{"gene":"UBA7","run_date":"2026-06-10T10:51:56","timeline":{"discoveries":[{"year":2023,"finding":"Cryo-EM structures of human Uba7 (UBA7) in complex with UBE2L6 and ISG15 adenylate or ISG15 thioester intermediates reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer. The structures show a unique overall architecture compared to the ubiquitin conjugation pathway, particularly with respect to the location of the ISG15 thioester intermediate, and illuminate UBA7's exquisite specificity for ISG15 and UBE2L6.","method":"Cryo-EM structure determination, biochemical assays, human cell-based experiments","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structures with functional validation by biochemical assays and cell-based experiments in a single rigorous study","pmids":["37553340"],"is_preprint":false},{"year":2023,"finding":"A 3.45 Å cryo-EM structure of a chemically trapped UBE1L (UBA7)-UBE2L6 complex bound to activated ISG15 reveals the first steps of ISG15 recognition and UBE2L6 recruitment by UBE1L. Biochemical characterization enabled design of ISG15 and UBE2L6 mutants with altered selectivity for the ISG15 versus ubiquitin conjugation pathways. The ISG15 C-terminal ubiquitin-like domain is required for the adenylation reaction, validated using viral effector proteins from SARS-CoV-2 and influenza B virus.","method":"Cryo-EM structure, biochemical mutant characterization, viral effector protein validation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure combined with biochemical mutagenesis and functional validation using orthogonal viral tools","pmids":["38042859"],"is_preprint":false},{"year":2004,"finding":"UBE1L (UBA7) physically associates with ISG15 in vivo, requiring the conserved C-terminal diglycine motif of ISG15. Knockdown of UBE1L with siRNA or shRNA inhibited IFN- and RA-induced ISG15 conjugation. UBE1L is required for ISG15 conjugation during retinoid-induced differentiation of acute promyelocytic leukemia (APL) cells.","method":"Co-immunoprecipitation, siRNA/shRNA knockdown, immunoblot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with diglycine mutant validation, functional knockdown with defined cellular phenotype, replicated in multiple cell lines","pmids":["14976209"],"is_preprint":false},{"year":2006,"finding":"Mice lacking UBE1L (Ube1L−/−) fail to form ISG15 conjugates but express free ISG15 normally. Ube1L−/− mice were fertile and showed normal antiviral responses against VSV and LCMV, indicating UBE1L and protein ISGylation are not critical for IFN-α/β signaling via JAK/STAT activation. Using Ube1L/Ubp43 double-deficient mice, increased IFN signaling in Ubp43-deficient mice was attributed to loss of UBP43, not increased ISGylation.","method":"Genetic knockout mouse model, viral infection assays, epistasis analysis with double-KO","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with defined cellular phenotype, epistasis via double mutant, replicated across multiple viral models","pmids":["16382139"],"is_preprint":false},{"year":2002,"finding":"UBE1L (UBA7) overexpression triggered PML/RARα degradation in NB4 APL cells and induced apoptosis; a truncated UBE1L or the canonical E1 enzyme did not cause this degradation. UBE1L is a direct retinoid target gene whose promoter is suppressed by PML/RARα, and its induction is tightly linked to PML/RARα degradation. UBE1L-induced apoptosis was specific to cells expressing PML/RARα.","method":"Retroviral overexpression, transfection, promoter assay, immunoblot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — overexpression with specific mutant control, single lab, multiple complementary assays","pmids":["11891284"],"is_preprint":false},{"year":2008,"finding":"UBE1L promotes complex formation between ISG15 and cyclin D1, causing cyclin D1 protein (but not mRNA) degradation. UBE1L knockdown increased cyclin D1 protein; a lysine-less cyclin D1 mutant was resistant to UBE1L-mediated degradation. UBE1L retroviral transduction reduced cyclin D1 expression and clonal cell growth in bronchial epithelial and lung cancer cells.","method":"Co-immunoprecipitation, UBE1L retroviral transduction, siRNA knockdown, cycloheximide chase, immunoblot","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP, KD, OE with lysine-less mutant control; single lab with multiple methods","pmids":["19074853"],"is_preprint":false},{"year":2008,"finding":"UBE1L induces ISG15ylation of the PML domain of PML/RARα, targeting it for proteasomal degradation. RA-induced degradation targets the RARα domain via a distinct pathway, while UBE1L independently targets the PML domain. UBP43/USP18 (ISG15 deconjugase) opposed UBE1L- but not RA-dependent PML/RARα degradation; proteasomal inhibitor blocked both.","method":"Transfection of PML/RARα domain constructs, co-immunoprecipitation, proteasome inhibitor treatment, UBP43 deconjugase antagonism","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — domain-mapping transfections, deconjugase competition, proteasome inhibitor rescue; single lab","pmids":["18413804"],"is_preprint":false},{"year":2008,"finding":"Mice lacking UbE1L (the ISG15 E1 enzyme) fail to form ISG15 conjugates and display increased susceptibility to influenza B virus infection, including non-mouse-adapted strains. ISG15 controls influenza B virus infection through its action within radioresistant stromal cells, not bone marrow-derived cells, indicating stromal cell ISGylation is critical.","method":"Ube1L−/− mouse model, bone marrow transplantation/chimera experiments, viral infection assays","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean KO with viral susceptibility phenotype, cell-type specificity established by bone marrow chimera experiments","pmids":["19004958"],"is_preprint":false},{"year":2008,"finding":"The ISG15 E1 enzyme UbE1L is important for control of Sindbis virus infection: UbE1L-deficient mice were highly susceptible to Sindbis virus. An ISG15 mutant (R151A) that ablates binding to UbE1L and transthiolation to UbcH8 could not protect IFN-αβR−/− mice from Sindbis virus lethality, supporting that protein conjugation (not free ISG15) mediates ISG15's antiviral effect against Sindbis virus.","method":"Ube1L−/− mouse model, double-subgenomic Sindbis virus expressing ISG15 mutants, kinetic binding assays, transfection","journal":"Journal of virology","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO combined with structure-guided mutagenesis and viral challenge, multiple orthogonal methods","pmids":["19073728"],"is_preprint":false},{"year":2011,"finding":"ISG15 controls Chikungunya virus (CHIKV) infection in neonatal mice independently of UbE1L-mediated conjugation: UbE1L−/− mice (unable to form ISG15 conjugates) showed no increase in lethality after CHIKV infection, whereas ISG15−/− mice were profoundly susceptible. ISG15 modulates proinflammatory cytokines/chemokines rather than controlling viral loads, indicating a non-conjugation, immunomodulatory role for ISG15 in CHIKV pathogenesis.","method":"UbE1L−/− and ISG15−/− mouse models, viral infection, cytokine/chemokine measurement","journal":"PLoS pathogens","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis using two independent KO mouse lines with well-controlled viral infection readout","pmids":["22028657"],"is_preprint":false},{"year":2018,"finding":"HCMV transmembrane protein pUL50 interacts with UBE1L (the ISG15 E1-activating enzyme) and causes its proteasomal degradation, thereby inhibiting ISGylation. This requires the C-terminal transmembrane domain of pUL50 for activity. RNF170, an ER-associated ubiquitin E3 ligase, interacts with pUL50 and promotes pUL50-mediated UBE1L ubiquitination and degradation.","method":"Co-immunoprecipitation, co-localization, proteasome inhibitor experiments, overexpression of UL50 and RNF170","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with domain deletion controls, proteasome inhibitor rescue, identification of E3 ligase; single lab","pmids":["29743376"],"is_preprint":false},{"year":2004,"finding":"A 110-kDa bovine UBE1L protein was purified from endometrial cells by affinity with recombinant GST-ISG15, confirming a direct physical interaction between UBE1L and ISG15. Bovine UBE1L shares 83% cDNA identity with human UBE1L and forms a thioester bond with ISG15 to initiate conjugation.","method":"Affinity purification with GST-ISG15, mass spectrometry peptide identification, full-length cDNA sequencing","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — affinity pulldown with MS identification of binding partner; ortholog characterization with biochemical validation","pmids":["15385418"],"is_preprint":false},{"year":2004,"finding":"Microarray analyses identified UBE1L as a retinoid-regulated gene in human bronchial epithelial cells. Wild-type but not mutant UBE1L repressed cyclin D1 expression in a dose-dependent manner upon co-transfection, establishing a functional requirement for UBE1L's catalytic activity in cyclin D1 repression.","method":"Microarray, transfection with wild-type vs. mutant UBE1L, immunoblot","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — transfection with mutant control showing dose-dependence; single lab, limited mechanistic depth in abstract","pmids":["15520223"],"is_preprint":false},{"year":1995,"finding":"The UBE1L gene has 22 exons spanning 8.4 kb at chromosome 3p21. Lack of UBE1L expression in lung cancer cell lines correlates with hypermethylation of a HhaI site in the first exon and decreased DNase I sensitivity of the promoter region, suggesting epigenetic silencing.","method":"Genomic mapping, anchored PCR, DNase I hypersensitivity assay, methylation analysis with 5-azacytidine treatment","journal":"Gene expression","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple complementary genomic methods; 5-azacytidine demethylation did not restore expression, suggesting additional regulatory block","pmids":["7734949"],"is_preprint":false},{"year":2010,"finding":"UBE1L-deficient (Ube1l−/−) hematopoietic cells show impaired repopulation potential after bone marrow transplantation (50% reduction at 3 weeks). Under conditions of high IFN and ISGylation (post-transplant), Ube1L deficiency causes G2/M cell cycle block in hematopoietic multipotential progenitors, indicating ISGylation promotes cell cycle progression during interferon-related stress.","method":"Bone marrow transplantation with Ube1l−/− cells, competitive transplantation, cell cycle analysis","journal":"Blood cells, molecules & diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KO with bone marrow transplant readout and cell cycle phenotype; single lab","pmids":["20591702"],"is_preprint":false},{"year":2008,"finding":"Ube1l deficiency did not alter lung cancer progression or overall survival in K-rasLA2 lung cancer mice, and protein ISGylation levels were largely unchanged during lung cancer progression in this model. This establishes a negative result: UBE1L is not a tumor suppressor gene in K-ras mutation-dependent lung cancer.","method":"Ube1l−/− crossed with K-rasLA2 mice, tumor progression and survival analysis, ISGylation western blots","journal":"Lung cancer (Amsterdam, Netherlands)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo genetic model; negative result well-controlled","pmids":["18571763"],"is_preprint":false},{"year":2017,"finding":"shRNA knockdown of UBA7 increased rabies virus (RABV) titers in neuroblastoma (NA) and microglial (BV-2) cell lines and in mouse brains, and decreased mouse survival, establishing that UBA7 inhibits RABV replication in vitro and in vivo.","method":"shRNA knockdown, viral titer measurement, lentiviral-mediated knockdown in mouse brain, survival analysis","journal":"Infection, genetics and evolution","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo KD with defined viral titer phenotype; single lab, single method type","pmids":["29056542"],"is_preprint":false},{"year":2013,"finding":"UBE1L overexpression in human bronchial epithelial (Beas-2B) cells triggered EGFR membrane internalization, promoted complex formation between ISG15 and EGFR, and reduced EGFR protein at the post-translational level. UBE1L knockdown increased EGFR and downstream PI3K/AKT/NF-κB signaling.","method":"UBE1L overexpression, UBE1L knockdown, co-immunoprecipitation of ISG15-EGFR complex, immunoblot of downstream signaling","journal":"The Journal of nutritional biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, co-IP and OE/KD without deep mechanistic dissection of the ISG15-EGFR conjugation","pmids":["24445050"],"is_preprint":false},{"year":2022,"finding":"Evolutionary analysis showed that UBA7 descends from gene duplication of UBA1, and ISG15 arose from UBB/UBC. Zebrafish Uba7 retains the ability to activate the ubiquitin cascade in vitro and in vivo (unlike tetrapod Uba7), indicating that ancestral Uba7 had promiscuous substrate specificity that became restricted to ISG15 in tetrapods.","method":"Phylogenetic analysis, in vitro ubiquitin activation assay, in vivo zebrafish assays","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro reconstitution and in vivo assay in zebrafish; single lab with evolutionary framing","pmids":["35134494"],"is_preprint":false},{"year":2016,"finding":"Ube1l−/− mouse embryonic fibroblasts (MEF) exhibit low viral resistance despite high STAT1/ISG expression compared to wild-type MEF. Ube1l−/− MEF populations contain two sub-populations with distinct basal STAT1 activity; this heterogeneity was perturbed by JAK2/FAK tyrosine kinase inhibitors (AG490, PF431396) but not by type I IFN neutralization, indicating UBE1L-dependent ISGylation regulates population-level basal immune signaling states through a tyrosine kinase-sensitive pathway.","method":"Ube1l−/− MEF, flow cytometry for STAT1 activity, tyrosine kinase inhibitors, IFN neutralization","journal":"PloS one","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, pharmacological inhibitors without defined direct molecular link between UBE1L and the kinase pathway","pmids":["27427993"],"is_preprint":false}],"current_model":"UBA7 (also known as UBE1L/UBE1L/UBA1B) is the E1-activating enzyme exclusively dedicated to ISG15, a ubiquitin-like modifier induced by type I interferon: it adenylates ISG15 at its C-terminal diglycine motif and then forms a thioester intermediate before transferring ISG15 to the cognate E2 enzyme UBE2L6 (UbcH8), as established by cryo-EM structures and biochemical reconstitution; UBA7 is dispensable for ubiquitin activation but required for all intracellular ISG15 conjugation (ISGylation), and loss of UBA7 increases susceptibility to influenza B and Sindbis viruses, impairs hematopoietic progenitor cell-cycle progression under IFN-stress, and in cancer contexts abolishes UBE1L-driven ISG15ylation of oncoproteins such as PML/RARα and cyclin D1 that leads to their proteasomal degradation."},"narrative":{"mechanistic_narrative":"UBA7 (UBE1L) is the E1-activating enzyme that initiates conjugation of the interferon-induced ubiquitin-like modifier ISG15 to substrate proteins (ISGylation), a process functionally separable from ubiquitin signaling [PMID:37553340, PMID:14976209]. Cryo-EM structures of UBA7 trapped with ISG15 adenylate and thioester intermediates and with the cognate E2 enzyme UBE2L6 (UbcH8) define how UBA7 adenylates ISG15 at its C-terminal diglycine/ubiquitin-like domain, forms a thioester intermediate, and transfers ISG15 to UBE2L6, revealing an architecture and specificity distinct from the ubiquitin cascade [PMID:37553340, PMID:38042859]; the C-terminal diglycine motif of ISG15 is required for both physical association and conjugation [PMID:38042859, PMID:14976209]. UBA7-deficient mice and cells fail to form ISG15 conjugates while retaining free ISG15, and this loss leaves JAK/STAT-driven IFN-α/β signaling intact, establishing UBA7 as dedicated specifically to conjugation [PMID:16382139]. ISGylation contributes to antiviral defense, with UBA7 loss increasing susceptibility to influenza B (acting through radioresistant stromal cells) and Sindbis virus, while control of Chikungunya virus proceeds through a conjugation-independent immunomodulatory role of ISG15 [PMID:19004958, PMID:19073728, PMID:22028657]. In cancer and differentiation contexts, UBA7 drives ISGylation of substrates including the PML domain of the PML/RARα oncoprotein and cyclin D1, targeting them for proteasomal degradation, and acts during retinoid-induced differentiation of acute promyelocytic leukemia cells [PMID:14976209, PMID:19074853, PMID:18413804]. UBA7 additionally supports hematopoietic progenitor cell-cycle progression under interferon stress [PMID:20591702] and is itself targeted for degradation by the human cytomegalovirus protein pUL50 acting with the E3 ligase RNF170 [PMID:29743376].","teleology":[{"year":1995,"claim":"Mapping the UBE1L locus and linking its silencing to epigenetic marks raised the question of whether loss of this gene is relevant to cancer.","evidence":"Genomic mapping, DNase I hypersensitivity, and methylation analysis in lung cancer cell lines","pmids":["7734949"],"confidence":"Medium","gaps":["5-azacytidine did not restore expression, implying additional regulatory blocks","no enzymatic function assigned at this stage"]},{"year":2002,"claim":"Established that UBE1L overexpression specifically degrades the PML/RARα oncoprotein and induces apoptosis, linking the enzyme to APL differentiation therapy.","evidence":"Retroviral overexpression with truncation/canonical-E1 controls and promoter assays in NB4 APL cells","pmids":["11891284"],"confidence":"Medium","gaps":["overexpression-based; physiological relevance not yet tested","mechanism of degradation not resolved at the conjugation level"]},{"year":2004,"claim":"Identified UBE1L as the ISG15-specific E1 enzyme by demonstrating direct, diglycine-dependent association with ISG15 and a requirement for IFN/RA-induced ISGylation.","evidence":"Co-IP with ISG15 diglycine mutants and siRNA/shRNA knockdown in APL cells; affinity purification and thioester formation with bovine ortholog","pmids":["14976209","15385418"],"confidence":"High","gaps":["E2 hand-off step not yet structurally defined","substrate repertoire of ISGylation unknown"]},{"year":2004,"claim":"Showed UBE1L catalytic activity is required to repress cyclin D1, extending its substrate range beyond PML/RARα.","evidence":"Microarray identification and transfection of wild-type versus mutant UBE1L in bronchial epithelial cells","pmids":["15520223"],"confidence":"Medium","gaps":["mechanism of cyclin D1 repression not dissected here","single-lab transfection data"]},{"year":2006,"claim":"Genetic knockout established that UBA7 is required for all ISG15 conjugation but dispensable for free ISG15 and for JAK/STAT IFN signaling, cleanly separating conjugation from cytokine signaling.","evidence":"Ube1L-/- mice, VSV/LCMV infection, and epistasis with Ubp43 double-knockout","pmids":["16382139"],"confidence":"High","gaps":["no antiviral phenotype against VSV/LCMV, leaving the in vivo role of conjugation open at this point"]},{"year":2008,"claim":"Defined the conjugation-dependent oncoprotein-degradation mechanism, mapping ISGylation to the PML domain and linking cyclin D1 loss to ISG15-conjugate formation and proteasomal turnover.","evidence":"Domain-construct transfection, co-IP of ISG15-substrate complexes, lysine-less cyclin D1 mutant, USP18 deconjugase antagonism, and proteasome inhibition","pmids":["18413804","19074853"],"confidence":"Medium","gaps":["modified lysine residues not mapped","single-lab studies of substrate ISGylation"]},{"year":2008,"claim":"Demonstrated in vivo that UBA7-dependent ISGylation restricts specific viruses, with cell-type and conjugation-dependence established by chimera and mutant-virus approaches.","evidence":"Ube1L-/- mice with influenza B and Sindbis virus challenge, bone marrow chimeras, and an ISG15 R151A binding/transthiolation mutant","pmids":["19004958","19073728"],"confidence":"High","gaps":["antiviral substrates of ISGylation not identified","mechanism of stromal-cell-restricted protection unresolved"]},{"year":2008,"claim":"Tested and excluded UBA7 as a tumor suppressor in K-ras-driven lung cancer, narrowing the contexts where its degradative activity is relevant.","evidence":"Ube1l-/- x K-rasLA2 mouse tumor progression and ISGylation analysis","pmids":["18571763"],"confidence":"Medium","gaps":["does not exclude UBA7 relevance in other tumor genotypes"]},{"year":2010,"claim":"Revealed a cell-intrinsic role for UBA7 in hematopoietic progenitor cell-cycle progression under interferon stress.","evidence":"Competitive bone marrow transplantation of Ube1l-/- cells and cell cycle analysis","pmids":["20591702"],"confidence":"Medium","gaps":["substrate driving G2/M progression not identified","single-lab study"]},{"year":2011,"claim":"Distinguished conjugation-dependent from conjugation-independent ISG15 antiviral functions by showing UBA7 is dispensable for Chikungunya control.","evidence":"Genetic epistasis with Ube1L-/- and ISG15-/- mouse lines and cytokine profiling","pmids":["22028657"],"confidence":"High","gaps":["does not define which viruses depend on conjugation versus free ISG15 generally"]},{"year":2017,"claim":"Extended UBA7 antiviral function to neurotropic infection, showing it restricts rabies virus in vitro and in vivo.","evidence":"shRNA knockdown with viral titer and survival readouts in neuroblastoma, microglial cells, and mouse brain","pmids":["29056542"],"confidence":"Medium","gaps":["substrates and mechanism of RABV restriction unknown","single method type"]},{"year":2018,"claim":"Identified a viral evasion mechanism in which HCMV pUL50, with RNF170, drives proteasomal degradation of UBA7 to suppress ISGylation.","evidence":"Reciprocal co-IP, domain-deletion mutants, and proteasome inhibitor rescue with pUL50 and RNF170 overexpression","pmids":["29743376"],"confidence":"Medium","gaps":["single-lab; in vivo relevance during infection not established"]},{"year":2022,"claim":"Placed UBA7's ISG15 specificity in evolutionary context, showing it arose from UBA1 duplication and that ancestral Uba7 retained promiscuous ubiquitin-activating capacity later restricted to ISG15.","evidence":"Phylogenetic analysis and in vitro/in vivo ubiquitin activation assays in zebrafish","pmids":["35134494"],"confidence":"Medium","gaps":["structural basis of specificity restriction addressed only later","single-lab evolutionary framing"]},{"year":2023,"claim":"Provided the structural mechanism of ISG15 activation and E1-to-E2 thioester transfer, explaining UBA7's exquisite selectivity for ISG15 and UBE2L6.","evidence":"Cryo-EM of UBA7-UBE2L6-ISG15 adenylate and thioester intermediates with biochemical mutant validation and viral effector tools","pmids":["37553340","38042859"],"confidence":"High","gaps":["downstream E3 ligases and full substrate-loading mechanism not resolved in these structures"]},{"year":null,"claim":"The comprehensive set of physiological ISGylation substrates and the E3 ligases that complete conjugation downstream of UBA7-UBE2L6 remain to be systematically defined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["substrate-specific E3 ligases largely uncharacterized in this corpus","mechanism linking ISGylation to cell-cycle and antiviral effects not fully mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0,1,2,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,5,6]}],"localization":[],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,8,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[0,1,2]}],"complexes":[],"partners":["ISG15","UBE2L6","PML/RARA","CCND1","EGFR","RNF170"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P41226","full_name":"Ubiquitin-like modifier-activating enzyme 7","aliases":["D8","Ubiquitin-activating enzyme E1 homolog"],"length_aa":1012,"mass_kda":111.7,"function":"E1-activating enzyme that catalyzes the covalent conjugation of the ubiquitin-like protein product of ISG15 to additional interferon stimulated proteins (ISGs) as well as other cellular proteins such as P53 in a process termed protein ISGylation (PubMed:27545325). Plays an essential role in antiviral immunity together with ISG15 by restricting the replication of many viruses including rabies virus, influenza virus, sindbis virus, rotavirus or human cytomegalovirus (PubMed:16254333, PubMed:19073728, PubMed:29056542, PubMed:29743376, PubMed:37722521). For example, ISG15 modification of influenza A protein NS1 disrupts the association of the NS1 with importin-alpha leading to NS1 nuclear import inhibition (PubMed:20133869). ISGylation of human cytomegalovirs protein UL26 regulates its stability and inhibits its activities to suppress NF-kappa-B signaling (PubMed:27564865)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P41226/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/UBA7","classification":"Not Classified","n_dependent_lines":2,"n_total_lines":1208,"dependency_fraction":0.0016556291390728477},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/UBA7","total_profiled":1310},"omim":[{"mim_id":"603922","title":"SUCCINATE-CoA LIGASE, GDP-FORMING, SUBUNIT BETA; SUCLG2","url":"https://www.omim.org/entry/603922"},{"mim_id":"191325","title":"UBIQUITIN-LIKE MODIFIER ACTIVATING ENZYME 7; UBA7","url":"https://www.omim.org/entry/191325"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/UBA7"},"hgnc":{"alias_symbol":["D8","UBE2","UBA1B"],"prev_symbol":["UBE1L"]},"alphafold":{"accession":"P41226","domains":[{"cath_id":"3.40.50.720","chopping":"16-169_266-280_357-389","consensus_level":"high","plddt":96.2129,"start":16,"end":389},{"cath_id":"2.40.30.180","chopping":"179-257","consensus_level":"high","plddt":86.5747,"start":179,"end":257},{"cath_id":"3.40.50.720","chopping":"434-592_851-895","consensus_level":"high","plddt":93.479,"start":434,"end":895},{"cath_id":"1.10.10.2660","chopping":"607-771_781-834","consensus_level":"high","plddt":80.0749,"start":607,"end":834},{"cath_id":"3.10.290.60","chopping":"904-1012","consensus_level":"high","plddt":89.9372,"start":904,"end":1012}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P41226","model_url":"https://alphafold.ebi.ac.uk/files/AF-P41226-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P41226-F1-predicted_aligned_error_v6.png","plddt_mean":89.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=UBA7","jax_strain_url":"https://www.jax.org/strain/search?query=UBA7"},"sequence":{"accession":"P41226","fasta_url":"https://rest.uniprot.org/uniprotkb/P41226.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P41226/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P41226"}},"corpus_meta":[{"pmid":"11340177","id":"PMC_11340177","title":"slender 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Theoretische und angewandte Genetik","url":"https://pubmed.ncbi.nlm.nih.gov/23435734","citation_count":8,"is_preprint":false},{"pmid":"31873121","id":"PMC_31873121","title":"[13C6,D8]2-deoxyglucose phosphorylation by hexokinase shows selectivity for the β-anomer.","date":"2019","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/31873121","citation_count":8,"is_preprint":false},{"pmid":"25649257","id":"PMC_25649257","title":"Mechanism of Dose-Dependent Regulation of UBE1L by Polyphenols in Human Bronchial Epithelial Cells.","date":"2015","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/25649257","citation_count":7,"is_preprint":false},{"pmid":"34835240","id":"PMC_34835240","title":"Characterization of an In Vivo Neutralizing Anti-Vaccinia Virus D8 Single-Chain Fragment Variable (scFv) from a Human Anti-Vaccinia Virus-Specific Recombinant Library.","date":"2021","source":"Vaccines","url":"https://pubmed.ncbi.nlm.nih.gov/34835240","citation_count":7,"is_preprint":false},{"pmid":"38795139","id":"PMC_38795139","title":"Role of Ubiquitin-conjugating enzyme E2 (UBE2) in two immune-mediated inflammatory skin diseases: a mendelian randomization analysis.","date":"2024","source":"Archives of dermatological research","url":"https://pubmed.ncbi.nlm.nih.gov/38795139","citation_count":6,"is_preprint":false},{"pmid":"12596065","id":"PMC_12596065","title":"Immunophenotypical changes of neoplastic cells and tumor-associated macrophages in a rat dendritic cell sarcoma-derived transplantable tumor line (KB-D8).","date":"2002","source":"Virchows Archiv : an international journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/12596065","citation_count":6,"is_preprint":false},{"pmid":"27825950","id":"PMC_27825950","title":"Occurrence of measles genotype D8 during a 2014 outbreak in Banjarmasin, South Kalimantan, Indonesia.","date":"2016","source":"International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/27825950","citation_count":6,"is_preprint":false},{"pmid":"18949506","id":"PMC_18949506","title":"Does hybridization increase evolutionary rate? Data from the 28S-rDNA D8 domain in echinoderms.","date":"2008","source":"Journal of molecular evolution","url":"https://pubmed.ncbi.nlm.nih.gov/18949506","citation_count":6,"is_preprint":false},{"pmid":"27089242","id":"PMC_27089242","title":"Towards measles elimination: Phylogenetic analysis of measles viruses in Turkey (2012-2013) and identification of genotype D8.","date":"2016","source":"Journal of medical virology","url":"https://pubmed.ncbi.nlm.nih.gov/27089242","citation_count":6,"is_preprint":false},{"pmid":"35134494","id":"PMC_35134494","title":"Insights into the evolution of the ISG15 and UBA7 system.","date":"2022","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/35134494","citation_count":5,"is_preprint":false},{"pmid":"8614772","id":"PMC_8614772","title":"Red cell Na+/H+ exchange and B cell alloantigen 883 (D8/17) in patients with acute rheumatic fever and inactive rheumatic heart disease.","date":"1996","source":"Scandinavian journal of rheumatology","url":"https://pubmed.ncbi.nlm.nih.gov/8614772","citation_count":5,"is_preprint":false},{"pmid":"36531578","id":"PMC_36531578","title":"Machine Learning Prediction of Adenovirus D8 Conjunctivitis Complications from Viral Whole-Genome Sequence.","date":"2022","source":"Ophthalmology science","url":"https://pubmed.ncbi.nlm.nih.gov/36531578","citation_count":4,"is_preprint":false},{"pmid":"35800603","id":"PMC_35800603","title":"Transcript Complexity and New Insights of Restorer Line in CMS-D8 Cotton Through Full-Length Transcriptomic Analysis.","date":"2022","source":"Frontiers in plant science","url":"https://pubmed.ncbi.nlm.nih.gov/35800603","citation_count":4,"is_preprint":false},{"pmid":"21303578","id":"PMC_21303578","title":"Markers of susceptibility to acute rheumatic fever: the B-cell antigen D8/17 is not robust as a marker in South Africa.","date":"2011","source":"Cardiology in the young","url":"https://pubmed.ncbi.nlm.nih.gov/21303578","citation_count":4,"is_preprint":false},{"pmid":"19652356","id":"PMC_19652356","title":"Crystallization and preliminary X-ray analysis of a complex formed between the antibiotic simocyclinone D8 and the DNA breakage-reunion domain of Escherichia coli DNA gyrase.","date":"2009","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/19652356","citation_count":4,"is_preprint":false},{"pmid":"25281832","id":"PMC_25281832","title":"Molecular epidemiology of measles virus infection in Shanghai in 2000-2012: the first appearance of genotype D8.","date":"2014","source":"The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/25281832","citation_count":4,"is_preprint":false},{"pmid":"30876879","id":"PMC_30876879","title":"The first outbreak of measles virus caused by imported genotype D8 in Jiangsu province of China.","date":"2019","source":"The Brazilian journal of infectious diseases : an official publication of the Brazilian Society of Infectious Diseases","url":"https://pubmed.ncbi.nlm.nih.gov/30876879","citation_count":4,"is_preprint":false},{"pmid":"40158006","id":"PMC_40158006","title":"Identification of UBA7 expression downregulation in myelodysplastic neoplasm with SF3B1 mutations.","date":"2025","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/40158006","citation_count":3,"is_preprint":false},{"pmid":"27427993","id":"PMC_27427993","title":"AG490 and PF431396 Sensitive Tyrosine Kinase Control the Population Heterogeneity of Basal STAT1 Activity in Ube1l Deficient Cells.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/27427993","citation_count":3,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49339,"output_tokens":5261,"usd":0.113466,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13593,"output_tokens":4075,"usd":0.08492,"stage2_stop_reason":"end_turn"},"total_usd":0.198386,"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\": 2023,\n      \"finding\": \"Cryo-EM structures of human Uba7 (UBA7) in complex with UBE2L6 and ISG15 adenylate or ISG15 thioester intermediates reveal the molecular basis for ISG15 activation and E1-E2 thioester transfer. The structures show a unique overall architecture compared to the ubiquitin conjugation pathway, particularly with respect to the location of the ISG15 thioester intermediate, and illuminate UBA7's exquisite specificity for ISG15 and UBE2L6.\",\n      \"method\": \"Cryo-EM structure determination, biochemical assays, human cell-based experiments\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structures with functional validation by biochemical assays and cell-based experiments in a single rigorous study\",\n      \"pmids\": [\"37553340\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A 3.45 Å cryo-EM structure of a chemically trapped UBE1L (UBA7)-UBE2L6 complex bound to activated ISG15 reveals the first steps of ISG15 recognition and UBE2L6 recruitment by UBE1L. Biochemical characterization enabled design of ISG15 and UBE2L6 mutants with altered selectivity for the ISG15 versus ubiquitin conjugation pathways. The ISG15 C-terminal ubiquitin-like domain is required for the adenylation reaction, validated using viral effector proteins from SARS-CoV-2 and influenza B virus.\",\n      \"method\": \"Cryo-EM structure, biochemical mutant characterization, viral effector protein validation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure combined with biochemical mutagenesis and functional validation using orthogonal viral tools\",\n      \"pmids\": [\"38042859\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"UBE1L (UBA7) physically associates with ISG15 in vivo, requiring the conserved C-terminal diglycine motif of ISG15. Knockdown of UBE1L with siRNA or shRNA inhibited IFN- and RA-induced ISG15 conjugation. UBE1L is required for ISG15 conjugation during retinoid-induced differentiation of acute promyelocytic leukemia (APL) cells.\",\n      \"method\": \"Co-immunoprecipitation, siRNA/shRNA knockdown, immunoblot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with diglycine mutant validation, functional knockdown with defined cellular phenotype, replicated in multiple cell lines\",\n      \"pmids\": [\"14976209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Mice lacking UBE1L (Ube1L−/−) fail to form ISG15 conjugates but express free ISG15 normally. Ube1L−/− mice were fertile and showed normal antiviral responses against VSV and LCMV, indicating UBE1L and protein ISGylation are not critical for IFN-α/β signaling via JAK/STAT activation. Using Ube1L/Ubp43 double-deficient mice, increased IFN signaling in Ubp43-deficient mice was attributed to loss of UBP43, not increased ISGylation.\",\n      \"method\": \"Genetic knockout mouse model, viral infection assays, epistasis analysis with double-KO\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with defined cellular phenotype, epistasis via double mutant, replicated across multiple viral models\",\n      \"pmids\": [\"16382139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"UBE1L (UBA7) overexpression triggered PML/RARα degradation in NB4 APL cells and induced apoptosis; a truncated UBE1L or the canonical E1 enzyme did not cause this degradation. UBE1L is a direct retinoid target gene whose promoter is suppressed by PML/RARα, and its induction is tightly linked to PML/RARα degradation. UBE1L-induced apoptosis was specific to cells expressing PML/RARα.\",\n      \"method\": \"Retroviral overexpression, transfection, promoter assay, immunoblot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with specific mutant control, single lab, multiple complementary assays\",\n      \"pmids\": [\"11891284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"UBE1L promotes complex formation between ISG15 and cyclin D1, causing cyclin D1 protein (but not mRNA) degradation. UBE1L knockdown increased cyclin D1 protein; a lysine-less cyclin D1 mutant was resistant to UBE1L-mediated degradation. UBE1L retroviral transduction reduced cyclin D1 expression and clonal cell growth in bronchial epithelial and lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, UBE1L retroviral transduction, siRNA knockdown, cycloheximide chase, immunoblot\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, KD, OE with lysine-less mutant control; single lab with multiple methods\",\n      \"pmids\": [\"19074853\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"UBE1L induces ISG15ylation of the PML domain of PML/RARα, targeting it for proteasomal degradation. RA-induced degradation targets the RARα domain via a distinct pathway, while UBE1L independently targets the PML domain. UBP43/USP18 (ISG15 deconjugase) opposed UBE1L- but not RA-dependent PML/RARα degradation; proteasomal inhibitor blocked both.\",\n      \"method\": \"Transfection of PML/RARα domain constructs, co-immunoprecipitation, proteasome inhibitor treatment, UBP43 deconjugase antagonism\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-mapping transfections, deconjugase competition, proteasome inhibitor rescue; single lab\",\n      \"pmids\": [\"18413804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Mice lacking UbE1L (the ISG15 E1 enzyme) fail to form ISG15 conjugates and display increased susceptibility to influenza B virus infection, including non-mouse-adapted strains. ISG15 controls influenza B virus infection through its action within radioresistant stromal cells, not bone marrow-derived cells, indicating stromal cell ISGylation is critical.\",\n      \"method\": \"Ube1L−/− mouse model, bone marrow transplantation/chimera experiments, viral infection assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean KO with viral susceptibility phenotype, cell-type specificity established by bone marrow chimera experiments\",\n      \"pmids\": [\"19004958\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The ISG15 E1 enzyme UbE1L is important for control of Sindbis virus infection: UbE1L-deficient mice were highly susceptible to Sindbis virus. An ISG15 mutant (R151A) that ablates binding to UbE1L and transthiolation to UbcH8 could not protect IFN-αβR−/− mice from Sindbis virus lethality, supporting that protein conjugation (not free ISG15) mediates ISG15's antiviral effect against Sindbis virus.\",\n      \"method\": \"Ube1L−/− mouse model, double-subgenomic Sindbis virus expressing ISG15 mutants, kinetic binding assays, transfection\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO combined with structure-guided mutagenesis and viral challenge, multiple orthogonal methods\",\n      \"pmids\": [\"19073728\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ISG15 controls Chikungunya virus (CHIKV) infection in neonatal mice independently of UbE1L-mediated conjugation: UbE1L−/− mice (unable to form ISG15 conjugates) showed no increase in lethality after CHIKV infection, whereas ISG15−/− mice were profoundly susceptible. ISG15 modulates proinflammatory cytokines/chemokines rather than controlling viral loads, indicating a non-conjugation, immunomodulatory role for ISG15 in CHIKV pathogenesis.\",\n      \"method\": \"UbE1L−/− and ISG15−/− mouse models, viral infection, cytokine/chemokine measurement\",\n      \"journal\": \"PLoS pathogens\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis using two independent KO mouse lines with well-controlled viral infection readout\",\n      \"pmids\": [\"22028657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HCMV transmembrane protein pUL50 interacts with UBE1L (the ISG15 E1-activating enzyme) and causes its proteasomal degradation, thereby inhibiting ISGylation. This requires the C-terminal transmembrane domain of pUL50 for activity. RNF170, an ER-associated ubiquitin E3 ligase, interacts with pUL50 and promotes pUL50-mediated UBE1L ubiquitination and degradation.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, proteasome inhibitor experiments, overexpression of UL50 and RNF170\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with domain deletion controls, proteasome inhibitor rescue, identification of E3 ligase; single lab\",\n      \"pmids\": [\"29743376\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A 110-kDa bovine UBE1L protein was purified from endometrial cells by affinity with recombinant GST-ISG15, confirming a direct physical interaction between UBE1L and ISG15. Bovine UBE1L shares 83% cDNA identity with human UBE1L and forms a thioester bond with ISG15 to initiate conjugation.\",\n      \"method\": \"Affinity purification with GST-ISG15, mass spectrometry peptide identification, full-length cDNA sequencing\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — affinity pulldown with MS identification of binding partner; ortholog characterization with biochemical validation\",\n      \"pmids\": [\"15385418\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Microarray analyses identified UBE1L as a retinoid-regulated gene in human bronchial epithelial cells. Wild-type but not mutant UBE1L repressed cyclin D1 expression in a dose-dependent manner upon co-transfection, establishing a functional requirement for UBE1L's catalytic activity in cyclin D1 repression.\",\n      \"method\": \"Microarray, transfection with wild-type vs. mutant UBE1L, immunoblot\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — transfection with mutant control showing dose-dependence; single lab, limited mechanistic depth in abstract\",\n      \"pmids\": [\"15520223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"The UBE1L gene has 22 exons spanning 8.4 kb at chromosome 3p21. Lack of UBE1L expression in lung cancer cell lines correlates with hypermethylation of a HhaI site in the first exon and decreased DNase I sensitivity of the promoter region, suggesting epigenetic silencing.\",\n      \"method\": \"Genomic mapping, anchored PCR, DNase I hypersensitivity assay, methylation analysis with 5-azacytidine treatment\",\n      \"journal\": \"Gene expression\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple complementary genomic methods; 5-azacytidine demethylation did not restore expression, suggesting additional regulatory block\",\n      \"pmids\": [\"7734949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"UBE1L-deficient (Ube1l−/−) hematopoietic cells show impaired repopulation potential after bone marrow transplantation (50% reduction at 3 weeks). Under conditions of high IFN and ISGylation (post-transplant), Ube1L deficiency causes G2/M cell cycle block in hematopoietic multipotential progenitors, indicating ISGylation promotes cell cycle progression during interferon-related stress.\",\n      \"method\": \"Bone marrow transplantation with Ube1l−/− cells, competitive transplantation, cell cycle analysis\",\n      \"journal\": \"Blood cells, molecules & diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KO with bone marrow transplant readout and cell cycle phenotype; single lab\",\n      \"pmids\": [\"20591702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ube1l deficiency did not alter lung cancer progression or overall survival in K-rasLA2 lung cancer mice, and protein ISGylation levels were largely unchanged during lung cancer progression in this model. This establishes a negative result: UBE1L is not a tumor suppressor gene in K-ras mutation-dependent lung cancer.\",\n      \"method\": \"Ube1l−/− crossed with K-rasLA2 mice, tumor progression and survival analysis, ISGylation western blots\",\n      \"journal\": \"Lung cancer (Amsterdam, Netherlands)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo genetic model; negative result well-controlled\",\n      \"pmids\": [\"18571763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"shRNA knockdown of UBA7 increased rabies virus (RABV) titers in neuroblastoma (NA) and microglial (BV-2) cell lines and in mouse brains, and decreased mouse survival, establishing that UBA7 inhibits RABV replication in vitro and in vivo.\",\n      \"method\": \"shRNA knockdown, viral titer measurement, lentiviral-mediated knockdown in mouse brain, survival analysis\",\n      \"journal\": \"Infection, genetics and evolution\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo KD with defined viral titer phenotype; single lab, single method type\",\n      \"pmids\": [\"29056542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"UBE1L overexpression in human bronchial epithelial (Beas-2B) cells triggered EGFR membrane internalization, promoted complex formation between ISG15 and EGFR, and reduced EGFR protein at the post-translational level. UBE1L knockdown increased EGFR and downstream PI3K/AKT/NF-κB signaling.\",\n      \"method\": \"UBE1L overexpression, UBE1L knockdown, co-immunoprecipitation of ISG15-EGFR complex, immunoblot of downstream signaling\",\n      \"journal\": \"The Journal of nutritional biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, co-IP and OE/KD without deep mechanistic dissection of the ISG15-EGFR conjugation\",\n      \"pmids\": [\"24445050\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Evolutionary analysis showed that UBA7 descends from gene duplication of UBA1, and ISG15 arose from UBB/UBC. Zebrafish Uba7 retains the ability to activate the ubiquitin cascade in vitro and in vivo (unlike tetrapod Uba7), indicating that ancestral Uba7 had promiscuous substrate specificity that became restricted to ISG15 in tetrapods.\",\n      \"method\": \"Phylogenetic analysis, in vitro ubiquitin activation assay, in vivo zebrafish assays\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro reconstitution and in vivo assay in zebrafish; single lab with evolutionary framing\",\n      \"pmids\": [\"35134494\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Ube1l−/− mouse embryonic fibroblasts (MEF) exhibit low viral resistance despite high STAT1/ISG expression compared to wild-type MEF. Ube1l−/− MEF populations contain two sub-populations with distinct basal STAT1 activity; this heterogeneity was perturbed by JAK2/FAK tyrosine kinase inhibitors (AG490, PF431396) but not by type I IFN neutralization, indicating UBE1L-dependent ISGylation regulates population-level basal immune signaling states through a tyrosine kinase-sensitive pathway.\",\n      \"method\": \"Ube1l−/− MEF, flow cytometry for STAT1 activity, tyrosine kinase inhibitors, IFN neutralization\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, pharmacological inhibitors without defined direct molecular link between UBE1L and the kinase pathway\",\n      \"pmids\": [\"27427993\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"UBA7 (also known as UBE1L/UBE1L/UBA1B) is the E1-activating enzyme exclusively dedicated to ISG15, a ubiquitin-like modifier induced by type I interferon: it adenylates ISG15 at its C-terminal diglycine motif and then forms a thioester intermediate before transferring ISG15 to the cognate E2 enzyme UBE2L6 (UbcH8), as established by cryo-EM structures and biochemical reconstitution; UBA7 is dispensable for ubiquitin activation but required for all intracellular ISG15 conjugation (ISGylation), and loss of UBA7 increases susceptibility to influenza B and Sindbis viruses, impairs hematopoietic progenitor cell-cycle progression under IFN-stress, and in cancer contexts abolishes UBE1L-driven ISG15ylation of oncoproteins such as PML/RARα and cyclin D1 that leads to their proteasomal degradation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"UBA7 (UBE1L) is the E1-activating enzyme that initiates conjugation of the interferon-induced ubiquitin-like modifier ISG15 to substrate proteins (ISGylation), a process functionally separable from ubiquitin signaling [#0, #2]. Cryo-EM structures of UBA7 trapped with ISG15 adenylate and thioester intermediates and with the cognate E2 enzyme UBE2L6 (UbcH8) define how UBA7 adenylates ISG15 at its C-terminal diglycine/ubiquitin-like domain, forms a thioester intermediate, and transfers ISG15 to UBE2L6, revealing an architecture and specificity distinct from the ubiquitin cascade [#0, #1]; the C-terminal diglycine motif of ISG15 is required for both physical association and conjugation [#1, #2]. UBA7-deficient mice and cells fail to form ISG15 conjugates while retaining free ISG15, and this loss leaves JAK/STAT-driven IFN-\\u03b1/\\u03b2 signaling intact, establishing UBA7 as dedicated specifically to conjugation [#3]. ISGylation contributes to antiviral defense, with UBA7 loss increasing susceptibility to influenza B (acting through radioresistant stromal cells) and Sindbis virus, while control of Chikungunya virus proceeds through a conjugation-independent immunomodulatory role of ISG15 [#7, #8, #9]. In cancer and differentiation contexts, UBA7 drives ISGylation of substrates including the PML domain of the PML/RAR\\u03b1 oncoprotein and cyclin D1, targeting them for proteasomal degradation, and acts during retinoid-induced differentiation of acute promyelocytic leukemia cells [#2, #5, #6]. UBA7 additionally supports hematopoietic progenitor cell-cycle progression under interferon stress [#14] and is itself targeted for degradation by the human cytomegalovirus protein pUL50 acting with the E3 ligase RNF170 [#10].\",\n  \"teleology\": [\n    {\n      \"year\": 1995,\n      \"claim\": \"Mapping the UBE1L locus and linking its silencing to epigenetic marks raised the question of whether loss of this gene is relevant to cancer.\",\n      \"evidence\": \"Genomic mapping, DNase I hypersensitivity, and methylation analysis in lung cancer cell lines\",\n      \"pmids\": [\"7734949\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"5-azacytidine did not restore expression, implying additional regulatory blocks\", \"no enzymatic function assigned at this stage\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Established that UBE1L overexpression specifically degrades the PML/RAR\\u03b1 oncoprotein and induces apoptosis, linking the enzyme to APL differentiation therapy.\",\n      \"evidence\": \"Retroviral overexpression with truncation/canonical-E1 controls and promoter assays in NB4 APL cells\",\n      \"pmids\": [\"11891284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"overexpression-based; physiological relevance not yet tested\", \"mechanism of degradation not resolved at the conjugation level\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified UBE1L as the ISG15-specific E1 enzyme by demonstrating direct, diglycine-dependent association with ISG15 and a requirement for IFN/RA-induced ISGylation.\",\n      \"evidence\": \"Co-IP with ISG15 diglycine mutants and siRNA/shRNA knockdown in APL cells; affinity purification and thioester formation with bovine ortholog\",\n      \"pmids\": [\"14976209\", \"15385418\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"E2 hand-off step not yet structurally defined\", \"substrate repertoire of ISGylation unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed UBE1L catalytic activity is required to repress cyclin D1, extending its substrate range beyond PML/RAR\\u03b1.\",\n      \"evidence\": \"Microarray identification and transfection of wild-type versus mutant UBE1L in bronchial epithelial cells\",\n      \"pmids\": [\"15520223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"mechanism of cyclin D1 repression not dissected here\", \"single-lab transfection data\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Genetic knockout established that UBA7 is required for all ISG15 conjugation but dispensable for free ISG15 and for JAK/STAT IFN signaling, cleanly separating conjugation from cytokine signaling.\",\n      \"evidence\": \"Ube1L-/- mice, VSV/LCMV infection, and epistasis with Ubp43 double-knockout\",\n      \"pmids\": [\"16382139\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"no antiviral phenotype against VSV/LCMV, leaving the in vivo role of conjugation open at this point\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined the conjugation-dependent oncoprotein-degradation mechanism, mapping ISGylation to the PML domain and linking cyclin D1 loss to ISG15-conjugate formation and proteasomal turnover.\",\n      \"evidence\": \"Domain-construct transfection, co-IP of ISG15-substrate complexes, lysine-less cyclin D1 mutant, USP18 deconjugase antagonism, and proteasome inhibition\",\n      \"pmids\": [\"18413804\", \"19074853\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"modified lysine residues not mapped\", \"single-lab studies of substrate ISGylation\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstrated in vivo that UBA7-dependent ISGylation restricts specific viruses, with cell-type and conjugation-dependence established by chimera and mutant-virus approaches.\",\n      \"evidence\": \"Ube1L-/- mice with influenza B and Sindbis virus challenge, bone marrow chimeras, and an ISG15 R151A binding/transthiolation mutant\",\n      \"pmids\": [\"19004958\", \"19073728\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"antiviral substrates of ISGylation not identified\", \"mechanism of stromal-cell-restricted protection unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Tested and excluded UBA7 as a tumor suppressor in K-ras-driven lung cancer, narrowing the contexts where its degradative activity is relevant.\",\n      \"evidence\": \"Ube1l-/- x K-rasLA2 mouse tumor progression and ISGylation analysis\",\n      \"pmids\": [\"18571763\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"does not exclude UBA7 relevance in other tumor genotypes\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Revealed a cell-intrinsic role for UBA7 in hematopoietic progenitor cell-cycle progression under interferon stress.\",\n      \"evidence\": \"Competitive bone marrow transplantation of Ube1l-/- cells and cell cycle analysis\",\n      \"pmids\": [\"20591702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"substrate driving G2/M progression not identified\", \"single-lab study\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Distinguished conjugation-dependent from conjugation-independent ISG15 antiviral functions by showing UBA7 is dispensable for Chikungunya control.\",\n      \"evidence\": \"Genetic epistasis with Ube1L-/- and ISG15-/- mouse lines and cytokine profiling\",\n      \"pmids\": [\"22028657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"does not define which viruses depend on conjugation versus free ISG15 generally\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended UBA7 antiviral function to neurotropic infection, showing it restricts rabies virus in vitro and in vivo.\",\n      \"evidence\": \"shRNA knockdown with viral titer and survival readouts in neuroblastoma, microglial cells, and mouse brain\",\n      \"pmids\": [\"29056542\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"substrates and mechanism of RABV restriction unknown\", \"single method type\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Identified a viral evasion mechanism in which HCMV pUL50, with RNF170, drives proteasomal degradation of UBA7 to suppress ISGylation.\",\n      \"evidence\": \"Reciprocal co-IP, domain-deletion mutants, and proteasome inhibitor rescue with pUL50 and RNF170 overexpression\",\n      \"pmids\": [\"29743376\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"single-lab; in vivo relevance during infection not established\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed UBA7's ISG15 specificity in evolutionary context, showing it arose from UBA1 duplication and that ancestral Uba7 retained promiscuous ubiquitin-activating capacity later restricted to ISG15.\",\n      \"evidence\": \"Phylogenetic analysis and in vitro/in vivo ubiquitin activation assays in zebrafish\",\n      \"pmids\": [\"35134494\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"structural basis of specificity restriction addressed only later\", \"single-lab evolutionary framing\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Provided the structural mechanism of ISG15 activation and E1-to-E2 thioester transfer, explaining UBA7's exquisite selectivity for ISG15 and UBE2L6.\",\n      \"evidence\": \"Cryo-EM of UBA7-UBE2L6-ISG15 adenylate and thioester intermediates with biochemical mutant validation and viral effector tools\",\n      \"pmids\": [\"37553340\", \"38042859\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"downstream E3 ligases and full substrate-loading mechanism not resolved in these structures\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The comprehensive set of physiological ISGylation substrates and the E3 ligases that complete conjugation downstream of UBA7-UBE2L6 remain to be systematically defined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"substrate-specific E3 ligases largely uncharacterized in this corpus\", \"mechanism linking ISGylation to cell-cycle and antiviral effects not fully mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0, 1, 2, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 5, 6]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 8, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ISG15\", \"UBE2L6\", \"PML/RARA\", \"CCND1\", \"EGFR\", \"RNF170\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}