{"gene":"UBE2E2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1997,"finding":"UBE2E2 protein forms a thioester bond with ubiquitin in an E1-dependent manner, confirming it is a functional ubiquitin-conjugating E2 enzyme. Its UBC domain shares >90% identity with human UbcH6, mouse UbcM2, and Drosophila UbcD2, and the gene was mapped to chromosome 3p24.2.","method":"In vitro thioester bond formation assay (E1-dependent ubiquitin loading), cDNA cloning, amino acid sequence analysis, fluorescence in situ hybridization (FISH)","journal":"Cytogenetics and cell genetics","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct in vitro biochemical assay demonstrating E1-dependent thioester bond formation, supported by sequence analysis and chromosomal mapping in a single rigorous study","pmids":["9371400"],"is_preprint":false},{"year":2023,"finding":"UBE2E2 interacts directly with Nrf2 via its N-terminal region (residues 1–52), promotes p62 accumulation and Nrf2-ARE antioxidant signaling, and stabilizes Snail protein by inhibiting its ubiquitin-mediated degradation, thereby driving EMT in ovarian cancer cells. Mutation of the active-site cysteine (Cys139) impaired both UBE2E2 function and its cellular distribution.","method":"Co-immunoprecipitation (co-IP), immunofluorescence, N-terminal deletion/truncation mapping, active-site cysteine mutagenesis (Cys139), siRNA knockdown and overexpression with migration/EMT readouts, xenograft mouse model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, domain mapping, active-site mutagenesis, and in vivo xenograft, all from a single lab with multiple orthogonal methods","pmids":["36765041"],"is_preprint":false},{"year":2024,"finding":"UBE2E2 mediates elongation of polyubiquitin chains in cooperation with the Nedd4 E3 ubiquitin ligase, as shown by ubiquitination assays in pancreatic β-cell-specific transgenic mice. Overexpression of UBE2E2 suppressed β-cell proliferation (associated with elevated p21 expression) and reduced β-cell mass, leading to glucose intolerance, without directly impairing glucose-stimulated insulin secretion from isolated islets.","method":"Ubiquitination assay, proteomic analysis of polyubiquitin chain types, pancreatic β-cell-specific transgenic mouse model, islet isolation/glucose-stimulated insulin secretion assay, gene expression analysis (p21), high-fat diet challenge","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ubiquitination assay plus proteomics plus in vivo transgenic model, single lab but multiple orthogonal methods","pmids":["38064504"],"is_preprint":false},{"year":2017,"finding":"In rat liver cells, downregulation of UBE2E2 leads to accumulation of its ubiquitination target proteins phosphorylated c-MYC, KDM4A, and KMT5A (but not p21WAF1/CIP1), resulting in increased cell proliferation (PCNA+) and slowed DNA damage response (γH2AX+) in GST-P+ preneoplastic foci.","method":"Immunohistochemistry for ubiquitination target proteins (p-c-MYC, KDM4A, KMT5A, p21), PCNA and γH2AX staining, rat hepatocarcinogenesis model with thioacetamide treatment","journal":"Toxicology and applied pharmacology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — immunohistochemical identification of putative substrates in tissue sections from a single lab, no direct in vitro ubiquitination assay confirming these as direct UBE2E2 substrates","pmids":["28899750"],"is_preprint":false},{"year":2024,"finding":"CRISPR excision of noncoding SNV-containing regions near UBE2E2 and CRISPRi screening across the locus suggest that T2D-associated noncoding variants concomitantly regulate UBE2E2, the neighboring UBE2E1, and other locus genes; compound heterozygous loss of both Ube2e2 and Ube2e1 in mice better replicated pathological adiposity and metabolic phenotypes than loss of either gene alone, implicating polygenic regulatory effects.","method":"CRISPR excision of noncoding regions, CRISPRi regulatory screen, compound heterozygous mouse knockouts, ex vivo adipogenesis assays, diet-induced obesity model","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple CRISPR approaches and mouse genetics from a single study, but causal gene nomination complicated by polygenic effects","pmids":["39656538"],"is_preprint":false}],"current_model":"UBE2E2 is a functional ubiquitin-conjugating E2 enzyme that forms an E1-dependent thioester bond with ubiquitin; it cooperates with the Nedd4 E3 ligase to elongate polyubiquitin chains, targets substrates including Snail (stabilizing it to promote EMT), and putative substrates c-MYC, KDM4A, and KMT5A for degradation; its active-site Cys139 is required for function and proper subcellular localization; in pancreatic β-cells its overexpression suppresses proliferation via p21 upregulation and reduces β-cell mass, while in ovarian cancer it drives metastasis through a UBE2E2–Nrf2–p62–Snail axis."},"narrative":{"mechanistic_narrative":"UBE2E2 is a functional ubiquitin-conjugating (E2) enzyme that forms an E1-dependent thioester bond with ubiquitin and operates within the ubiquitin-proteasome system to regulate cell proliferation and protein stability [PMID:9371400]. It elongates polyubiquitin chains in cooperation with the Nedd4 E3 ligase, and its active-site Cys139 is required both for catalytic function and for proper subcellular distribution [PMID:38064504, PMID:36765041]. In ovarian cancer cells, UBE2E2 binds Nrf2 directly through its N-terminal region (residues 1–52), promotes p62 accumulation and Nrf2-ARE antioxidant signaling, and stabilizes the EMT driver Snail by protecting it from ubiquitin-mediated degradation, thereby promoting migration and metastasis [PMID:36765041]. In pancreatic β-cells, UBE2E2 overexpression suppresses proliferation in association with elevated p21 and reduces β-cell mass, producing glucose intolerance without directly impairing glucose-stimulated insulin secretion [PMID:38064504]. Genetic dissection of the T2D-associated locus indicates that noncoding regulatory variants co-regulate UBE2E2 with the neighboring UBE2E1, and combined loss of both genes in mice recapitulates metabolic phenotypes more completely than loss of either alone [PMID:39656538].","teleology":[{"year":1997,"claim":"Established that UBE2E2 is a genuine catalytic E2 enzyme rather than an inert homolog, defining its biochemical identity within the ubiquitin system.","evidence":"In vitro E1-dependent thioester ubiquitin-loading assay with cDNA cloning, sequence analysis, and FISH mapping to 3p24.2","pmids":["9371400"],"confidence":"High","gaps":["No cognate E3 ligases or substrates identified at this stage","Chain-type specificity not determined","No cellular or physiological role established"]},{"year":2017,"claim":"Began linking UBE2E2 to substrate turnover by nominating phosphorylated c-MYC, KDM4A, and KMT5A as ubiquitination targets controlling proliferation and the DNA damage response.","evidence":"Immunohistochemistry of putative substrates with PCNA/γH2AX staining in a rat thioacetamide hepatocarcinogenesis model","pmids":["28899750"],"confidence":"Low","gaps":["No in vitro ubiquitination assay confirms these as direct UBE2E2 substrates","Correlative tissue immunostaining only, no biochemical reconstitution","Mechanism of substrate selection unknown"]},{"year":2023,"claim":"Defined a substrate-stabilizing role and a direct binding partner, showing UBE2E2 drives EMT via an Nrf2–p62–Snail axis and that catalytic Cys139 is essential.","evidence":"Reciprocal co-IP, N-terminal truncation mapping, Cys139 active-site mutagenesis, knockdown/overexpression with EMT readouts, and xenograft in ovarian cancer cells","pmids":["36765041"],"confidence":"Medium","gaps":["Whether UBE2E2 ubiquitinates Snail or Nrf2 directly versus regulating their stability indirectly is not resolved","Single-lab study without independent replication","Chain linkage on Snail not characterized"]},{"year":2024,"claim":"Connected UBE2E2 enzymatic activity to a specific E3 partner and an in vivo metabolic phenotype, showing it elongates polyubiquitin chains with Nedd4 and restrains β-cell proliferation.","evidence":"Ubiquitination assay with proteomic chain-type analysis plus β-cell-specific transgenic mice with islet/GSIS assays and high-fat-diet challenge","pmids":["38064504"],"confidence":"Medium","gaps":["Direct substrates ubiquitinated via the UBE2E2–Nedd4 pair not identified","Mechanistic link from chain elongation to p21 induction unresolved","Single overexpression model; loss-of-function consequences not assessed here"]},{"year":2024,"claim":"Addressed which gene at the T2D locus is causal, finding polygenic regulatory effects implicating UBE2E2 together with UBE2E1 rather than UBE2E2 alone.","evidence":"CRISPR excision and CRISPRi of noncoding regions, compound heterozygous mouse knockouts, ex vivo adipogenesis, and diet-induced obesity","pmids":["39656538"],"confidence":"Medium","gaps":["Cannot cleanly isolate UBE2E2-specific contribution from UBE2E1 and other locus genes","Molecular target of the regulatory variants not pinpointed","Tissue of primary effect not definitively established"]},{"year":null,"claim":"The direct, biochemically validated substrate repertoire of UBE2E2 and the chain linkages it builds with specific E3 ligases remain undefined.","evidence":"","pmids":[],"confidence":"Low","gaps":["No reconstituted E2-E3-substrate ubiquitination defining direct targets","Structural basis of E3 partnering and Cys139-dependent localization unknown","Reconciliation of growth-suppressive (β-cell) versus oncogenic (ovarian) roles not mechanistically explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":["NEDD4","NFE2L2","SQSTM1","SNAI1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q96LR5","full_name":"Ubiquitin-conjugating enzyme E2 E2","aliases":["E2 ubiquitin-conjugating enzyme E2","UbcH8","Ubiquitin carrier protein E2","Ubiquitin-protein ligase E2"],"length_aa":201,"mass_kda":22.3,"function":"Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'- and 'Lys-48'-, as well as 'Lys-63'-linked polyubiquitination. Catalyzes the ISGylation of influenza A virus NS1 protein","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q96LR5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBE2E2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UBE2E2","total_profiled":1310},"omim":[{"mim_id":"606692","title":"TNF RECEPTOR-ASSOCIATED FACTOR 7; TRAF7","url":"https://www.omim.org/entry/606692"},{"mim_id":"602163","title":"UBIQUITIN-CONJUGATING ENZYME E2 E2; UBE2E2","url":"https://www.omim.org/entry/602163"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBE2E2"},"hgnc":{"alias_symbol":["UbcH8","FLJ25157"],"prev_symbol":[]},"alphafold":{"accession":"Q96LR5","domains":[{"cath_id":"3.10.110.10","chopping":"54-199","consensus_level":"high","plddt":97.6896,"start":54,"end":199}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96LR5","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96LR5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96LR5-F1-predicted_aligned_error_v6.png","plddt_mean":85.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBE2E2","jax_strain_url":"https://www.jax.org/strain/search?query=UBE2E2"},"sequence":{"accession":"Q96LR5","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96LR5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96LR5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96LR5"}},"corpus_meta":[{"pmid":"20818381","id":"PMC_20818381","title":"A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B.","date":"2010","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20818381","citation_count":211,"is_preprint":false},{"pmid":"29871606","id":"PMC_29871606","title":"Impact of KCNQ1, CDKN2A/2B, CDKAL1, HHEX, MTNR1B, SLC30A8, TCF7L2, and UBE2E2 on risk of developing type 2 diabetes in Thai population.","date":"2018","source":"BMC medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/29871606","citation_count":27,"is_preprint":false},{"pmid":"9371400","id":"PMC_9371400","title":"cDNA cloning, characterization, and chromosome mapping of UBE2E2 encoding a human ubiquitin-conjugating E2 enzyme.","date":"1997","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/9371400","citation_count":15,"is_preprint":false},{"pmid":"27175665","id":"PMC_27175665","title":"Type 2 Diabetes Risk Allele UBE2E2 Is Associated With Decreased Glucose-Stimulated Insulin Release in Elderly Chinese Han Individuals.","date":"2016","source":"Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27175665","citation_count":12,"is_preprint":false},{"pmid":"36765041","id":"PMC_36765041","title":"UBE2E2 enhances Snail-mediated epithelial-mesenchymal transition and Nrf2-mediated antioxidant activity in ovarian cancer.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/36765041","citation_count":10,"is_preprint":false},{"pmid":"27914986","id":"PMC_27914986","title":"Identification of epigenetically downregulated Tmem70 and Ube2e2 in rat liver after 28-day treatment with hepatocarcinogenic thioacetamide showing gene product downregulation in hepatocellular preneoplastic and neoplastic lesions produced by tumor promotion.","date":"2016","source":"Toxicology letters","url":"https://pubmed.ncbi.nlm.nih.gov/27914986","citation_count":10,"is_preprint":false},{"pmid":"23862583","id":"PMC_23862583","title":"Putative association between UBE2E2 polymorphisms and the risk of gestational diabetes mellitus.","date":"2013","source":"Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/23862583","citation_count":9,"is_preprint":false},{"pmid":"26020062","id":"PMC_26020062","title":"Association between UBE2E2 variant rs7612463 and type 2 diabetes mellitus in a Chinese Han population.","date":"2015","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/26020062","citation_count":8,"is_preprint":false},{"pmid":"25337779","id":"PMC_25337779","title":"Lack of association between UBE2E2 gene polymorphism (rs7612463) and type 2 diabetes mellitus in a Saudi population.","date":"2014","source":"Acta biochimica Polonica","url":"https://pubmed.ncbi.nlm.nih.gov/25337779","citation_count":5,"is_preprint":false},{"pmid":"35207731","id":"PMC_35207731","title":"PPARG, TMEM163, UBE2E2, and WFS1 Gene Polymorphisms Are Not Significant Risk Factors for Gestational Diabetes in the Polish Population.","date":"2022","source":"Journal of personalized medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35207731","citation_count":4,"is_preprint":false},{"pmid":"38064504","id":"PMC_38064504","title":"Overexpression of UBE2E2 in Mouse Pancreatic β-Cells Leads to Glucose Intolerance via Reduction of β-Cell Mass.","date":"2024","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/38064504","citation_count":4,"is_preprint":false},{"pmid":"39656538","id":"PMC_39656538","title":"Noncoding variation near UBE2E2 orchestrates cardiometabolic pathophenotypes through polygenic effectors.","date":"2024","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/39656538","citation_count":3,"is_preprint":false},{"pmid":"28899750","id":"PMC_28899750","title":"Downregulation of UBE2E2 in rat liver cells after hepatocarcinogen treatment facilitates cell proliferation and slowing down of DNA damage response in GST-P-expressing preneoplastic lesions.","date":"2017","source":"Toxicology and applied pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28899750","citation_count":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9253,"output_tokens":1644,"usd":0.02621,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8421,"output_tokens":2329,"usd":0.050165,"stage2_stop_reason":"end_turn"},"total_usd":0.076375,"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\": 1997,\n      \"finding\": \"UBE2E2 protein forms a thioester bond with ubiquitin in an E1-dependent manner, confirming it is a functional ubiquitin-conjugating E2 enzyme. Its UBC domain shares >90% identity with human UbcH6, mouse UbcM2, and Drosophila UbcD2, and the gene was mapped to chromosome 3p24.2.\",\n      \"method\": \"In vitro thioester bond formation assay (E1-dependent ubiquitin loading), cDNA cloning, amino acid sequence analysis, fluorescence in situ hybridization (FISH)\",\n      \"journal\": \"Cytogenetics and cell genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct in vitro biochemical assay demonstrating E1-dependent thioester bond formation, supported by sequence analysis and chromosomal mapping in a single rigorous study\",\n      \"pmids\": [\"9371400\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"UBE2E2 interacts directly with Nrf2 via its N-terminal region (residues 1–52), promotes p62 accumulation and Nrf2-ARE antioxidant signaling, and stabilizes Snail protein by inhibiting its ubiquitin-mediated degradation, thereby driving EMT in ovarian cancer cells. Mutation of the active-site cysteine (Cys139) impaired both UBE2E2 function and its cellular distribution.\",\n      \"method\": \"Co-immunoprecipitation (co-IP), immunofluorescence, N-terminal deletion/truncation mapping, active-site cysteine mutagenesis (Cys139), siRNA knockdown and overexpression with migration/EMT readouts, xenograft mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, domain mapping, active-site mutagenesis, and in vivo xenograft, all from a single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36765041\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2E2 mediates elongation of polyubiquitin chains in cooperation with the Nedd4 E3 ubiquitin ligase, as shown by ubiquitination assays in pancreatic β-cell-specific transgenic mice. Overexpression of UBE2E2 suppressed β-cell proliferation (associated with elevated p21 expression) and reduced β-cell mass, leading to glucose intolerance, without directly impairing glucose-stimulated insulin secretion from isolated islets.\",\n      \"method\": \"Ubiquitination assay, proteomic analysis of polyubiquitin chain types, pancreatic β-cell-specific transgenic mouse model, islet isolation/glucose-stimulated insulin secretion assay, gene expression analysis (p21), high-fat diet challenge\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ubiquitination assay plus proteomics plus in vivo transgenic model, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38064504\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In rat liver cells, downregulation of UBE2E2 leads to accumulation of its ubiquitination target proteins phosphorylated c-MYC, KDM4A, and KMT5A (but not p21WAF1/CIP1), resulting in increased cell proliferation (PCNA+) and slowed DNA damage response (γH2AX+) in GST-P+ preneoplastic foci.\",\n      \"method\": \"Immunohistochemistry for ubiquitination target proteins (p-c-MYC, KDM4A, KMT5A, p21), PCNA and γH2AX staining, rat hepatocarcinogenesis model with thioacetamide treatment\",\n      \"journal\": \"Toxicology and applied pharmacology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — immunohistochemical identification of putative substrates in tissue sections from a single lab, no direct in vitro ubiquitination assay confirming these as direct UBE2E2 substrates\",\n      \"pmids\": [\"28899750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CRISPR excision of noncoding SNV-containing regions near UBE2E2 and CRISPRi screening across the locus suggest that T2D-associated noncoding variants concomitantly regulate UBE2E2, the neighboring UBE2E1, and other locus genes; compound heterozygous loss of both Ube2e2 and Ube2e1 in mice better replicated pathological adiposity and metabolic phenotypes than loss of either gene alone, implicating polygenic regulatory effects.\",\n      \"method\": \"CRISPR excision of noncoding regions, CRISPRi regulatory screen, compound heterozygous mouse knockouts, ex vivo adipogenesis assays, diet-induced obesity model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple CRISPR approaches and mouse genetics from a single study, but causal gene nomination complicated by polygenic effects\",\n      \"pmids\": [\"39656538\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBE2E2 is a functional ubiquitin-conjugating E2 enzyme that forms an E1-dependent thioester bond with ubiquitin; it cooperates with the Nedd4 E3 ligase to elongate polyubiquitin chains, targets substrates including Snail (stabilizing it to promote EMT), and putative substrates c-MYC, KDM4A, and KMT5A for degradation; its active-site Cys139 is required for function and proper subcellular localization; in pancreatic β-cells its overexpression suppresses proliferation via p21 upregulation and reduces β-cell mass, while in ovarian cancer it drives metastasis through a UBE2E2–Nrf2–p62–Snail axis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBE2E2 is a functional ubiquitin-conjugating (E2) enzyme that forms an E1-dependent thioester bond with ubiquitin and operates within the ubiquitin-proteasome system to regulate cell proliferation and protein stability [#0]. It elongates polyubiquitin chains in cooperation with the Nedd4 E3 ligase, and its active-site Cys139 is required both for catalytic function and for proper subcellular distribution [#2, #1]. In ovarian cancer cells, UBE2E2 binds Nrf2 directly through its N-terminal region (residues 1\\u201352), promotes p62 accumulation and Nrf2-ARE antioxidant signaling, and stabilizes the EMT driver Snail by protecting it from ubiquitin-mediated degradation, thereby promoting migration and metastasis [#1]. In pancreatic \\u03b2-cells, UBE2E2 overexpression suppresses proliferation in association with elevated p21 and reduces \\u03b2-cell mass, producing glucose intolerance without directly impairing glucose-stimulated insulin secretion [#2]. Genetic dissection of the T2D-associated locus indicates that noncoding regulatory variants co-regulate UBE2E2 with the neighboring UBE2E1, and combined loss of both genes in mice recapitulates metabolic phenotypes more completely than loss of either alone [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that UBE2E2 is a genuine catalytic E2 enzyme rather than an inert homolog, defining its biochemical identity within the ubiquitin system.\",\n      \"evidence\": \"In vitro E1-dependent thioester ubiquitin-loading assay with cDNA cloning, sequence analysis, and FISH mapping to 3p24.2\",\n      \"pmids\": [\"9371400\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No cognate E3 ligases or substrates identified at this stage\",\n        \"Chain-type specificity not determined\",\n        \"No cellular or physiological role established\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Began linking UBE2E2 to substrate turnover by nominating phosphorylated c-MYC, KDM4A, and KMT5A as ubiquitination targets controlling proliferation and the DNA damage response.\",\n      \"evidence\": \"Immunohistochemistry of putative substrates with PCNA/\\u03b3H2AX staining in a rat thioacetamide hepatocarcinogenesis model\",\n      \"pmids\": [\"28899750\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No in vitro ubiquitination assay confirms these as direct UBE2E2 substrates\",\n        \"Correlative tissue immunostaining only, no biochemical reconstitution\",\n        \"Mechanism of substrate selection unknown\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined a substrate-stabilizing role and a direct binding partner, showing UBE2E2 drives EMT via an Nrf2\\u2013p62\\u2013Snail axis and that catalytic Cys139 is essential.\",\n      \"evidence\": \"Reciprocal co-IP, N-terminal truncation mapping, Cys139 active-site mutagenesis, knockdown/overexpression with EMT readouts, and xenograft in ovarian cancer cells\",\n      \"pmids\": [\"36765041\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether UBE2E2 ubiquitinates Snail or Nrf2 directly versus regulating their stability indirectly is not resolved\",\n        \"Single-lab study without independent replication\",\n        \"Chain linkage on Snail not characterized\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected UBE2E2 enzymatic activity to a specific E3 partner and an in vivo metabolic phenotype, showing it elongates polyubiquitin chains with Nedd4 and restrains \\u03b2-cell proliferation.\",\n      \"evidence\": \"Ubiquitination assay with proteomic chain-type analysis plus \\u03b2-cell-specific transgenic mice with islet/GSIS assays and high-fat-diet challenge\",\n      \"pmids\": [\"38064504\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct substrates ubiquitinated via the UBE2E2\\u2013Nedd4 pair not identified\",\n        \"Mechanistic link from chain elongation to p21 induction unresolved\",\n        \"Single overexpression model; loss-of-function consequences not assessed here\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Addressed which gene at the T2D locus is causal, finding polygenic regulatory effects implicating UBE2E2 together with UBE2E1 rather than UBE2E2 alone.\",\n      \"evidence\": \"CRISPR excision and CRISPRi of noncoding regions, compound heterozygous mouse knockouts, ex vivo adipogenesis, and diet-induced obesity\",\n      \"pmids\": [\"39656538\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Cannot cleanly isolate UBE2E2-specific contribution from UBE2E1 and other locus genes\",\n        \"Molecular target of the regulatory variants not pinpointed\",\n        \"Tissue of primary effect not definitively established\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The direct, biochemically validated substrate repertoire of UBE2E2 and the chain linkages it builds with specific E3 ligases remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No reconstituted E2-E3-substrate ubiquitination defining direct targets\",\n        \"Structural basis of E3 partnering and Cys139-dependent localization unknown\",\n        \"Reconciliation of growth-suppressive (\\u03b2-cell) versus oncogenic (ovarian) roles not mechanistically explained\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"NEDD4\", \"NFE2L2\", \"SQSTM1\", \"SNAI1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":5,"faith_total":5,"faith_pct":100.0}}