two-hybrid screen; NCBI BLAST alignment for protein identification\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — yeast two-hybrid only, no biochemical confirmation of TMUB2–PRL interaction was reported in the abstract\",\n      \"pmids\": [\"27882103\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMUB2 is a ubiquitin-like domain-containing component of an ER membrane quality-control complex (with RNF185, TMUB1, and Membralin/TMEM259) that cooperates with UBE3C and the p97 ATPase to ubiquitinate and degrade a subset of misfolded ER membrane proteins via the ERAD pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMUB2 is a ubiquitin-like domain-containing transmembrane protein that functions in endoplasmic reticulum-associated degradation (ERAD) of misfolded ER membrane proteins [#0]. It is a component of an ER membrane quality-control complex that includes the ubiquitin ligase RNF185, TMUB1, and TMEM259/Membralin, and that cooperates with the cytosolic ubiquitin ligase UBE3C and the p97 ATPase to ubiquitinate and extract a subset of misfolded ER membrane substrates for degradation [#0]. Beyond its membership in this RNF185-Membralin ERAD complex, no further mechanistic detail for TMUB2 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"An initial interaction screen placed TMUB2 in the candidate interactome of the PRL-1/PRL-3 oncogenic phosphatases, raising the possibility of a role in phosphatase-associated signaling.\",\n      \"evidence\": \"Yeast two-hybrid screen with BLAST-based identification, in which TMUB2 was recovered as a candidate partner but not validated biochemically\",\n      \"pmids\": [\n        \"27882103\"\n      ],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"TMUB2-PRL interaction was not confirmed by immunoprecipitation or any independent biochemical method\",\n        \"no functional consequence of a TMUB2-PRL association was demonstrated\",\n        \"yeast two-hybrid hits frequently reflect indirect or spurious binding\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defining TMUB2's molecular function, it was established as a subunit of an ER membrane ERAD complex that drives degradation of a subset of misfolded ER membrane proteins, anchoring the gene to protein quality control.\",\n      \"evidence\": \"Genome-wide CRISPR-Cas9 screen, biochemical fractionation and mass spectrometry for complex membership, plus functional ERAD assays with model substrates\",\n      \"pmids\": [\n        \"32738194\"\n      ],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"the specific contribution of the TMUB2 ubiquitin-like domain to complex assembly or substrate handoff is not resolved\",\n        \"the full substrate repertoire selected by this complex is not defined\",\n        \"no structural model of TMUB2 within the RNF185-Membralin complex is available\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TMUB2 specifically recognizes or coordinates substrate ubiquitination within the RNF185-Membralin-UBE3C-p97 axis, and whether its earlier reported phosphatase association is biologically relevant, remain unresolved.\",\n      \"evidence\": \"No experiment in the available corpus addresses TMUB2 substrate selectivity or reconciles its ERAD role with the candidate PRL interaction\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"mechanistic role of the ubiquitin-like domain is uncharacterized\",\n        \"no reconciliation of ERAD function with the 2016 PRL phosphatase screen\",\n        \"no quantitative substrate spectrum or kinetics reported\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0140096\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005783\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-392499\",\n        \"supporting_discovery_ids\": [\n          0\n        ]\n      }\n    ],\n    \"complexes\": [\n      \"RNF185-Membralin ER membrane ERAD complex\"\n    ],\n    \"partners\": [\n      \"RNF185\",\n      \"TMUB1\",\n      \"TMEM259\",\n      \"UBE3C\",\n      \"VCP\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":2,"faith_total":2,"faith_pct":100.0}}