{"gene":"ASB11","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2006,"finding":"d-Asb11 knockdown in zebrafish altered expression of neural precursor genes sox2 and sox3, caused expansion of neurogenin1-positive proneural cells followed by premature neuronal differentiation, while forced misexpression of d-asb11 ectopically induced sox2 and abolished neurogenesis. Overexpression in pluripotent and neural-committed progenitor cell lines inhibited terminal neuronal differentiation and enhanced proliferation, establishing d-Asb11 as a regulator of neural progenitor compartment size that maintains precursors in an undifferentiated proliferating state, possibly through control of SoxB1 transcription factors.","method":"Morpholino knockdown, forced misexpression in zebrafish embryos, overexpression in progenitor cell lines, HuC labeling, sox2/sox3/neurogenin1 expression analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function experiments with multiple orthogonal readouts in zebrafish and cell lines, single lab","pmids":["16893969"],"is_preprint":false},{"year":2008,"finding":"d-Asb11 is an essential mediator of canonical Delta-Notch lateral inhibition signaling in zebrafish. Morpholino knockdown repressed Delta-Notch elements and their transcriptional targets; misexpression activated Notch reporters cell-non-autonomously. d-Asb11 was shown to specifically ubiquitylate and degrade DeltaA both in vitro and in vivo, identifying DeltaA as a direct substrate for ASB11-mediated ubiquitination and degradation.","method":"Morpholino knockdown, misexpression in zebrafish embryos, Notch reporter assays (cell-autonomous and non-autonomous), in vitro and in vivo ubiquitylation and degradation assays for DeltaA","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro and in vivo ubiquitylation assay combined with genetic knockdown/overexpression and reporter assays, replicated across multiple experimental systems","pmids":["18776899"],"is_preprint":false},{"year":2010,"finding":"The Cul5 box domain of d-Asb11 is required in vivo for proper Notch signaling and neural cell fate. A zebrafish mutant lacking the Cul5 box (Asb11(Cul)) was defective in Notch signaling, unable to degrade DeltaA during embryogenesis, showed impaired neural cell fate specification, and Asb11(Cul) mRNA failed to transactivate a her4::gfp Notch reporter. This establishes that the Cul5 box domain is essential for d-Asb11 function in the ECS ubiquitin ligase complex.","method":"Zebrafish Cul5-box domain mutant generation and characterization, Notch target gene expression, DeltaA degradation assay in vivo, her4::gfp reporter assay","journal":"PloS one","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain-specific mutant with multiple functional readouts (substrate degradation, reporter, target gene expression, cell fate) in vivo, single lab","pmids":["21124961"],"is_preprint":false},{"year":2012,"finding":"Asb11 localizes specifically to Pax7+ muscle satellite cells across vertebrates. Forced expression of d-asb11 impaired terminal differentiation and caused enhanced proliferation in myogenic progenitors in vivo and in vitro. A germline hypomorphic zebrafish d-asb11 mutation caused premature differentiation of muscle progenitors and delayed regenerative responses in adult injured muscle, establishing d-Asb11 as a principal regulator of embryonic and adult regenerative myogenesis.","method":"Expression/localization analysis (Pax7+ satellite cell compartment), forced overexpression in zebrafish and cell lines, germline hypomorphic zebrafish mutant, adult muscle regeneration assay","journal":"Stem cells and development","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal gain- and loss-of-function with specific cellular phenotype (proliferation vs. differentiation) and localization data, single lab","pmids":["22512762"],"is_preprint":false},{"year":2013,"finding":"ASB11 is a novel endoplasmic reticulum-resident ubiquitin ligase that interacts with and promotes ubiquitination of Ribophorin 1, an integral component of the oligosaccharyltransferase (OST) glycosylation complex. Expression of ASB11 increases Ribophorin 1 protein turnover in vivo. ASB11 was also found to form complexes with Cullin 5 and Elongins B/C, and Cullin 5 complexes can oligomerize.","method":"SILAC-based protein/protein interaction analysis, Co-IP, in vivo ubiquitination assay, protein turnover assay, subcellular localization (ER-resident)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — SILAC interactomics plus Co-IP, ubiquitination, and turnover assays with multiple orthogonal methods in one study","pmids":["24337577"],"is_preprint":false},{"year":2019,"finding":"Cul5-ASB11 is the E3 ligase that ubiquitinates the pro-apoptotic protein BIK, targeting it for degradation. ER stress activates ASB11 through the IRE1α-XBP1s arm of the unfolded protein response, stimulating BIK ubiquitination, interaction with p97/VCP, and proteolysis, thereby promoting cell survival during ER stress adaptation. Genotoxic agents down-regulate this IRE1α-XBP1s-ASB11 axis to stabilize BIK, contributing to apoptosis. XBP1s was identified as the transcriptional activator of ASB11 in response to ER stress.","method":"Co-IP, ubiquitination assay, knockdown/overexpression, IRE1α inhibitor treatment, ER stress induction, genotoxic agent treatment, cell survival/apoptosis assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination assay, genetic KD/OE, pharmacological inhibition) with defined cellular phenotype and upstream activator identified, single lab","pmids":["31387940"],"is_preprint":false},{"year":2022,"finding":"The aspariginyl hydroxylase FIH (factor inhibiting HIF) catalyzes hydroxylation of asparaginyl residues in ankyrin repeat domain-containing proteins including ASB11. Biochemical and crystallographic evidence showed that FIH hydroxylates both asparaginyl residues in 'VNVN' motifs of ASB11's ankyrin repeat domain, representing a post-translational modification of ASB11.","method":"Biochemical hydroxylation assay, X-ray crystallography, mass spectrometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — biochemical in vitro assay combined with crystallographic structure, single lab but multiple orthogonal methods","pmids":["35537551"],"is_preprint":false},{"year":2023,"finding":"The Cul5/ASB11-based ubiquitin ligase polyubiquitinates PAICS (a de novo purine synthesis enzyme) with K6-linked chains, driving purinosome assembly via phase separation. Polyubiquitinated PAICS recruits UBAP2, a ubiquitin-binding protein with intrinsically disordered regions, inducing phase separation for purinosome assembly and enhancing de novo purine synthesis flux. In melanoma, ASB11 is upregulated by relief of H3K9me3/HP1α-mediated transcriptional silencing, leading to constitutive purinosome formation required for melanoma cell proliferation and tumorigenesis.","method":"Ubiquitination assay (K6-linkage identification), Co-IP, phase separation assay, ASB11 knockdown/overexpression, xenograft tumor model, chromatin immunoprecipitation (H3K9me3/HP1α), DNPS flux assay","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (ubiquitination assay with linkage specificity, phase separation, genetic KD/OE, in vivo xenograft, epigenetic mechanism) in a single rigorous study","pmids":["37848033"],"is_preprint":false},{"year":2024,"finding":"UBE2F neddylates CUL5 to activate CRL5-ASB11 E3 ligase, which ubiquitylates DIRAS2 for degradation. Ube2f deletion in a mouse KrasG12D PDAC model inactivates Mapk-c-Myc signaling by blocking DIRAS2 ubiquitylation, suppressing pancreatitis and pancreatic intraepithelial neoplasia. DIRAS2 deletion largely rescues Ube2f-deletion phenotypes, establishing UBE2F-CRL5ASB11-DIRAS2 as an oncogenic axis in pancreatic cancer.","method":"Genetic mouse KrasG12D PDAC model with Ube2f deletion, DIRAS2 knockout/rescue experiments, ubiquitylation assay, Mapk-c-Myc signaling readouts, epistasis analysis","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic epistasis (double-mutant rescue), ubiquitylation assay, and MAPK pathway readout across multiple model systems, single lab","pmids":["38574733"],"is_preprint":false},{"year":2026,"finding":"Under hypoxia, FIH-dependent hydroxylation of ASB11 at asparagine residues 90 and 92 is impaired, which enhances ASB11-mediated degradation of ERLIN1. ERLIN1 stabilizes the INSIG1-SCAP-SREBP2 axis to maintain cholesterol homeostasis in hepatocellular carcinoma. Pharmacological targeting using zoledronic acid weakens the ASB11-ERLIN1 interaction and restores cholesterol homeostasis, establishing ERLIN1 as a substrate of ASB11 regulated by FIH hydroxylation.","method":"In vitro and in vivo HCC models, FIH hydroxylation assay at specific Asn residues, Co-IP (ASB11-ERLIN1 interaction), subcutaneous and orthotopic mouse tumor models, zoledronic acid pharmacological intervention","journal":"Clinical and molecular hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, novel substrate (ERLIN1) identified with Co-IP and hydroxylation site mapping, supported by in vivo pharmacological data, but not yet replicated","pmids":["41668292"],"is_preprint":false}],"current_model":"ASB11 functions as the substrate-recognition subunit of a Cullin-5/Elongin-BC E3 ubiquitin ligase complex (CRL5-ASB11), residing at the endoplasmic reticulum, where it ubiquitinates and promotes degradation of multiple substrates including DeltaA (regulating Delta-Notch lateral inhibition during neurogenesis), BIK (determining cell fate during ER stress via the IRE1α-XBP1s axis), PAICS (driving K6-polyubiquitination-dependent purinosome phase separation for de novo purine synthesis), DIRAS2 (activating MAPK-c-Myc signaling in pancreatic cancer), Ribophorin 1 (OST complex), and ERLIN1 (cholesterol homeostasis regulator); its activity is post-translationally regulated by FIH-mediated asparagine hydroxylation within its ankyrin repeat domain, and it requires its Cul5-box domain for proper complex formation and function in vivo."},"narrative":{"mechanistic_narrative":"ASB11 is the substrate-recognition subunit of a Cullin-5/Elongin-BC E3 ubiquitin ligase complex (CRL5-ASB11) that controls cell fate, progenitor maintenance, and metabolic and survival programs by directing the polyubiquitination and turnover of specific substrates [PMID:24337577, PMID:21124961]. It assembles with Cullin 5 and Elongins B/C, and its Cul5-box domain is essential for complex formation and in vivo activity [PMID:24337577, PMID:21124961]. In developmental contexts, ASB11 maintains neural and myogenic progenitors in an undifferentiated, proliferating state and acts as an essential mediator of Delta-Notch lateral inhibition by directly ubiquitinating and degrading the Notch ligand DeltaA [PMID:16893969, PMID:22512762, PMID:18776899]. Beyond development, ASB11 governs several stress and metabolic pathways through dedicated substrates: during ER stress it is transcriptionally activated by the IRE1α-XBP1s arm of the unfolded protein response and ubiquitinates the pro-apoptotic protein BIK to promote survival [PMID:31387940]; it drives K6-linked polyubiquitination of the purine-synthesis enzyme PAICS to recruit UBAP2 and nucleate purinosome phase separation [PMID:37848033]; it ubiquitinates DIRAS2 within a UBE2F-neddylation-activated CRL5-ASB11 axis that sustains MAPK-c-Myc signaling in pancreatic cancer [PMID:38574733]; and it degrades the cholesterol-homeostasis regulator ERLIN1 [PMID:41668292]. ASB11 activity is post-translationally tuned by FIH-mediated hydroxylation of asparaginyl residues in its ankyrin repeat domain, a modification relieved under hypoxia to enhance substrate degradation [PMID:35537551, PMID:41668292]. Its localization to the endoplasmic reticulum is consistent with substrates spanning ER glycosylation and lipid-homeostasis machinery, including Ribophorin 1 of the OST complex [PMID:24337577].","teleology":[{"year":2006,"claim":"Established ASB11 as a regulator of neural progenitor compartment size, defining its biological role before its molecular activity was known.","evidence":"Morpholino knockdown and forced misexpression in zebrafish embryos with sox2/sox3/neurogenin1 readouts, plus overexpression in progenitor cell lines","pmids":["16893969"],"confidence":"High","gaps":["Molecular mechanism (E3 ligase activity, substrates) not yet identified","Link to SoxB1 factors correlative, not direct"]},{"year":2008,"claim":"Identified the first direct substrate, DeltaA, demonstrating ASB11 acts through targeted ubiquitination to control Delta-Notch lateral inhibition.","evidence":"Morpholino knockdown, misexpression, Notch reporter assays, and in vitro and in vivo ubiquitylation/degradation assays in zebrafish","pmids":["18776899"],"confidence":"High","gaps":["Composition of the E3 complex not yet defined","Recognition determinants on DeltaA unmapped"]},{"year":2010,"claim":"Showed the Cul5-box domain is required for ASB11 function in vivo, linking its activity to the ECS/CRL5 ligase architecture.","evidence":"Zebrafish Cul5-box deletion mutant with DeltaA degradation, Notch reporter, and cell-fate readouts","pmids":["21124961"],"confidence":"High","gaps":["Direct biochemical reconstitution of the complex not performed","Whether all substrates require the Cul5-box untested at this stage"]},{"year":2012,"claim":"Extended ASB11's progenitor-maintenance role from neural to myogenic lineages, generalizing its function across stem/progenitor compartments.","evidence":"Pax7+ satellite cell localization, forced overexpression, germline hypomorphic zebrafish mutant, and adult muscle regeneration assays","pmids":["22512762"],"confidence":"High","gaps":["Substrate driving the myogenic phenotype not identified","Mechanistic connection to the Notch/DeltaA axis in muscle unresolved"]},{"year":2013,"claim":"Defined ASB11 as an ER-resident CRL5 ligase and identified Ribophorin 1 as a substrate, placing it within the secretory/glycosylation machinery.","evidence":"SILAC interactomics, Co-IP, in vivo ubiquitination and turnover assays, subcellular localization","pmids":["24337577"],"confidence":"High","gaps":["Functional consequence for OST/glycosylation not established","Physiological context of Ribophorin 1 regulation unclear"]},{"year":2019,"claim":"Connected ASB11 to ER-stress survival decisions by showing IRE1α-XBP1s induces ASB11 to degrade pro-apoptotic BIK.","evidence":"Co-IP, ubiquitination assays, KD/OE, IRE1α inhibition, ER stress and genotoxic treatments, apoptosis assays","pmids":["31387940"],"confidence":"High","gaps":["Direct demonstration that XBP1s binds the ASB11 promoter limited to expression-level evidence","Generality across cell types untested"]},{"year":2022,"claim":"Revealed a post-translational regulatory layer: FIH hydroxylates asparaginyl residues in ASB11's ankyrin repeats.","evidence":"In vitro hydroxylation assay, X-ray crystallography, mass spectrometry","pmids":["35537551"],"confidence":"High","gaps":["Functional consequence of hydroxylation on ligase activity not shown in this study","Cellular conditions controlling hydroxylation undefined here"]},{"year":2023,"claim":"Showed ASB11 uses K6-linked polyubiquitination of PAICS to nucleate purinosome phase separation, linking it to metabolic compartmentalization and melanoma proliferation.","evidence":"Linkage-specific ubiquitination assay, Co-IP, phase separation assay, KD/OE, xenografts, ChIP for H3K9me3/HP1α, DNPS flux","pmids":["37848033"],"confidence":"High","gaps":["Whether K6-ubiquitination is signal rather than degradative for other substrates unknown","Structural basis of UBAP2 recruitment unresolved"]},{"year":2024,"claim":"Demonstrated CRL5-ASB11 is activated by UBE2F-mediated CUL5 neddylation and degrades DIRAS2 to sustain oncogenic MAPK-c-Myc signaling.","evidence":"Genetic KrasG12D PDAC mouse model with Ube2f deletion and DIRAS2 knockout/rescue epistasis, ubiquitylation assays, MAPK pathway readouts","pmids":["38574733"],"confidence":"High","gaps":["DIRAS2 recognition determinants not mapped","Relative contribution of ASB11 versus other CRL5 substrate receptors in PDAC unresolved"]},{"year":2026,"claim":"Linked FIH hydroxylation status to substrate selection, showing hypoxia-impaired hydroxylation of Asn90/92 enhances ASB11-mediated ERLIN1 degradation in cholesterol homeostasis.","evidence":"HCC in vitro and in vivo models, site-specific FIH hydroxylation assay, Co-IP, mouse tumor models, zoledronic acid intervention","pmids":["41668292"],"confidence":"Medium","gaps":["Single lab, not yet independently replicated","Mechanism by which hydroxylation alters substrate engagement not biochemically resolved","Direct effect of hydroxylation on ligase catalytic output untested"]},{"year":null,"claim":"How a single CRL5-ASB11 ligase selects among its diverse substrates (DeltaA, BIK, PAICS, DIRAS2, Ribophorin 1, ERLIN1) across tissues and stress states, and how FIH hydroxylation reprograms this selectivity, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying substrate-recognition code defined","Tissue-specific determinants of which substrate predominates unknown","Quantitative link between hydroxylation state and per-substrate degradation not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,4,5,7,8,9]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[1,4,5,7,8]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,4,5,7,8]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1,3]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[5,9]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[7,8,9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,8]}],"complexes":["CRL5-ASB11 (Cullin5-Elongin BC E3 ubiquitin ligase)"],"partners":["CUL5","ELOB","ELOC","UBE2F","FIH","DELTAA","BIK","PAICS"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8WXH4","full_name":"Ankyrin repeat and SOCS box protein 11","aliases":[],"length_aa":323,"mass_kda":35.4,"function":"Substrate-recognition component of a cullin-5-RING E3 ubiquitin-protein ligase complex (ECS complex, also named CRL5 complex), which mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as BIK, DIRAS2 and RPN1 (PubMed:24337577, PubMed:31387940, PubMed:38574733). The ECS(ASB11) complex acts as a regulator of the endoplasmic reticulum unfolded protein response by mediating ubiquitination and degradation of BIK (PubMed:31387940)","subcellular_location":"Endoplasmic reticulum","url":"https://www.uniprot.org/uniprotkb/Q8WXH4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ASB11","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ASB11","total_profiled":1310},"omim":[{"mim_id":"300626","title":"ANKYRIN REPEAT- AND SOCS BOX-CONTAINING PROTEIN 11; ASB11","url":"https://www.omim.org/entry/300626"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"heart muscle","ntpm":31.3},{"tissue":"skeletal muscle","ntpm":107.3},{"tissue":"tongue","ntpm":57.4}],"url":"https://www.proteinatlas.org/search/ASB11"},"hgnc":{"alias_symbol":["DKFZp779E2460"],"prev_symbol":[]},"alphafold":{"accession":"Q8WXH4","domains":[{"cath_id":"1.25.40.20","chopping":"70-188","consensus_level":"medium","plddt":94.8995,"start":70,"end":188},{"cath_id":"-","chopping":"294-323","consensus_level":"medium","plddt":84.9747,"start":294,"end":323}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXH4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXH4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8WXH4-F1-predicted_aligned_error_v6.png","plddt_mean":87.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ASB11","jax_strain_url":"https://www.jax.org/strain/search?query=ASB11"},"sequence":{"accession":"Q8WXH4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8WXH4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8WXH4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8WXH4"}},"corpus_meta":[{"pmid":"24337577","id":"PMC_24337577","title":"Protein interaction screening for the ankyrin repeats and suppressor of cytokine signaling (SOCS) box (ASB) family identify Asb11 as a novel endoplasmic reticulum resident ubiquitin ligase.","date":"2013","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/24337577","citation_count":43,"is_preprint":false},{"pmid":"34968235","id":"PMC_34968235","title":"Epigenetics of Skeletal Muscle-Associated Genes in the ASB, LRRC, TMEM, and OSBPL Gene Families.","date":"2020","source":"Epigenomes","url":"https://pubmed.ncbi.nlm.nih.gov/34968235","citation_count":32,"is_preprint":false},{"pmid":"37848033","id":"PMC_37848033","title":"PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/37848033","citation_count":28,"is_preprint":false},{"pmid":"16893969","id":"PMC_16893969","title":"The novel gene asb11: a regulator of the size of the neural progenitor compartment.","date":"2006","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16893969","citation_count":27,"is_preprint":false},{"pmid":"16685460","id":"PMC_16685460","title":"Comparative integromics on VEGF family members.","date":"2006","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16685460","citation_count":25,"is_preprint":false},{"pmid":"31387940","id":"PMC_31387940","title":"BIK ubiquitination by the E3 ligase Cul5-ASB11 determines cell fate during cellular stress.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31387940","citation_count":21,"is_preprint":false},{"pmid":"25599194","id":"PMC_25599194","title":"Circulating E3 ligases are novel and sensitive biomarkers for diagnosis of acute myocardial infarction.","date":"2015","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/25599194","citation_count":21,"is_preprint":false},{"pmid":"39706197","id":"PMC_39706197","title":"Chromosome X-wide common variant association study in autism spectrum disorder.","date":"2024","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39706197","citation_count":18,"is_preprint":false},{"pmid":"38574733","id":"PMC_38574733","title":"The UBE2F-CRL5ASB11-DIRAS2 axis is an oncogene and tumor suppressor cascade in pancreatic cancer cells.","date":"2024","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/38574733","citation_count":17,"is_preprint":false},{"pmid":"18776899","id":"PMC_18776899","title":"d-Asb11 is an essential mediator of canonical Delta-Notch signalling.","date":"2008","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18776899","citation_count":14,"is_preprint":false},{"pmid":"21124961","id":"PMC_21124961","title":"Essential role for the d-Asb11 cul5 Box domain for proper notch signaling and neural cell fate decisions in vivo.","date":"2010","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21124961","citation_count":13,"is_preprint":false},{"pmid":"22512762","id":"PMC_22512762","title":"asb11 is a regulator of embryonic and adult regenerative myogenesis.","date":"2012","source":"Stem cells and development","url":"https://pubmed.ncbi.nlm.nih.gov/22512762","citation_count":12,"is_preprint":false},{"pmid":"35537551","id":"PMC_35537551","title":"Factor inhibiting HIF can catalyze two asparaginyl hydroxylations in VNVN motifs of ankyrin fold proteins.","date":"2022","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35537551","citation_count":8,"is_preprint":false},{"pmid":"37662987","id":"PMC_37662987","title":"Uncovering the candidate genes related to sheep body weight using multi-trait genome-wide association analysis.","date":"2023","source":"Frontiers in veterinary 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39108515","citation_count":2,"is_preprint":false},{"pmid":"41668292","id":"PMC_41668292","title":"Targeting ER lipid raft-associated 1 reveals a coordinated cholesterol-dependent vulnerability in hepatocellular carcinoma.","date":"2026","source":"Clinical and molecular hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/41668292","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11562,"output_tokens":3360,"usd":0.042543,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":10878,"output_tokens":3725,"usd":0.073758,"stage2_stop_reason":"end_turn"},"total_usd":0.116301,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2006,\n      \"finding\": \"d-Asb11 knockdown in zebrafish altered expression of neural precursor genes sox2 and sox3, caused expansion of neurogenin1-positive proneural cells followed by premature neuronal differentiation, while forced misexpression of d-asb11 ectopically induced sox2 and abolished neurogenesis. Overexpression in pluripotent and neural-committed progenitor cell lines inhibited terminal neuronal differentiation and enhanced proliferation, establishing d-Asb11 as a regulator of neural progenitor compartment size that maintains precursors in an undifferentiated proliferating state, possibly through control of SoxB1 transcription factors.\",\n      \"method\": \"Morpholino knockdown, forced misexpression in zebrafish embryos, overexpression in progenitor cell lines, HuC labeling, sox2/sox3/neurogenin1 expression analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function experiments with multiple orthogonal readouts in zebrafish and cell lines, single lab\",\n      \"pmids\": [\"16893969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"d-Asb11 is an essential mediator of canonical Delta-Notch lateral inhibition signaling in zebrafish. Morpholino knockdown repressed Delta-Notch elements and their transcriptional targets; misexpression activated Notch reporters cell-non-autonomously. d-Asb11 was shown to specifically ubiquitylate and degrade DeltaA both in vitro and in vivo, identifying DeltaA as a direct substrate for ASB11-mediated ubiquitination and degradation.\",\n      \"method\": \"Morpholino knockdown, misexpression in zebrafish embryos, Notch reporter assays (cell-autonomous and non-autonomous), in vitro and in vivo ubiquitylation and degradation assays for DeltaA\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro and in vivo ubiquitylation assay combined with genetic knockdown/overexpression and reporter assays, replicated across multiple experimental systems\",\n      \"pmids\": [\"18776899\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The Cul5 box domain of d-Asb11 is required in vivo for proper Notch signaling and neural cell fate. A zebrafish mutant lacking the Cul5 box (Asb11(Cul)) was defective in Notch signaling, unable to degrade DeltaA during embryogenesis, showed impaired neural cell fate specification, and Asb11(Cul) mRNA failed to transactivate a her4::gfp Notch reporter. This establishes that the Cul5 box domain is essential for d-Asb11 function in the ECS ubiquitin ligase complex.\",\n      \"method\": \"Zebrafish Cul5-box domain mutant generation and characterization, Notch target gene expression, DeltaA degradation assay in vivo, her4::gfp reporter assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain-specific mutant with multiple functional readouts (substrate degradation, reporter, target gene expression, cell fate) in vivo, single lab\",\n      \"pmids\": [\"21124961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Asb11 localizes specifically to Pax7+ muscle satellite cells across vertebrates. Forced expression of d-asb11 impaired terminal differentiation and caused enhanced proliferation in myogenic progenitors in vivo and in vitro. A germline hypomorphic zebrafish d-asb11 mutation caused premature differentiation of muscle progenitors and delayed regenerative responses in adult injured muscle, establishing d-Asb11 as a principal regulator of embryonic and adult regenerative myogenesis.\",\n      \"method\": \"Expression/localization analysis (Pax7+ satellite cell compartment), forced overexpression in zebrafish and cell lines, germline hypomorphic zebrafish mutant, adult muscle regeneration assay\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal gain- and loss-of-function with specific cellular phenotype (proliferation vs. differentiation) and localization data, single lab\",\n      \"pmids\": [\"22512762\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ASB11 is a novel endoplasmic reticulum-resident ubiquitin ligase that interacts with and promotes ubiquitination of Ribophorin 1, an integral component of the oligosaccharyltransferase (OST) glycosylation complex. Expression of ASB11 increases Ribophorin 1 protein turnover in vivo. ASB11 was also found to form complexes with Cullin 5 and Elongins B/C, and Cullin 5 complexes can oligomerize.\",\n      \"method\": \"SILAC-based protein/protein interaction analysis, Co-IP, in vivo ubiquitination assay, protein turnover assay, subcellular localization (ER-resident)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — SILAC interactomics plus Co-IP, ubiquitination, and turnover assays with multiple orthogonal methods in one study\",\n      \"pmids\": [\"24337577\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cul5-ASB11 is the E3 ligase that ubiquitinates the pro-apoptotic protein BIK, targeting it for degradation. ER stress activates ASB11 through the IRE1α-XBP1s arm of the unfolded protein response, stimulating BIK ubiquitination, interaction with p97/VCP, and proteolysis, thereby promoting cell survival during ER stress adaptation. Genotoxic agents down-regulate this IRE1α-XBP1s-ASB11 axis to stabilize BIK, contributing to apoptosis. XBP1s was identified as the transcriptional activator of ASB11 in response to ER stress.\",\n      \"method\": \"Co-IP, ubiquitination assay, knockdown/overexpression, IRE1α inhibitor treatment, ER stress induction, genotoxic agent treatment, cell survival/apoptosis assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (Co-IP, ubiquitination assay, genetic KD/OE, pharmacological inhibition) with defined cellular phenotype and upstream activator identified, single lab\",\n      \"pmids\": [\"31387940\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"The aspariginyl hydroxylase FIH (factor inhibiting HIF) catalyzes hydroxylation of asparaginyl residues in ankyrin repeat domain-containing proteins including ASB11. Biochemical and crystallographic evidence showed that FIH hydroxylates both asparaginyl residues in 'VNVN' motifs of ASB11's ankyrin repeat domain, representing a post-translational modification of ASB11.\",\n      \"method\": \"Biochemical hydroxylation assay, X-ray crystallography, mass spectrometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — biochemical in vitro assay combined with crystallographic structure, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35537551\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"The Cul5/ASB11-based ubiquitin ligase polyubiquitinates PAICS (a de novo purine synthesis enzyme) with K6-linked chains, driving purinosome assembly via phase separation. Polyubiquitinated PAICS recruits UBAP2, a ubiquitin-binding protein with intrinsically disordered regions, inducing phase separation for purinosome assembly and enhancing de novo purine synthesis flux. In melanoma, ASB11 is upregulated by relief of H3K9me3/HP1α-mediated transcriptional silencing, leading to constitutive purinosome formation required for melanoma cell proliferation and tumorigenesis.\",\n      \"method\": \"Ubiquitination assay (K6-linkage identification), Co-IP, phase separation assay, ASB11 knockdown/overexpression, xenograft tumor model, chromatin immunoprecipitation (H3K9me3/HP1α), DNPS flux assay\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (ubiquitination assay with linkage specificity, phase separation, genetic KD/OE, in vivo xenograft, epigenetic mechanism) in a single rigorous study\",\n      \"pmids\": [\"37848033\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"UBE2F neddylates CUL5 to activate CRL5-ASB11 E3 ligase, which ubiquitylates DIRAS2 for degradation. Ube2f deletion in a mouse KrasG12D PDAC model inactivates Mapk-c-Myc signaling by blocking DIRAS2 ubiquitylation, suppressing pancreatitis and pancreatic intraepithelial neoplasia. DIRAS2 deletion largely rescues Ube2f-deletion phenotypes, establishing UBE2F-CRL5ASB11-DIRAS2 as an oncogenic axis in pancreatic cancer.\",\n      \"method\": \"Genetic mouse KrasG12D PDAC model with Ube2f deletion, DIRAS2 knockout/rescue experiments, ubiquitylation assay, Mapk-c-Myc signaling readouts, epistasis analysis\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic epistasis (double-mutant rescue), ubiquitylation assay, and MAPK pathway readout across multiple model systems, single lab\",\n      \"pmids\": [\"38574733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Under hypoxia, FIH-dependent hydroxylation of ASB11 at asparagine residues 90 and 92 is impaired, which enhances ASB11-mediated degradation of ERLIN1. ERLIN1 stabilizes the INSIG1-SCAP-SREBP2 axis to maintain cholesterol homeostasis in hepatocellular carcinoma. Pharmacological targeting using zoledronic acid weakens the ASB11-ERLIN1 interaction and restores cholesterol homeostasis, establishing ERLIN1 as a substrate of ASB11 regulated by FIH hydroxylation.\",\n      \"method\": \"In vitro and in vivo HCC models, FIH hydroxylation assay at specific Asn residues, Co-IP (ASB11-ERLIN1 interaction), subcutaneous and orthotopic mouse tumor models, zoledronic acid pharmacological intervention\",\n      \"journal\": \"Clinical and molecular hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, novel substrate (ERLIN1) identified with Co-IP and hydroxylation site mapping, supported by in vivo pharmacological data, but not yet replicated\",\n      \"pmids\": [\"41668292\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ASB11 functions as the substrate-recognition subunit of a Cullin-5/Elongin-BC E3 ubiquitin ligase complex (CRL5-ASB11), residing at the endoplasmic reticulum, where it ubiquitinates and promotes degradation of multiple substrates including DeltaA (regulating Delta-Notch lateral inhibition during neurogenesis), BIK (determining cell fate during ER stress via the IRE1α-XBP1s axis), PAICS (driving K6-polyubiquitination-dependent purinosome phase separation for de novo purine synthesis), DIRAS2 (activating MAPK-c-Myc signaling in pancreatic cancer), Ribophorin 1 (OST complex), and ERLIN1 (cholesterol homeostasis regulator); its activity is post-translationally regulated by FIH-mediated asparagine hydroxylation within its ankyrin repeat domain, and it requires its Cul5-box domain for proper complex formation and function in vivo.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ASB11 is the substrate-recognition subunit of a Cullin-5/Elongin-BC E3 ubiquitin ligase complex (CRL5-ASB11) that controls cell fate, progenitor maintenance, and metabolic and survival programs by directing the polyubiquitination and turnover of specific substrates [#4, #2]. It assembles with Cullin 5 and Elongins B/C, and its Cul5-box domain is essential for complex formation and in vivo activity [#4, #2]. In developmental contexts, ASB11 maintains neural and myogenic progenitors in an undifferentiated, proliferating state and acts as an essential mediator of Delta-Notch lateral inhibition by directly ubiquitinating and degrading the Notch ligand DeltaA [#0, #3, #1]. Beyond development, ASB11 governs several stress and metabolic pathways through dedicated substrates: during ER stress it is transcriptionally activated by the IRE1\\u03b1-XBP1s arm of the unfolded protein response and ubiquitinates the pro-apoptotic protein BIK to promote survival [#5]; it drives K6-linked polyubiquitination of the purine-synthesis enzyme PAICS to recruit UBAP2 and nucleate purinosome phase separation [#7]; it ubiquitinates DIRAS2 within a UBE2F-neddylation-activated CRL5-ASB11 axis that sustains MAPK-c-Myc signaling in pancreatic cancer [#8]; and it degrades the cholesterol-homeostasis regulator ERLIN1 [#9]. ASB11 activity is post-translationally tuned by FIH-mediated hydroxylation of asparaginyl residues in its ankyrin repeat domain, a modification relieved under hypoxia to enhance substrate degradation [#6, #9]. Its localization to the endoplasmic reticulum is consistent with substrates spanning ER glycosylation and lipid-homeostasis machinery, including Ribophorin 1 of the OST complex [#4].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"Established ASB11 as a regulator of neural progenitor compartment size, defining its biological role before its molecular activity was known.\",\n      \"evidence\": \"Morpholino knockdown and forced misexpression in zebrafish embryos with sox2/sox3/neurogenin1 readouts, plus overexpression in progenitor cell lines\",\n      \"pmids\": [\"16893969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism (E3 ligase activity, substrates) not yet identified\", \"Link to SoxB1 factors correlative, not direct\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Identified the first direct substrate, DeltaA, demonstrating ASB11 acts through targeted ubiquitination to control Delta-Notch lateral inhibition.\",\n      \"evidence\": \"Morpholino knockdown, misexpression, Notch reporter assays, and in vitro and in vivo ubiquitylation/degradation assays in zebrafish\",\n      \"pmids\": [\"18776899\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Composition of the E3 complex not yet defined\", \"Recognition determinants on DeltaA unmapped\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed the Cul5-box domain is required for ASB11 function in vivo, linking its activity to the ECS/CRL5 ligase architecture.\",\n      \"evidence\": \"Zebrafish Cul5-box deletion mutant with DeltaA degradation, Notch reporter, and cell-fate readouts\",\n      \"pmids\": [\"21124961\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct biochemical reconstitution of the complex not performed\", \"Whether all substrates require the Cul5-box untested at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended ASB11's progenitor-maintenance role from neural to myogenic lineages, generalizing its function across stem/progenitor compartments.\",\n      \"evidence\": \"Pax7+ satellite cell localization, forced overexpression, germline hypomorphic zebrafish mutant, and adult muscle regeneration assays\",\n      \"pmids\": [\"22512762\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate driving the myogenic phenotype not identified\", \"Mechanistic connection to the Notch/DeltaA axis in muscle unresolved\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined ASB11 as an ER-resident CRL5 ligase and identified Ribophorin 1 as a substrate, placing it within the secretory/glycosylation machinery.\",\n      \"evidence\": \"SILAC interactomics, Co-IP, in vivo ubiquitination and turnover assays, subcellular localization\",\n      \"pmids\": [\"24337577\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence for OST/glycosylation not established\", \"Physiological context of Ribophorin 1 regulation unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Connected ASB11 to ER-stress survival decisions by showing IRE1\\u03b1-XBP1s induces ASB11 to degrade pro-apoptotic BIK.\",\n      \"evidence\": \"Co-IP, ubiquitination assays, KD/OE, IRE1\\u03b1 inhibition, ER stress and genotoxic treatments, apoptosis assays\",\n      \"pmids\": [\"31387940\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct demonstration that XBP1s binds the ASB11 promoter limited to expression-level evidence\", \"Generality across cell types untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Revealed a post-translational regulatory layer: FIH hydroxylates asparaginyl residues in ASB11's ankyrin repeats.\",\n      \"evidence\": \"In vitro hydroxylation assay, X-ray crystallography, mass spectrometry\",\n      \"pmids\": [\"35537551\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of hydroxylation on ligase activity not shown in this study\", \"Cellular conditions controlling hydroxylation undefined here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Showed ASB11 uses K6-linked polyubiquitination of PAICS to nucleate purinosome phase separation, linking it to metabolic compartmentalization and melanoma proliferation.\",\n      \"evidence\": \"Linkage-specific ubiquitination assay, Co-IP, phase separation assay, KD/OE, xenografts, ChIP for H3K9me3/HP1\\u03b1, DNPS flux\",\n      \"pmids\": [\"37848033\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether K6-ubiquitination is signal rather than degradative for other substrates unknown\", \"Structural basis of UBAP2 recruitment unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated CRL5-ASB11 is activated by UBE2F-mediated CUL5 neddylation and degrades DIRAS2 to sustain oncogenic MAPK-c-Myc signaling.\",\n      \"evidence\": \"Genetic KrasG12D PDAC mouse model with Ube2f deletion and DIRAS2 knockout/rescue epistasis, ubiquitylation assays, MAPK pathway readouts\",\n      \"pmids\": [\"38574733\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"DIRAS2 recognition determinants not mapped\", \"Relative contribution of ASB11 versus other CRL5 substrate receptors in PDAC unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Linked FIH hydroxylation status to substrate selection, showing hypoxia-impaired hydroxylation of Asn90/92 enhances ASB11-mediated ERLIN1 degradation in cholesterol homeostasis.\",\n      \"evidence\": \"HCC in vitro and in vivo models, site-specific FIH hydroxylation assay, Co-IP, mouse tumor models, zoledronic acid intervention\",\n      \"pmids\": [\"41668292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab, not yet independently replicated\", \"Mechanism by which hydroxylation alters substrate engagement not biochemically resolved\", \"Direct effect of hydroxylation on ligase catalytic output untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single CRL5-ASB11 ligase selects among its diverse substrates (DeltaA, BIK, PAICS, DIRAS2, Ribophorin 1, ERLIN1) across tissues and stress states, and how FIH hydroxylation reprograms this selectivity, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying substrate-recognition code defined\", \"Tissue-specific determinants of which substrate predominates unknown\", \"Quantitative link between hydroxylation state and per-substrate degradation not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 4, 5, 7, 8, 9]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [1, 4, 5, 7, 8]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 4, 5, 7, 8]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1, 3]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [5, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [7, 8, 9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 8]}\n    ],\n    \"complexes\": [\"CRL5-ASB11 (Cullin5-Elongin BC E3 ubiquitin ligase)\"],\n    \"partners\": [\"CUL5\", \"ELOB\", \"ELOC\", \"UBE2F\", \"FIH\", \"DeltaA\", \"BIK\", \"PAICS\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}