{"gene":"TMEM129","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2014,"finding":"TMEM129 is an E3 ubiquitin ligase with an unconventional C4C4-type RING finger domain that resides within an ER-resident dislocation complex containing Derlin-1, Derlin-2, VIMP, and p97, and is essential for US11-mediated HLA class I ubiquitination and retrotranslocation for proteasomal degradation.","method":"Genome-wide shRNA screen, co-immunoprecipitation, knockdown with HLA class I degradation assay","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP establishing complex, functional KD with defined degradation phenotype, independently replicated in a second paper (PMID:25030448)","pmids":["24807418"],"is_preprint":false},{"year":2014,"finding":"TMEM129 contains an unusual cysteine-only RING domain with intrinsic E3 ligase activity, is recruited to US11 via Derlin-1, and together with its E2 conjugase UBE2J2 is responsible for ubiquitination and dislocation of US11-associated MHC-I from the ER; identified by a forward genetic screen in near-haploid KBM7 cells.","method":"Forward genetic screen (near-haploid KBM7 cells), in vitro E3 ligase activity assay, Co-IP, MHC-I degradation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — intrinsic E3 ligase activity demonstrated in vitro, forward genetic screen plus Co-IP, replicated across two independent labs (PMID:24807418)","pmids":["25030448"],"is_preprint":false},{"year":2014,"finding":"US11 engages two distinct degradation pathways: a Derlin-1/TMEM129-dependent pathway required for MHC-I degradation and a SEL1L/HRD1-dependent pathway required for degradation of free US11 itself.","method":"Genetic epistasis using KO/KD of pathway components, MHC-I and US11 degradation assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with multiple KO/KD conditions, two orthogonal substrates, replicated in independent lab (PMID:24807418)","pmids":["25030448"],"is_preprint":false},{"year":2016,"finding":"TMEM129 is a non-glycosylated, tri-spanning ER-membrane protein with a non-cleaved signal anchor sequence that adopts an Nexo-Ccyto orientation, positioning its C-terminal RING domain in the cytosol where it can catalyze ubiquitination reactions required for cytosolic degradation of secretory proteins.","method":"Glycosylation scanning mutagenesis, topology mapping, immunofluorescence/fractionation","journal":"Viruses","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — glycosylation scanning mutagenesis with functional interpretation, single lab, two orthogonal topology methods","pmids":["27854284"],"is_preprint":false},{"year":2019,"finding":"US11 recruits TMEM129 (along with Derlin-1 and UBE2J2) to engage the neonatal Fc receptor FcRn, initiating its dislocation from the ER to the cytosol and degradation, thereby blocking FcRn trafficking to the endosome and inhibiting IgG transcytosis.","method":"Co-immunoprecipitation, ER retention and degradation assays, IgG transcytosis functional assay","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus functional degradation and transcytosis assays, single lab, multiple orthogonal readouts","pmids":["31289263"],"is_preprint":false},{"year":2015,"finding":"TMEM129 is identified as a novel RING-C2 E3 ligase responsible for US11-mediated MHC-I degradation; US11-mediated degradation is MHC-I-specific, and TMEM129 operates in an auto-regulatory loop where free US11 is itself degraded by HRD1/SEL1L.","method":"Review/synthesis of genetic screen data and biochemical assays (as described in primary papers PMID:24807418 and PMID:25030448)","journal":"Molecular immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — synthesis of prior genetic screen and biochemical evidence, single review paper consolidating two independent labs","pmids":["26210183"],"is_preprint":false}],"current_model":"TMEM129 is a non-glycosylated, tri-spanning ER-resident E3 ubiquitin ligase with a cytosol-facing cysteine-only RING domain that forms a complex with Derlin-1, Derlin-2, VIMP, and p97; together with the E2 enzyme UBE2J2, it ubiquitinates substrates (including MHC-I and FcRn) at the ER membrane to drive their retrotranslocation and proteasomal degradation via the ERAD pathway, and is hijacked by the HCMV protein US11 for viral immune evasion."},"narrative":{"mechanistic_narrative":"TMEM129 is an ER-resident E3 ubiquitin ligase that drives ER-associated degradation (ERAD) of membrane substrates by coupling target ubiquitination to retrotranslocation and proteasomal turnover [PMID:24807418, PMID:25030448]. It is a non-glycosylated, tri-spanning ER-membrane protein that adopts an Nexo-Ccyto orientation, placing its unconventional cysteine-only RING (RING-C2 / C4C4-type) domain in the cytosol where it catalyzes ubiquitin transfer [PMID:25030448, PMID:27854284]. TMEM129 functions within a dislocation complex containing Derlin-1, Derlin-2, VIMP, and the AAA-ATPase p97, and pairs with the E2 conjugating enzyme UBE2J2 to ubiquitinate substrates at the ER membrane [PMID:24807418, PMID:25030448]. It is the cellular ligase hijacked by the HCMV immunoevasin US11: US11 recruits TMEM129 via Derlin-1 to ubiquitinate and dislocate MHC class I for degradation, an activity that is genetically separable from the SEL1L/HRD1 pathway that degrades free US11 itself [PMID:25030448]. The same US11–TMEM129–Derlin-1–UBE2J2 machinery targets the neonatal Fc receptor FcRn, blocking its ER export and thereby inhibiting IgG transcytosis [PMID:31289263].","teleology":[{"year":2014,"claim":"Identifying which cellular factor executes US11-driven MHC-I destruction resolved how HCMV exploits host ERAD, establishing TMEM129 as an E3 ligase embedded in a Derlin/p97 dislocation complex.","evidence":"Genome-wide shRNA screen with reciprocal Co-IP and HLA class I degradation assays","pmids":["24807418"],"confidence":"High","gaps":["Did not demonstrate intrinsic catalytic activity in vitro","Endogenous (non-viral) substrates not defined"]},{"year":2014,"claim":"An independent forward genetic screen confirmed TMEM129 as the ligase and showed its cysteine-only RING has intrinsic E3 activity paired with UBE2J2, defining the catalytic core of the dislocation reaction.","evidence":"Forward genetic screen in haploid KBM7 cells, in vitro E3 ligase assay, Co-IP, MHC-I degradation assay","pmids":["25030448"],"confidence":"High","gaps":["E2/E3 ubiquitin chain topology on substrate not resolved","Recruitment mediated through Derlin-1 but interface not structurally mapped"]},{"year":2014,"claim":"Genetic epistasis distinguished two US11-engaged routes, showing TMEM129/Derlin-1 degrades MHC-I while SEL1L/HRD1 degrades free US11, clarifying that substrate identity dictates pathway choice.","evidence":"Epistasis using KO/KD of pathway components with two orthogonal degradation substrates","pmids":["25030448"],"confidence":"High","gaps":["Molecular basis for substrate-specific channeling between the two pathways unknown"]},{"year":2015,"claim":"Synthesis of the screen and biochemical data consolidated TMEM129 as a RING-C2 ligase acting in an auto-regulatory loop, framing its specificity for MHC-I.","evidence":"Review synthesizing prior genetic and biochemical evidence","pmids":["26210183"],"confidence":"Medium","gaps":["No new primary data","Specificity determinants for MHC-I not experimentally dissected"]},{"year":2016,"claim":"Determining the membrane topology established that TMEM129 is a tri-spanning, non-glycosylated protein with a cytosolic C-terminal RING, explaining how its catalytic domain accesses cytosolic ubiquitination machinery.","evidence":"Glycosylation scanning mutagenesis and orthogonal topology mapping with fractionation","pmids":["27854284"],"confidence":"Medium","gaps":["Single lab","Structural model of the transmembrane region absent","How topology coordinates with Derlin channel not shown"]},{"year":2019,"claim":"Showing that US11 redirects TMEM129 onto FcRn extended its substrate range beyond MHC-I and linked its activity to suppression of IgG transcytosis, broadening its role in viral immune evasion.","evidence":"Co-IP, ER retention/degradation assays, and IgG transcytosis functional assay","pmids":["31289263"],"confidence":"Medium","gaps":["Single lab","Whether FcRn is also a TMEM129 substrate in the absence of US11 unknown"]},{"year":null,"claim":"The physiological, virus-independent substrates and cellular function of TMEM129 outside the US11 hijacking context remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No endogenous substrate identified in the absence of US11","Native regulation and tissue context uncharacterized","No structural data on the RING or transmembrane domain"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,4]}],"complexes":["ER dislocation complex (Derlin-1/Derlin-2/VIMP/p97)"],"partners":["DERL1","DERL2","SELENOS","VCP","UBE2J2","US11"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A0AVI4","full_name":"E3 ubiquitin-protein ligase TM129","aliases":["RING-type E3 ubiquitin transferase TM129"],"length_aa":362,"mass_kda":40.5,"function":"E3 ubiquitin-protein ligase involved in ER-associated protein degradation, preferentially associates with the E2 enzyme UBE2J2. Exploited by viral US11 proteins to mediate HLA class I proteins degradation","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/A0AVI4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM129","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":[],"url":"https://opencell.sf.czbiohub.org/search/TMEM129","total_profiled":1310},"omim":[{"mim_id":"615975","title":"TRANSMEMBRANE PROTEIN 129; TMEM129","url":"https://www.omim.org/entry/615975"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM129"},"hgnc":{"alias_symbol":["D4S2561E"],"prev_symbol":[]},"alphafold":{"accession":"A0AVI4","domains":[{"cath_id":"-","chopping":"3-115","consensus_level":"high","plddt":89.6553,"start":3,"end":115},{"cath_id":"2.30.29.30","chopping":"122-195_208-245","consensus_level":"medium","plddt":90.4146,"start":122,"end":245},{"cath_id":"-","chopping":"263-359","consensus_level":"high","plddt":89.418,"start":263,"end":359}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A0AVI4","model_url":"https://alphafold.ebi.ac.uk/files/AF-A0AVI4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A0AVI4-F1-predicted_aligned_error_v6.png","plddt_mean":88.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM129","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM129"},"sequence":{"accession":"A0AVI4","fasta_url":"https://rest.uniprot.org/uniprotkb/A0AVI4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A0AVI4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A0AVI4"}},"corpus_meta":[{"pmid":"24807418","id":"PMC_24807418","title":"A high-coverage shRNA screen identifies TMEM129 as an E3 ligase involved in ER-associated protein degradation.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24807418","citation_count":101,"is_preprint":false},{"pmid":"25030448","id":"PMC_25030448","title":"TMEM129 is a Derlin-1 associated ERAD E3 ligase essential for virus-induced degradation of MHC-I.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25030448","citation_count":86,"is_preprint":false},{"pmid":"26210183","id":"PMC_26210183","title":"Identifying the ERAD ubiquitin E3 ligases for viral and cellular targeting of MHC class I.","date":"2015","source":"Molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/26210183","citation_count":41,"is_preprint":false},{"pmid":"26374428","id":"PMC_26374428","title":"Modification of Occupational Exposures on Bladder Cancer Risk by Common Genetic Polymorphisms.","date":"2015","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/26374428","citation_count":37,"is_preprint":false},{"pmid":"31289263","id":"PMC_31289263","title":"Human cytomegalovirus evades antibody-mediated immunity through endoplasmic reticulum-associated degradation of the FcRn receptor.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31289263","citation_count":35,"is_preprint":false},{"pmid":"33830302","id":"PMC_33830302","title":"Analysis of overlapping genetic association in type 1 and type 2 diabetes.","date":"2021","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/33830302","citation_count":35,"is_preprint":false},{"pmid":"25774220","id":"PMC_25774220","title":"Report of a patient and further clinical and molecular characterization of interstitial 4p16.3 microduplication.","date":"2015","source":"Molecular cytogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/25774220","citation_count":10,"is_preprint":false},{"pmid":"35941660","id":"PMC_35941660","title":"Identification of TMEM129, encoding a ubiquitin-protein ligase, as an effector gene of osteoarthritis genetic risk.","date":"2022","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/35941660","citation_count":8,"is_preprint":false},{"pmid":"27854284","id":"PMC_27854284","title":"The E3 Ubiquitin Ligase TMEM129 Is a Tri-Spanning Transmembrane Protein.","date":"2016","source":"Viruses","url":"https://pubmed.ncbi.nlm.nih.gov/27854284","citation_count":6,"is_preprint":false},{"pmid":"40644891","id":"PMC_40644891","title":"Biomarker discovery for early breast cancer diagnosis using machine learning on transcriptomic data for biosensor development.","date":"2025","source":"Computers in biology and medicine","url":"https://pubmed.ncbi.nlm.nih.gov/40644891","citation_count":2,"is_preprint":false},{"pmid":"32619252","id":"PMC_32619252","title":"[Identification of a critical region on chromosome 4p16.3 for Wolf-Hirschhorn syndrome-associated fetal growth retardation].","date":"2020","source":"Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32619252","citation_count":2,"is_preprint":false},{"pmid":"40978103","id":"PMC_40978103","title":"Genetic susceptibility and environmental risk factors in bladder cancer: Evidence from the UK biobank.","date":"2025","source":"Bladder cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/40978103","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8455,"output_tokens":1562,"usd":0.024397,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8233,"output_tokens":2271,"usd":0.04897,"stage2_stop_reason":"end_turn"},"total_usd":0.073367,"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\": 2014,\n      \"finding\": \"TMEM129 is an E3 ubiquitin ligase with an unconventional C4C4-type RING finger domain that resides within an ER-resident dislocation complex containing Derlin-1, Derlin-2, VIMP, and p97, and is essential for US11-mediated HLA class I ubiquitination and retrotranslocation for proteasomal degradation.\",\n      \"method\": \"Genome-wide shRNA screen, co-immunoprecipitation, knockdown with HLA class I degradation assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP establishing complex, functional KD with defined degradation phenotype, independently replicated in a second paper (PMID:25030448)\",\n      \"pmids\": [\"24807418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TMEM129 contains an unusual cysteine-only RING domain with intrinsic E3 ligase activity, is recruited to US11 via Derlin-1, and together with its E2 conjugase UBE2J2 is responsible for ubiquitination and dislocation of US11-associated MHC-I from the ER; identified by a forward genetic screen in near-haploid KBM7 cells.\",\n      \"method\": \"Forward genetic screen (near-haploid KBM7 cells), in vitro E3 ligase activity assay, Co-IP, MHC-I degradation assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — intrinsic E3 ligase activity demonstrated in vitro, forward genetic screen plus Co-IP, replicated across two independent labs (PMID:24807418)\",\n      \"pmids\": [\"25030448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"US11 engages two distinct degradation pathways: a Derlin-1/TMEM129-dependent pathway required for MHC-I degradation and a SEL1L/HRD1-dependent pathway required for degradation of free US11 itself.\",\n      \"method\": \"Genetic epistasis using KO/KD of pathway components, MHC-I and US11 degradation assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with multiple KO/KD conditions, two orthogonal substrates, replicated in independent lab (PMID:24807418)\",\n      \"pmids\": [\"25030448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TMEM129 is a non-glycosylated, tri-spanning ER-membrane protein with a non-cleaved signal anchor sequence that adopts an Nexo-Ccyto orientation, positioning its C-terminal RING domain in the cytosol where it can catalyze ubiquitination reactions required for cytosolic degradation of secretory proteins.\",\n      \"method\": \"Glycosylation scanning mutagenesis, topology mapping, immunofluorescence/fractionation\",\n      \"journal\": \"Viruses\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — glycosylation scanning mutagenesis with functional interpretation, single lab, two orthogonal topology methods\",\n      \"pmids\": [\"27854284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"US11 recruits TMEM129 (along with Derlin-1 and UBE2J2) to engage the neonatal Fc receptor FcRn, initiating its dislocation from the ER to the cytosol and degradation, thereby blocking FcRn trafficking to the endosome and inhibiting IgG transcytosis.\",\n      \"method\": \"Co-immunoprecipitation, ER retention and degradation assays, IgG transcytosis functional assay\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus functional degradation and transcytosis assays, single lab, multiple orthogonal readouts\",\n      \"pmids\": [\"31289263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"TMEM129 is identified as a novel RING-C2 E3 ligase responsible for US11-mediated MHC-I degradation; US11-mediated degradation is MHC-I-specific, and TMEM129 operates in an auto-regulatory loop where free US11 is itself degraded by HRD1/SEL1L.\",\n      \"method\": \"Review/synthesis of genetic screen data and biochemical assays (as described in primary papers PMID:24807418 and PMID:25030448)\",\n      \"journal\": \"Molecular immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — synthesis of prior genetic screen and biochemical evidence, single review paper consolidating two independent labs\",\n      \"pmids\": [\"26210183\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM129 is a non-glycosylated, tri-spanning ER-resident E3 ubiquitin ligase with a cytosol-facing cysteine-only RING domain that forms a complex with Derlin-1, Derlin-2, VIMP, and p97; together with the E2 enzyme UBE2J2, it ubiquitinates substrates (including MHC-I and FcRn) at the ER membrane to drive their retrotranslocation and proteasomal degradation via the ERAD pathway, and is hijacked by the HCMV protein US11 for viral immune evasion.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM129 is an ER-resident E3 ubiquitin ligase that drives ER-associated degradation (ERAD) of membrane substrates by coupling target ubiquitination to retrotranslocation and proteasomal turnover [#0, #1]. It is a non-glycosylated, tri-spanning ER-membrane protein that adopts an Nexo-Ccyto orientation, placing its unconventional cysteine-only RING (RING-C2 / C4C4-type) domain in the cytosol where it catalyzes ubiquitin transfer [#1, #3]. TMEM129 functions within a dislocation complex containing Derlin-1, Derlin-2, VIMP, and the AAA-ATPase p97, and pairs with the E2 conjugating enzyme UBE2J2 to ubiquitinate substrates at the ER membrane [#0, #1]. It is the cellular ligase hijacked by the HCMV immunoevasin US11: US11 recruits TMEM129 via Derlin-1 to ubiquitinate and dislocate MHC class I for degradation, an activity that is genetically separable from the SEL1L/HRD1 pathway that degrades free US11 itself [#1, #2]. The same US11–TMEM129–Derlin-1–UBE2J2 machinery targets the neonatal Fc receptor FcRn, blocking its ER export and thereby inhibiting IgG transcytosis [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2014,\n      \"claim\": \"Identifying which cellular factor executes US11-driven MHC-I destruction resolved how HCMV exploits host ERAD, establishing TMEM129 as an E3 ligase embedded in a Derlin/p97 dislocation complex.\",\n      \"evidence\": \"Genome-wide shRNA screen with reciprocal Co-IP and HLA class I degradation assays\",\n      \"pmids\": [\"24807418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not demonstrate intrinsic catalytic activity in vitro\", \"Endogenous (non-viral) substrates not defined\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"An independent forward genetic screen confirmed TMEM129 as the ligase and showed its cysteine-only RING has intrinsic E3 activity paired with UBE2J2, defining the catalytic core of the dislocation reaction.\",\n      \"evidence\": \"Forward genetic screen in haploid KBM7 cells, in vitro E3 ligase assay, Co-IP, MHC-I degradation assay\",\n      \"pmids\": [\"25030448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E2/E3 ubiquitin chain topology on substrate not resolved\", \"Recruitment mediated through Derlin-1 but interface not structurally mapped\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic epistasis distinguished two US11-engaged routes, showing TMEM129/Derlin-1 degrades MHC-I while SEL1L/HRD1 degrades free US11, clarifying that substrate identity dictates pathway choice.\",\n      \"evidence\": \"Epistasis using KO/KD of pathway components with two orthogonal degradation substrates\",\n      \"pmids\": [\"25030448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis for substrate-specific channeling between the two pathways unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Synthesis of the screen and biochemical data consolidated TMEM129 as a RING-C2 ligase acting in an auto-regulatory loop, framing its specificity for MHC-I.\",\n      \"evidence\": \"Review synthesizing prior genetic and biochemical evidence\",\n      \"pmids\": [\"26210183\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No new primary data\", \"Specificity determinants for MHC-I not experimentally dissected\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Determining the membrane topology established that TMEM129 is a tri-spanning, non-glycosylated protein with a cytosolic C-terminal RING, explaining how its catalytic domain accesses cytosolic ubiquitination machinery.\",\n      \"evidence\": \"Glycosylation scanning mutagenesis and orthogonal topology mapping with fractionation\",\n      \"pmids\": [\"27854284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Structural model of the transmembrane region absent\", \"How topology coordinates with Derlin channel not shown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing that US11 redirects TMEM129 onto FcRn extended its substrate range beyond MHC-I and linked its activity to suppression of IgG transcytosis, broadening its role in viral immune evasion.\",\n      \"evidence\": \"Co-IP, ER retention/degradation assays, and IgG transcytosis functional assay\",\n      \"pmids\": [\"31289263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Whether FcRn is also a TMEM129 substrate in the absence of US11 unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The physiological, virus-independent substrates and cellular function of TMEM129 outside the US11 hijacking context remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No endogenous substrate identified in the absence of US11\", \"Native regulation and tissue context uncharacterized\", \"No structural data on the RING or transmembrane domain\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"complexes\": [\"ER dislocation complex (Derlin-1/Derlin-2/VIMP/p97)\"],\n    \"partners\": [\"DERL1\", \"DERL2\", \"SELENOS\", \"VCP\", \"UBE2J2\", \"US11\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}