{"gene":"UBA2","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":1999,"finding":"Human UBA2 forms a heterodimeric SUMO E1-activating enzyme complex with AOS1 (SAE1). UBA2 forms a beta-mercaptoethanol-sensitive thioester conjugate with SUMO-1/sentrin family members in the presence of AOS1, but not with ubiquitin or NEDD8, establishing it as the catalytic subunit of the SUMO E1.","method":"In vitro conjugation assay, thioester formation assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro biochemical reconstitution of E1 thioester formation with mutagenesis control (beta-ME sensitivity), founding paper replicated by multiple subsequent studies","pmids":["10217437"],"is_preprint":false},{"year":2001,"finding":"The SAE1/SAE2 (AOS1/UBA2) heterodimeric E1 enzyme and Ubc9 E2 catalyze formation of polymeric SUMO-2 and SUMO-3 chains on protein substrates in vitro, because SUMO-2/3 contain the consensus SUMO modification site (psiKXE) that SUMO-1 lacks. SUMO-2 chains are also detected in vivo.","method":"In vitro SUMOylation assay with purified SAE1/SAE2 and Ubc9; in vivo detection of SUMO-2 chains","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro with purified components, confirmed in vivo, mechanistically explains SUMO-2/3 chain specificity","pmids":["11451954"],"is_preprint":false},{"year":2010,"finding":"Crystal structure of the ubiquitin fold domain (ufd) of yeast Uba2 alone and in complex with Ubc9 reveals the E1-E2 interaction surface for SUMO transfer. The Uba2(ufd)-Ubc9 structure shows overlap between Uba2 and E3 binding sites on Ubc9, indicating that SUMO loading and E3-catalyzed transfer are strictly separate steps. Structural modeling supports large conformational changes in Uba2 during the reaction.","method":"X-ray crystallography; structural comparison with prior full-length human Uba2 structure","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures of both free and complex forms determined, functionally interpreted by structural overlap analysis","pmids":["21209884"],"is_preprint":false},{"year":2012,"finding":"The SAE2 subunit of human SUMO activation enzyme (SAE1/UBA2 heterodimer) undergoes rapid nucleocytoplasmic shuttling, and its nuclear accumulation depends on SUMO modification at its C terminus. SUMOylation occurs at three Lys residues on the bipartite NLS and two adjacent Lys residues, catalyzed by Ubc9. Because SAE2 forms a tight heterodimer with SAE1 and controls trafficking of the heterodimer, SAE2 SUMOylation is the mechanism for nuclear localization of the SAE complex.","method":"Subcellular fractionation, site-directed mutagenesis of SUMOylation sites, live-cell imaging of GFP-tagged SAE2, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal localization experiments with mutagenesis of modification sites, mechanistic link between PTM and localization established","pmids":["23095757"],"is_preprint":false},{"year":2021,"finding":"SAE1/UBA2-mediated SUMOylation of pyruvate kinase M2 (PKM2) promotes PKM2 phosphorylation and nuclear translocation and decreases PK activity in rheumatoid arthritis fibroblast-like synoviocytes, driving glycolysis. STAT5A mediates SUMOylated PKM2-induced glycolysis. SAE1/UBA2 siRNA knockdown and the SUMOylation inhibitor GA reduced glycolysis, aggressive phenotype, and inflammation.","method":"siRNA knockdown, immunoprecipitation, western blotting, functional metabolic assays, mouse arthritis model","journal":"JCI insight","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for SUMOylation of PKM2, functional rescue with inhibitor, in vivo confirmation; single lab","pmids":["32938830"],"is_preprint":false},{"year":2025,"finding":"HDAC6-dependent deacetylation of SAE2 at lysine 164 during mitosis selectively promotes SUMO1 (over SUMO2/3) activation and conjugation. A non-deacetylatable SAE2-K164Q acetyl-mimetic mutant suppresses mitotic SUMO1 conjugation and promotes multipolar spindle formation. NuMA is identified as a SUMO E1-dependent substrate; mitotic defects from SAE2-K164Q or HDAC6 inhibition are rescued by SUMO1 overexpression or SUMO1-NuMA fusion. Thus, HDAC6-catalyzed deacetylation of SAE2-K164 is required for mitotic SUMO1 fidelity.","method":"Site-directed mutagenesis, HDAC6 inhibition/knockdown, western blotting, immunofluorescence for spindle geometry, co-immunoprecipitation, rescue experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mutagenesis of modification site, identification of writer (HDAC6), phenotypic rescue with SUMO1 or NuMA fusion, multiple orthogonal methods in one study","pmids":["40836035"],"is_preprint":false},{"year":1997,"finding":"Yeast Uba2 interacts with poly(A) polymerase (Pap1) via its C-terminal 115 amino acids (a region not present in previously characterized E1 enzymes). Both Uba2 and Ufd1 co-immunoprecipitate with Pap1 from cell extracts. Depletion of Uba2 from cells produces extracts with increased polyadenylation efficiency, suggesting Uba2 negatively regulates poly(A) polymerase activity.","method":"Yeast two-hybrid, co-immunoprecipitation, in vitro polyadenylation assay with Uba2-depleted extracts","journal":"Molecular & general genetics : MGG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP confirms two-hybrid interaction; functional consequence shown by depletion assay; single lab","pmids":["9236779"],"is_preprint":false},{"year":2021,"finding":"UBA2 SUMOylates NQO1 at lysine K240 in hepatocellular carcinoma cells; mutation of NQO1-K240 abolishes this modification. UBA2-mediated SUMOylation of NQO1 promotes HCC cell growth, invasion, and migration through the MAPK pathway. The SUMO inhibitor ML792 reverses UBA2-driven oncogenic effects in vivo and in vitro.","method":"Immunoprecipitation for SUMOylation, site-directed mutagenesis (K240R), RNA-seq, western blotting, in vivo tumor models","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP-based substrate identification with mutational validation, functional assays; single lab","pmids":["39013843"],"is_preprint":false},{"year":2021,"finding":"Ang II promotes SUMO2/3 (but not SUMO1) modification of RhoGDI1 through Aos1 and Uba2 subunits in vascular smooth muscle cells. Suppression of Uba2 by siRNA inhibited Ang II-induced SUMO2/3 modification of RhoGDI1, promoted RhoGDI1 ubiquitination and degradation, and inhibited cell proliferation, demonstrating that Uba2 is required for SUMO2/3-dependent stabilization of RhoGDI1.","method":"siRNA knockdown of Uba2, co-immunoprecipitation for SUMOylation and ubiquitination, EdU proliferation assay","journal":"Cardiovascular drugs and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP demonstrates substrate modification, functional assay shows proliferation effect; single lab, single method for each endpoint","pmids":["33891248"],"is_preprint":false},{"year":2001,"finding":"Drosophila Uba2 (dUba2) is nucleoplasmic throughout most of the cell cycle but is lost from the nucleus during mitosis, as demonstrated by immunofluorescence. dUba2 does not localize to sites of chorion gene amplification in ovaries, indicating it is not recruited to active DNA replication sites.","method":"Immunofluorescence, cell fractionation by localization imaging","journal":"Biochimica et biophysica acta","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization study without functional rescue or mechanistic follow-up","pmids":["11267682"],"is_preprint":false},{"year":2021,"finding":"UBA2 (SUMO E1) is required for normal porcine oocyte maturation and embryonic development in vitro; addition of exogenous UBA2 protein increases SUMO-1 protein content in mature oocytes, promotes maturation rate, blastocyst rate, and modulates expression of apoptosis genes (Bcl-2, Bax, Caspase3), showing UBA2 regulates SUMO-1 conjugation during oocyte development.","method":"Exogenous UBA2 protein supplementation, western blotting for SUMO-1, RT-qPCR for apoptosis genes, developmental rate scoring","journal":"Animal science journal","confidence":"Low","confidence_rationale":"Tier 3 / Weak — functional phenotype in oocytes with exogenous protein; no mechanistic substrate identified; single study","pmids":["33835647"],"is_preprint":false}],"current_model":"UBA2 (SAE2) is the catalytic subunit of the heterodimeric SUMO E1-activating enzyme (SAE1/UBA2), which forms an adenylate intermediate with SUMO's C-terminus and then transfers SUMO to the E2 enzyme Ubc9 via a thioester bond at UBA2's active-site cysteine; the complex preferentially activates SUMO-2/3 for polychain formation; UBA2's nuclear localization is regulated by Ubc9-catalyzed SUMOylation of UBA2's own NLS lysines, and during mitosis HDAC6-dependent deacetylation of UBA2 at K164 selectively promotes SUMO1 (over SUMO2/3) conjugation to substrates such as NuMA to ensure mitotic fidelity."},"narrative":{"mechanistic_narrative":"UBA2 (SAE2) is the catalytic subunit of the heterodimeric SUMO E1-activating enzyme, partnering with AOS1/SAE1 to initiate the SUMO conjugation cascade; in the presence of AOS1 it forms a beta-mercaptoethanol-sensitive thioester with SUMO-1/sentrin family members but not with ubiquitin or NEDD8, defining its dedicated role in SUMO activation [PMID:10217437]. Working with the E2 enzyme Ubc9, the SAE1/UBA2 E1 charges SUMO and enables formation of polymeric SUMO-2/3 chains on substrates bearing the psiKXE consensus motif [PMID:11451954], and structural analysis of the UBA2 ubiquitin-fold domain bound to Ubc9 shows that SUMO loading onto Ubc9 and E3-catalyzed transfer are sterically separated steps requiring large conformational changes in UBA2 [PMID:21209884]. UBA2 activity is itself regulated by post-translational control of the enzyme: Ubc9-catalyzed SUMOylation of lysines within its bipartite NLS drives nuclear accumulation of the SAE1/UBA2 heterodimer [PMID:23095757], while during mitosis HDAC6-dependent deacetylation of UBA2 at lysine 164 selectively biases the enzyme toward SUMO1 conjugation of substrates such as NuMA to ensure proper spindle geometry and mitotic fidelity [PMID:40836035]. Through this activity UBA2 controls substrate-specific SUMOylation events with downstream physiological consequences, including SUMOylation of PKM2 to drive glycolysis [PMID:32938830], of NQO1 to promote hepatocellular carcinoma growth via MAPK signaling [PMID:39013843], and SUMO-2/3 modification of RhoGDI1 that protects it from ubiquitin-mediated degradation [PMID:33891248].","teleology":[{"year":1999,"claim":"Established that UBA2 is the catalytic subunit of a heterodimeric SUMO-specific E1 enzyme, answering whether SUMO activation uses a dedicated machinery distinct from ubiquitin/NEDD8.","evidence":"In vitro thioester conjugation assay with AOS1, testing SUMO-1 vs ubiquitin vs NEDD8 and beta-ME sensitivity","pmids":["10217437"],"confidence":"High","gaps":["Did not define the active-site cysteine residue directly","SUMO paralog selectivity not addressed"]},{"year":2001,"claim":"Showed that the SAE1/UBA2 E1 together with Ubc9 builds SUMO-2/3 polychains via the psiKXE consensus, explaining a mechanistic basis for paralog-specific chain formation.","evidence":"In vitro SUMOylation with purified SAE1/SAE2 and Ubc9 plus in vivo detection of SUMO-2 chains","pmids":["11451954"],"confidence":"High","gaps":["Physiological substrates of polychains not identified","Does not explain how SUMO1 vs SUMO2/3 choice is regulated in cells"]},{"year":2010,"claim":"Defined the structural basis for handoff of SUMO from UBA2 to Ubc9, establishing that E1 loading and E3 transfer are mutually exclusive on Ubc9.","evidence":"X-ray crystallography of yeast Uba2 ufd alone and bound to Ubc9, with binding-site overlap analysis","pmids":["21209884"],"confidence":"High","gaps":["Conformational changes inferred from modeling rather than captured directly","Human full-cycle structure not resolved here"]},{"year":2012,"claim":"Revealed that UBA2 SUMOylation on its NLS lysines controls nuclear import of the entire SAE complex, linking an autoregulatory PTM to enzyme localization.","evidence":"Subcellular fractionation, SUMOylation-site mutagenesis, live-cell imaging of GFP-SAE2, co-IP","pmids":["23095757"],"confidence":"High","gaps":["Functional consequence of cytoplasmic vs nuclear E1 pool on substrate choice unresolved","Trigger for shuttling not defined"]},{"year":2021,"claim":"Extended UBA2 function to substrate-specific physiological SUMOylation, showing it modifies metabolic and signaling proteins (PKM2, NQO1, RhoGDI1) with disease-relevant consequences.","evidence":"siRNA knockdown, co-IP for SUMOylation, site mutagenesis, functional assays and in vivo tumor/arthritis models across three independent studies","pmids":["32938830","39013843","33891248"],"confidence":"Medium","gaps":["Each substrate validated by co-IP in a single lab","Direct vs indirect requirement for UBA2 not always distinguished"]},{"year":2025,"claim":"Identified an acetylation switch on UBA2 (K164) read out by HDAC6 that biases the E1 toward SUMO1 during mitosis, providing a mechanism for paralog selection at a cell-cycle stage.","evidence":"K164 acetyl-mimetic mutagenesis, HDAC6 inhibition/knockdown, spindle immunofluorescence, and rescue with SUMO1 or SUMO1-NuMA fusion","pmids":["40836035"],"confidence":"High","gaps":["Structural basis for how K164 acetylation alters paralog preference not resolved","Acetyltransferase opposing HDAC6 not identified"]},{"year":null,"claim":"How distinct regulatory inputs (NLS SUMOylation, K164 acetylation, paralog selection) are integrated to direct UBA2 toward specific substrates in different cellular contexts remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking UBA2 PTM state to substrate/paralog output","Genome-wide substrate map of UBA2-dependent SUMOylation lacking"]}],"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":[0,1,5]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[3]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[5]}],"complexes":["SUMO E1 activating enzyme (SAE1/UBA2 heterodimer)"],"partners":["SAE1","AOS1","UBE2I","HDAC6"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBT2","full_name":"SUMO-activating enzyme subunit 2","aliases":["Anthracycline-associated resistance ARX","Ubiquitin-like 1-activating enzyme E1B","Ubiquitin-like modifier-activating enzyme 2"],"length_aa":640,"mass_kda":71.2,"function":"The heterodimer acts as an E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/Q9UBT2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/UBA2","classification":"Common Essential","n_dependent_lines":1195,"n_total_lines":1208,"dependency_fraction":0.9892384105960265},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"SAE1","stoichiometry":10.0},{"gene":"SAR1B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/UBA2","total_profiled":1310},"omim":[{"mim_id":"619959","title":"ACCES SYNDROME; ACCES","url":"https://www.omim.org/entry/619959"},{"mim_id":"613295","title":"UBIQUITIN-LIKE MODIFIER-ACTIVATING ENZYME 2; UBA2","url":"https://www.omim.org/entry/613295"},{"mim_id":"613294","title":"SUMO1-ACTIVATING ENZYME, SUBUNIT 1; SAE1","url":"https://www.omim.org/entry/613294"},{"mim_id":"613026","title":"CHROMOSOME 19q13.11 DELETION SYNDROME, DISTAL","url":"https://www.omim.org/entry/613026"},{"mim_id":"608760","title":"AUTOPHAGY-RELATED 7; ATG7","url":"https://www.omim.org/entry/608760"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBA2"},"hgnc":{"alias_symbol":["FLJ13058","HRIHFB2115"],"prev_symbol":["SAE2"]},"alphafold":{"accession":"Q9UBT2","domains":[{"cath_id":"3.40.50.720","chopping":"8-165_384-431","consensus_level":"high","plddt":96.4991,"start":8,"end":431},{"cath_id":"1.10.10.520","chopping":"171-216_237-290_307-380","consensus_level":"high","plddt":91.9603,"start":171,"end":380},{"cath_id":"3.10.290.20","chopping":"448-546","consensus_level":"high","plddt":94.7026,"start":448,"end":546}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBT2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBT2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBT2-F1-predicted_aligned_error_v6.png","plddt_mean":85.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBA2","jax_strain_url":"https://www.jax.org/strain/search?query=UBA2"},"sequence":{"accession":"Q9UBT2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBT2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBT2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBT2"}},"corpus_meta":[{"pmid":"18806779","id":"PMC_18806779","title":"Sae2, 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UBA2 forms a beta-mercaptoethanol-sensitive thioester conjugate with SUMO-1/sentrin family members in the presence of AOS1, but not with ubiquitin or NEDD8, establishing it as the catalytic subunit of the SUMO E1.\",\n      \"method\": \"In vitro conjugation assay, thioester formation assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro biochemical reconstitution of E1 thioester formation with mutagenesis control (beta-ME sensitivity), founding paper replicated by multiple subsequent studies\",\n      \"pmids\": [\"10217437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The SAE1/SAE2 (AOS1/UBA2) heterodimeric E1 enzyme and Ubc9 E2 catalyze formation of polymeric SUMO-2 and SUMO-3 chains on protein substrates in vitro, because SUMO-2/3 contain the consensus SUMO modification site (psiKXE) that SUMO-1 lacks. SUMO-2 chains are also detected in vivo.\",\n      \"method\": \"In vitro SUMOylation assay with purified SAE1/SAE2 and Ubc9; in vivo detection of SUMO-2 chains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro with purified components, confirmed in vivo, mechanistically explains SUMO-2/3 chain specificity\",\n      \"pmids\": [\"11451954\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Crystal structure of the ubiquitin fold domain (ufd) of yeast Uba2 alone and in complex with Ubc9 reveals the E1-E2 interaction surface for SUMO transfer. The Uba2(ufd)-Ubc9 structure shows overlap between Uba2 and E3 binding sites on Ubc9, indicating that SUMO loading and E3-catalyzed transfer are strictly separate steps. Structural modeling supports large conformational changes in Uba2 during the reaction.\",\n      \"method\": \"X-ray crystallography; structural comparison with prior full-length human Uba2 structure\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures of both free and complex forms determined, functionally interpreted by structural overlap analysis\",\n      \"pmids\": [\"21209884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The SAE2 subunit of human SUMO activation enzyme (SAE1/UBA2 heterodimer) undergoes rapid nucleocytoplasmic shuttling, and its nuclear accumulation depends on SUMO modification at its C terminus. SUMOylation occurs at three Lys residues on the bipartite NLS and two adjacent Lys residues, catalyzed by Ubc9. Because SAE2 forms a tight heterodimer with SAE1 and controls trafficking of the heterodimer, SAE2 SUMOylation is the mechanism for nuclear localization of the SAE complex.\",\n      \"method\": \"Subcellular fractionation, site-directed mutagenesis of SUMOylation sites, live-cell imaging of GFP-tagged SAE2, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal localization experiments with mutagenesis of modification sites, mechanistic link between PTM and localization established\",\n      \"pmids\": [\"23095757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SAE1/UBA2-mediated SUMOylation of pyruvate kinase M2 (PKM2) promotes PKM2 phosphorylation and nuclear translocation and decreases PK activity in rheumatoid arthritis fibroblast-like synoviocytes, driving glycolysis. STAT5A mediates SUMOylated PKM2-induced glycolysis. SAE1/UBA2 siRNA knockdown and the SUMOylation inhibitor GA reduced glycolysis, aggressive phenotype, and inflammation.\",\n      \"method\": \"siRNA knockdown, immunoprecipitation, western blotting, functional metabolic assays, mouse arthritis model\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for SUMOylation of PKM2, functional rescue with inhibitor, in vivo confirmation; single lab\",\n      \"pmids\": [\"32938830\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"HDAC6-dependent deacetylation of SAE2 at lysine 164 during mitosis selectively promotes SUMO1 (over SUMO2/3) activation and conjugation. A non-deacetylatable SAE2-K164Q acetyl-mimetic mutant suppresses mitotic SUMO1 conjugation and promotes multipolar spindle formation. NuMA is identified as a SUMO E1-dependent substrate; mitotic defects from SAE2-K164Q or HDAC6 inhibition are rescued by SUMO1 overexpression or SUMO1-NuMA fusion. Thus, HDAC6-catalyzed deacetylation of SAE2-K164 is required for mitotic SUMO1 fidelity.\",\n      \"method\": \"Site-directed mutagenesis, HDAC6 inhibition/knockdown, western blotting, immunofluorescence for spindle geometry, co-immunoprecipitation, rescue experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mutagenesis of modification site, identification of writer (HDAC6), phenotypic rescue with SUMO1 or NuMA fusion, multiple orthogonal methods in one study\",\n      \"pmids\": [\"40836035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Yeast Uba2 interacts with poly(A) polymerase (Pap1) via its C-terminal 115 amino acids (a region not present in previously characterized E1 enzymes). Both Uba2 and Ufd1 co-immunoprecipitate with Pap1 from cell extracts. Depletion of Uba2 from cells produces extracts with increased polyadenylation efficiency, suggesting Uba2 negatively regulates poly(A) polymerase activity.\",\n      \"method\": \"Yeast two-hybrid, co-immunoprecipitation, in vitro polyadenylation assay with Uba2-depleted extracts\",\n      \"journal\": \"Molecular & general genetics : MGG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP confirms two-hybrid interaction; functional consequence shown by depletion assay; single lab\",\n      \"pmids\": [\"9236779\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UBA2 SUMOylates NQO1 at lysine K240 in hepatocellular carcinoma cells; mutation of NQO1-K240 abolishes this modification. UBA2-mediated SUMOylation of NQO1 promotes HCC cell growth, invasion, and migration through the MAPK pathway. The SUMO inhibitor ML792 reverses UBA2-driven oncogenic effects in vivo and in vitro.\",\n      \"method\": \"Immunoprecipitation for SUMOylation, site-directed mutagenesis (K240R), RNA-seq, western blotting, in vivo tumor models\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP-based substrate identification with mutational validation, functional assays; single lab\",\n      \"pmids\": [\"39013843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Ang II promotes SUMO2/3 (but not SUMO1) modification of RhoGDI1 through Aos1 and Uba2 subunits in vascular smooth muscle cells. Suppression of Uba2 by siRNA inhibited Ang II-induced SUMO2/3 modification of RhoGDI1, promoted RhoGDI1 ubiquitination and degradation, and inhibited cell proliferation, demonstrating that Uba2 is required for SUMO2/3-dependent stabilization of RhoGDI1.\",\n      \"method\": \"siRNA knockdown of Uba2, co-immunoprecipitation for SUMOylation and ubiquitination, EdU proliferation assay\",\n      \"journal\": \"Cardiovascular drugs and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP demonstrates substrate modification, functional assay shows proliferation effect; single lab, single method for each endpoint\",\n      \"pmids\": [\"33891248\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Drosophila Uba2 (dUba2) is nucleoplasmic throughout most of the cell cycle but is lost from the nucleus during mitosis, as demonstrated by immunofluorescence. dUba2 does not localize to sites of chorion gene amplification in ovaries, indicating it is not recruited to active DNA replication sites.\",\n      \"method\": \"Immunofluorescence, cell fractionation by localization imaging\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization study without functional rescue or mechanistic follow-up\",\n      \"pmids\": [\"11267682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"UBA2 (SUMO E1) is required for normal porcine oocyte maturation and embryonic development in vitro; addition of exogenous UBA2 protein increases SUMO-1 protein content in mature oocytes, promotes maturation rate, blastocyst rate, and modulates expression of apoptosis genes (Bcl-2, Bax, Caspase3), showing UBA2 regulates SUMO-1 conjugation during oocyte development.\",\n      \"method\": \"Exogenous UBA2 protein supplementation, western blotting for SUMO-1, RT-qPCR for apoptosis genes, developmental rate scoring\",\n      \"journal\": \"Animal science journal\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — functional phenotype in oocytes with exogenous protein; no mechanistic substrate identified; single study\",\n      \"pmids\": [\"33835647\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBA2 (SAE2) is the catalytic subunit of the heterodimeric SUMO E1-activating enzyme (SAE1/UBA2), which forms an adenylate intermediate with SUMO's C-terminus and then transfers SUMO to the E2 enzyme Ubc9 via a thioester bond at UBA2's active-site cysteine; the complex preferentially activates SUMO-2/3 for polychain formation; UBA2's nuclear localization is regulated by Ubc9-catalyzed SUMOylation of UBA2's own NLS lysines, and during mitosis HDAC6-dependent deacetylation of UBA2 at K164 selectively promotes SUMO1 (over SUMO2/3) conjugation to substrates such as NuMA to ensure mitotic fidelity.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBA2 (SAE2) is the catalytic subunit of the heterodimeric SUMO E1-activating enzyme, partnering with AOS1/SAE1 to initiate the SUMO conjugation cascade; in the presence of AOS1 it forms a beta-mercaptoethanol-sensitive thioester with SUMO-1/sentrin family members but not with ubiquitin or NEDD8, defining its dedicated role in SUMO activation [#0]. Working with the E2 enzyme Ubc9, the SAE1/UBA2 E1 charges SUMO and enables formation of polymeric SUMO-2/3 chains on substrates bearing the psiKXE consensus motif [#1], and structural analysis of the UBA2 ubiquitin-fold domain bound to Ubc9 shows that SUMO loading onto Ubc9 and E3-catalyzed transfer are sterically separated steps requiring large conformational changes in UBA2 [#2]. UBA2 activity is itself regulated by post-translational control of the enzyme: Ubc9-catalyzed SUMOylation of lysines within its bipartite NLS drives nuclear accumulation of the SAE1/UBA2 heterodimer [#3], while during mitosis HDAC6-dependent deacetylation of UBA2 at lysine 164 selectively biases the enzyme toward SUMO1 conjugation of substrates such as NuMA to ensure proper spindle geometry and mitotic fidelity [#5]. Through this activity UBA2 controls substrate-specific SUMOylation events with downstream physiological consequences, including SUMOylation of PKM2 to drive glycolysis [#4], of NQO1 to promote hepatocellular carcinoma growth via MAPK signaling [#7], and SUMO-2/3 modification of RhoGDI1 that protects it from ubiquitin-mediated degradation [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1999,\n      \"claim\": \"Established that UBA2 is the catalytic subunit of a heterodimeric SUMO-specific E1 enzyme, answering whether SUMO activation uses a dedicated machinery distinct from ubiquitin/NEDD8.\",\n      \"evidence\": \"In vitro thioester conjugation assay with AOS1, testing SUMO-1 vs ubiquitin vs NEDD8 and beta-ME sensitivity\",\n      \"pmids\": [\"10217437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the active-site cysteine residue directly\", \"SUMO paralog selectivity not addressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that the SAE1/UBA2 E1 together with Ubc9 builds SUMO-2/3 polychains via the psiKXE consensus, explaining a mechanistic basis for paralog-specific chain formation.\",\n      \"evidence\": \"In vitro SUMOylation with purified SAE1/SAE2 and Ubc9 plus in vivo detection of SUMO-2 chains\",\n      \"pmids\": [\"11451954\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological substrates of polychains not identified\", \"Does not explain how SUMO1 vs SUMO2/3 choice is regulated in cells\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined the structural basis for handoff of SUMO from UBA2 to Ubc9, establishing that E1 loading and E3 transfer are mutually exclusive on Ubc9.\",\n      \"evidence\": \"X-ray crystallography of yeast Uba2 ufd alone and bound to Ubc9, with binding-site overlap analysis\",\n      \"pmids\": [\"21209884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational changes inferred from modeling rather than captured directly\", \"Human full-cycle structure not resolved here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed that UBA2 SUMOylation on its NLS lysines controls nuclear import of the entire SAE complex, linking an autoregulatory PTM to enzyme localization.\",\n      \"evidence\": \"Subcellular fractionation, SUMOylation-site mutagenesis, live-cell imaging of GFP-SAE2, co-IP\",\n      \"pmids\": [\"23095757\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of cytoplasmic vs nuclear E1 pool on substrate choice unresolved\", \"Trigger for shuttling not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended UBA2 function to substrate-specific physiological SUMOylation, showing it modifies metabolic and signaling proteins (PKM2, NQO1, RhoGDI1) with disease-relevant consequences.\",\n      \"evidence\": \"siRNA knockdown, co-IP for SUMOylation, site mutagenesis, functional assays and in vivo tumor/arthritis models across three independent studies\",\n      \"pmids\": [\"32938830\", \"39013843\", \"33891248\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each substrate validated by co-IP in a single lab\", \"Direct vs indirect requirement for UBA2 not always distinguished\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified an acetylation switch on UBA2 (K164) read out by HDAC6 that biases the E1 toward SUMO1 during mitosis, providing a mechanism for paralog selection at a cell-cycle stage.\",\n      \"evidence\": \"K164 acetyl-mimetic mutagenesis, HDAC6 inhibition/knockdown, spindle immunofluorescence, and rescue with SUMO1 or SUMO1-NuMA fusion\",\n      \"pmids\": [\"40836035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for how K164 acetylation alters paralog preference not resolved\", \"Acetyltransferase opposing HDAC6 not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct regulatory inputs (NLS SUMOylation, K164 acetylation, paralog selection) are integrated to direct UBA2 toward specific substrates in different cellular contexts remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking UBA2 PTM state to substrate/paralog output\", \"Genome-wide substrate map of UBA2-dependent SUMOylation lacking\"]\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, 5]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"SUMO E1 activating enzyme (SAE1/UBA2 heterodimer)\"],\n    \"partners\": [\"SAE1\", \"AOS1\", \"UBE2I\", \"HDAC6\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":4,"faith_pct":100.0}}