{"gene":"TMUB2","run_date":"2026-04-28T21:42:59","timeline":{"discoveries":[{"year":2020,"finding":"TMUB1 and TMUB2 (ubiquitin-like domain-containing proteins) are components of an ER membrane ERAD complex together with the ubiquitin ligase RNF185 and TMEM259/Membralin. This complex, identified by CRISPR-Cas9 genome-wide screening and biochemical/mass spectrometry approaches, cooperates with cytosolic ubiquitin ligase UBE3C and the p97 ATPase to degrade a subset of misfolded ER membrane proteins, defining a specific branch of ERAD for membrane substrate quality control.","method":"CRISPR-Cas9 genome-wide library screen, co-immunoprecipitation, mass spectrometry, biochemical degradation assays","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetic screen, Co-IP, MS, functional degradation assays) in a single rigorous study","pmids":["32738194"],"is_preprint":false},{"year":2016,"finding":"TMUB2 (transmembrane and ubiquitin-like domain-containing 2) was identified as a binding partner of oncogenic phosphatases PRL-1 and PRL-3 via yeast two-hybrid screening, placing TMUB2 in the context of PRL-family-mediated signaling.","method":"Yeast two-hybrid screening","journal":"Experimental and therapeutic medicine","confidence":"Low","confidence_rationale":"Tier 3 — single yeast two-hybrid result for TMUB2 interaction; interaction not independently validated for TMUB2 specifically","pmids":["27882103"],"is_preprint":false}],"current_model":"TMUB2 is a ubiquitin-like domain-containing ER membrane protein that functions as a component of the RNF185/Membralin ERAD complex, cooperating with the ubiquitin ligase RNF185, TMUB1, TMEM259/Membralin, UBE3C, and p97 ATPase to mediate quality control degradation of a specific subset of misfolded ER membrane substrates."},"narrative":{"teleology":[{"year":2016,"claim":"Before TMUB2's ER quality-control role was known, a yeast two-hybrid screen identified it as a binding partner of the oncogenic phosphatases PRL-1 and PRL-3, providing the first reported physical interaction for this protein.","evidence":"Yeast two-hybrid screening","pmids":["27882103"],"confidence":"Low","gaps":["Interaction was not independently validated for TMUB2 by reciprocal or orthogonal methods","Functional significance of the TMUB2–PRL interaction is unexplored","No in vivo or endogenous-level confirmation"]},{"year":2020,"claim":"A genome-wide CRISPR screen and biochemical dissection revealed that TMUB2 is an integral component of a previously unrecognized RNF185/Membralin ER membrane complex that, together with UBE3C and p97, degrades misfolded ER membrane proteins — establishing TMUB2's primary function in a specific ERAD branch.","evidence":"CRISPR-Cas9 genome-wide library screen, co-immunoprecipitation, mass spectrometry, and functional degradation assays in human cells","pmids":["32738194"],"confidence":"High","gaps":["The specific molecular contribution of TMUB2's ubiquitin-like domain within the complex is undefined","Whether TMUB2 and TMUB1 have redundant or distinct substrate-selection roles is unresolved","No structural model of the RNF185/Membralin complex including TMUB2 is available"]},{"year":null,"claim":"Key open questions include whether TMUB2's ubiquitin-like domain directly engages ubiquitin-binding partners to recruit substrates or cofactors, what distinguishes TMUB2 from TMUB1 within the complex, and whether loss of TMUB2 contributes to disease phenotypes.","evidence":"","pmids":[],"confidence":"Low","gaps":["No direct enzymatic or structural role assigned to TMUB2 itself","Physiological consequences of TMUB2 loss in organismal models are unexplored","Relationship between the reported PRL interaction and ERAD function is unexamined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","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 ERAD complex"],"partners":["RNF185","TMUB1","TMEM259","UBE3C"],"other_free_text":[]},"mechanistic_narrative":"TMUB2 is a transmembrane and ubiquitin-like domain-containing ER membrane protein that functions as a component of the RNF185/Membralin ERAD complex, together with TMUB1, TMEM259/Membralin, the ubiquitin ligase RNF185, the cytosolic ubiquitin ligase UBE3C, and the p97 ATPase, to mediate quality-control degradation of a specific subset of misfolded ER membrane substrates [PMID:32738194]. This complex defines a dedicated branch of ER-associated degradation (ERAD) specialized for membrane protein substrates, as established by CRISPR-Cas9 genome-wide screening and biochemical reconstitution [PMID:32738194]."},"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 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biology","url":"https://pubmed.ncbi.nlm.nih.gov/40355756","citation_count":9,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":2428,"output_tokens":563,"usd":0.007864},"stage2":{"model":"claude-opus-4-6","input_tokens":3726,"output_tokens":1034,"usd":0.06672},"total_usd":0.169202,"stage1_batch_id":"msgbatch_01RPbVc9PDH9zQmYK5Hs6srm","stage2_batch_id":"msgbatch_01JVbVLzeKN2yVrsGp3zC8aM","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":12704,"output_tokens":902,"usd":0.025821},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":4018,"output_tokens":1031,"usd":0.068797}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"TMUB2 (along with TMUB1) is a ubiquitin-like domain-containing component of an ER membrane complex together with the ubiquitin ligase RNF185 and TMEM259/Membralin, which functions as an ERAD branch for quality control of a subset of ER membrane proteins, cooperating with cytosolic ubiquitin ligase UBE3C and p97 ATPase to degrade membrane substrates.\",\n      \"method\": \"CRISPR-Cas9 genome-wide screen, biochemical fractionation, mass spectrometry-based interactome, Co-immunoprecipitation\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, MS interactome, and functional CRISPR screen with defined substrate degradation phenotype in a single rigorous 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 an interacting protein of oncogenic phosphatase PRL-1 by yeast two-hybrid screening, suggesting a physical interaction between TMUB2 and PRL-1.\",\n      \"method\": \"Yeast two-hybrid screen\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single yeast two-hybrid result for TMUB2 with no biochemical confirmation of the TMUB2-PRL1 interaction specifically\",\n      \"pmids\": [\"27882103\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMUB2 is a ubiquitin-like domain-containing ER membrane protein that forms part of the RNF185/Membralin ERAD complex (with TMUB1 and TMEM259/Membralin), cooperating with UBE3C and p97 ATPase to ubiquitinate and degrade a subset of misfolded ER membrane substrates.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries only from KEPT papers.\n\n**Classification:**\n\n- Paper [1] (PMID:32738194): KEEP — directly describes TMUB1/2 as part of the RNF185/Membralin ERAD complex with mechanistic detail.\n- Paper [2] (PMID:27882103): KEEP — identifies TMUB2 (transmembrane and ubiquitin-like domain-containing 2) as a yeast two-hybrid interactor of PRL-1/PRL-3.\n- Gene2pubmed papers: Most are large-scale genomic/interactome resources with no specific mechanistic findings about TMUB2. PMID:32738194 already covered. PMID:28514442, 25416956, 32296183, 33961781 are proteome-wide interactome maps — may contain TMUB2 interaction data but no specific mechanistic findings. Others are cDNA sequencing projects, methodology papers, etc. — EXCLUDE for mechanistic purposes. PMID:32614325 (eLife, RNF26 complex) — does not specifically describe TMUB2 mechanism. None of the remaining gene2pubmed papers contain specific mechanistic findings about TMUB2.\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2020,\n      \"finding\": \"TMUB1 and TMUB2 (ubiquitin-like domain-containing proteins) are components of an ER membrane ERAD complex together with the ubiquitin ligase RNF185 and TMEM259/Membralin. This complex, identified by CRISPR-Cas9 genome-wide screening and biochemical/mass spectrometry approaches, cooperates with cytosolic ubiquitin ligase UBE3C and the p97 ATPase to degrade a subset of misfolded ER membrane proteins, defining a specific branch of ERAD for membrane substrate quality control.\",\n      \"method\": \"CRISPR-Cas9 genome-wide library screen, co-immunoprecipitation, mass spectrometry, biochemical degradation assays\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic screen, Co-IP, MS, functional degradation assays) in a single rigorous 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 oncogenic phosphatases PRL-1 and PRL-3 via yeast two-hybrid screening, placing TMUB2 in the context of PRL-family-mediated signaling.\",\n      \"method\": \"Yeast two-hybrid screening\",\n      \"journal\": \"Experimental and therapeutic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single yeast two-hybrid result for TMUB2 interaction; interaction not independently validated for TMUB2 specifically\",\n      \"pmids\": [\"27882103\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMUB2 is a ubiquitin-like domain-containing ER membrane protein that functions as a component of the RNF185/Membralin ERAD complex, cooperating with the ubiquitin ligase RNF185, TMUB1, TMEM259/Membralin, UBE3C, and p97 ATPase to mediate quality control degradation of a specific subset of misfolded ER membrane substrates.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TMUB2 is a ubiquitin-like domain-containing ER membrane protein that functions as a component of the RNF185/Membralin ERAD complex, together with TMUB1 and TMEM259/Membralin, to mediate quality control of a subset of misfolded ER membrane substrates [PMID:32738194]. This complex cooperates with the cytosolic ubiquitin ligase UBE3C and the p97 ATPase to ubiquitinate and retrotranslocate substrates for proteasomal degradation [PMID:32738194].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"An initial yeast two-hybrid screen identified TMUB2 as a physical interactor of the oncogenic phosphatase PRL-1, providing a first hint that TMUB2 participates in protein–protein interactions, though the functional significance was unclear.\",\n      \"evidence\": \"Yeast two-hybrid screening in a mammalian cDNA library\",\n      \"pmids\": [\"27882103\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No biochemical confirmation (Co-IP or pulldown) of the TMUB2–PRL-1 interaction was provided\",\n        \"Functional relevance of a TMUB2–PRL-1 interaction is unknown\",\n        \"Single detection method without reciprocal validation\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A genome-wide CRISPR screen and comprehensive interactome analysis established that TMUB2 is a stable subunit of a previously uncharacterized ER-associated degradation (ERAD) complex comprising RNF185, TMUB1, and TMEM259/Membralin, resolving its molecular function as a component of a membrane protein quality-control pathway that cooperates with UBE3C and p97.\",\n      \"evidence\": \"CRISPR-Cas9 genome-wide screen for ERAD substrate stabilization, mass spectrometry-based interactome, reciprocal Co-IP, and substrate degradation assays in human cells\",\n      \"pmids\": [\"32738194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific biochemical role of TMUB2's ubiquitin-like domain within the complex (e.g., whether it directly engages ubiquitin-pathway enzymes) is unresolved\",\n        \"Whether TMUB2 and TMUB1 are functionally redundant or have distinct substrate specificities is not established\",\n        \"Structural basis of complex assembly and the stoichiometry of TMUB2 within the RNF185 complex are unknown\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether TMUB2 has functions independent of the RNF185/Membralin ERAD complex, what the full range of its physiological substrates is, and what role its ubiquitin-like domain plays mechanistically in substrate recognition or ubiquitin transfer.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural data exist for TMUB2 or the RNF185 complex\",\n        \"In vivo phenotypes of TMUB2 loss in animal models have not been reported\",\n        \"The relationship between TMUB2 and PRL-1 identified by yeast two-hybrid has not been validated or functionally characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"RNF185/Membralin ERAD complex\"\n    ],\n    \"partners\": [\n      \"RNF185\",\n      \"TMUB1\",\n      \"TMEM259\",\n      \"UBE3C\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"TMUB2 is a transmembrane and ubiquitin-like domain-containing ER membrane protein that functions as a component of the RNF185/Membralin ERAD complex, together with TMUB1, TMEM259/Membralin, the ubiquitin ligase RNF185, the cytosolic ubiquitin ligase UBE3C, and the p97 ATPase, to mediate quality-control degradation of a specific subset of misfolded ER membrane substrates [PMID:32738194]. This complex defines a dedicated branch of ER-associated degradation (ERAD) specialized for membrane protein substrates, as established by CRISPR-Cas9 genome-wide screening and biochemical reconstitution [PMID:32738194].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Before TMUB2's ER quality-control role was known, a yeast two-hybrid screen identified it as a binding partner of the oncogenic phosphatases PRL-1 and PRL-3, providing the first reported physical interaction for this protein.\",\n      \"evidence\": \"Yeast two-hybrid screening\",\n      \"pmids\": [\"27882103\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Interaction was not independently validated for TMUB2 by reciprocal or orthogonal methods\",\n        \"Functional significance of the TMUB2–PRL interaction is unexplored\",\n        \"No in vivo or endogenous-level confirmation\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"A genome-wide CRISPR screen and biochemical dissection revealed that TMUB2 is an integral component of a previously unrecognized RNF185/Membralin ER membrane complex that, together with UBE3C and p97, degrades misfolded ER membrane proteins — establishing TMUB2's primary function in a specific ERAD branch.\",\n      \"evidence\": \"CRISPR-Cas9 genome-wide library screen, co-immunoprecipitation, mass spectrometry, and functional degradation assays in human cells\",\n      \"pmids\": [\"32738194\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The specific molecular contribution of TMUB2's ubiquitin-like domain within the complex is undefined\",\n        \"Whether TMUB2 and TMUB1 have redundant or distinct substrate-selection roles is unresolved\",\n        \"No structural model of the RNF185/Membralin complex including TMUB2 is available\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key open questions include whether TMUB2's ubiquitin-like domain directly engages ubiquitin-binding partners to recruit substrates or cofactors, what distinguishes TMUB2 from TMUB1 within the complex, and whether loss of TMUB2 contributes to disease phenotypes.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No direct enzymatic or structural role assigned to TMUB2 itself\",\n        \"Physiological consequences of TMUB2 loss in organismal models are unexplored\",\n        \"Relationship between the reported PRL interaction and ERAD function is unexamined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\n      \"RNF185/Membralin ERAD complex\"\n    ],\n    \"partners\": [\n      \"RNF185\",\n      \"TMUB1\",\n      \"TMEM259\",\n      \"UBE3C\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}