{"gene":"ASB1","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":1998,"finding":"ASB1 was identified as a member of a new family of proteins containing ankyrin repeats N-terminal of a SOCS box motif, placing it in the SOCS box protein superfamily alongside SOCS, WSB, and SSB families.","method":"Database sequence homology search using SOCS box consensus; structural classification","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — foundational classification paper, highly cited, but functional role of ASB1 itself not experimentally defined here","pmids":["9419338"],"is_preprint":false},{"year":2000,"finding":"ASB1 (Asb-1) was cloned and characterized as an ankyrin repeat and SOCS box-containing protein; the SOCS box was proposed to couple ASB proteins and their binding partners to the elongin B/C complex, potentially targeting them for degradation.","method":"Molecular cloning, expression analysis, sequence characterization","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 3 — cloning and expression data with mechanistic inference from SOCS box homology, single lab","pmids":["11111040"],"is_preprint":false},{"year":2001,"finding":"Asb-1 knockout mice develop normally with normal hematopoiesis, but display diminished spermatogenesis with less complete filling of seminiferous tubules, establishing a specific role for Asb-1 in testicular spermatogenesis.","method":"Genetic knockout and overexpression mouse models; histological analysis of testes and hematopoietic compartment","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype in vivo, replicated with overexpression controls","pmids":["11509662"],"is_preprint":false},{"year":2005,"finding":"ASB proteins, including ASB1, interact with Cullin5 (Cul5) and Rbx2 to form E3 ubiquitin ligase complexes; the BC box and Cul5 box sequences within the SOCS box of ASB1 are essential for interaction with Cul5-Rbx2, and the resulting complex has E3 ubiquitin ligase activity.","method":"Co-immunoprecipitation in cells; mutational analysis of BC box and Cul5 box; in vitro ubiquitin ligase activity assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal Co-IP, mutagenesis, and in vitro E3 ligase activity assay in a single study","pmids":["16325183"],"is_preprint":false},{"year":2013,"finding":"Crystal structures of the related family member ASB9 in ternary complex with Elongin B/C and the N-terminal domain of Cul5 revealed that ASB ankyrin domains are positioned coaxial to the SOCS box-Elongin B/C complex, providing a model for how the ankyrin substrate-binding domain is presented toward the E2-ubiquitin in the complete Cul5-based E3 ligase; this architecture is distinct from other repeat-domain E3 ligases.","method":"X-ray crystallography of ASB9-ElonginB/C ternary complex; structural comparison modeling","journal":"Journal of molecular biology","confidence":"High","confidence_rationale":"Tier 1 — crystal structure of ASB family ternary complex with functional modeling; directly relevant to ASB1 family mechanism","pmids":["23806657"],"is_preprint":false},{"year":2021,"finding":"ASB1 positively regulates inflammatory responses by binding TAB2 and inhibiting its K48-linked polyubiquitination, thereby stabilizing TAB2 protein and promoting downstream NF-κB and MAPK signaling upon cytokine and LPS stimulation; this is a non-canonical function distinct from the typical E3 ligase-mediated degradation role of ASB family members.","method":"Co-immunoprecipitation; ubiquitination assays (K48-linkage specific); Asb1 knockout mice challenged with Salmonella typhimurium or LPS; dextran sodium sulfate colitis model; cycloheximide chase; Western blot","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, ubiquitination assays with linkage specificity, multiple in vivo KO models with defined phenotypes","pmids":["33431678"],"is_preprint":false},{"year":2024,"finding":"ASB1 acts as the substrate recognition subunit of a CRL5 E3 ubiquitin ligase that interacts with Elongin B (ELOB) and targets sulfide-quinone oxidoreductase (SQOR) for K48-linked ubiquitination at residues K207 and K344, leading to proteasomal degradation of SQOR; this process maintains H2S homeostasis and redox balance during spermiogenesis.","method":"Co-immunoprecipitation (ASB1-ELOB interaction); K48-linked ubiquitination assay; site-directed mutagenesis of SQOR ubiquitination sites (K207, K344); Asb1 knockout mouse model; NaHS rescue experiment; oxidative stress and H2S level measurements","journal":"Redox biology","confidence":"High","confidence_rationale":"Tier 1-2 — Co-IP, in cellulo ubiquitination with mutagenesis of specific sites, KO mouse with rescue, multiple orthogonal methods","pmids":["39733518"],"is_preprint":false},{"year":2024,"finding":"ASB1 interacts with CHCHD3 and promotes its degradation via K48-linked ubiquitination, thereby suppressing prostate cancer cell proliferation, clonogenicity, and migration through the CHCHD3/ROS pathway.","method":"Quantitative mass spectrometry interactome analysis; co-immunoprecipitation; cycloheximide chase assay; ubiquitination assay; ASB1 knockdown/overexpression with phenotypic readout; cell rescue experiments","journal":"American journal of cancer research","confidence":"High","confidence_rationale":"Tier 2 — MS interactome, Co-IP, ubiquitination assay, and functional rescue with multiple orthogonal methods in single study","pmids":["39113857"],"is_preprint":false}],"current_model":"Human/mammalian ASB1 is the substrate-recognition subunit of a Cullin5-Rbx2-ElonginB/C CRL5 E3 ubiquitin ligase complex, where its ankyrin repeats recruit substrates (including SQOR and CHCHD3) for K48-linked ubiquitination and proteasomal degradation; however, ASB1 also has a non-canonical function in which it stabilizes TAB2 by inhibiting its K48-linked ubiquitination, thereby promoting NF-κB and MAPK inflammatory signaling, and in the testis it is specifically required for spermatogenesis and H2S homeostasis."},"narrative":{"teleology":[{"year":1998,"claim":"ASB1 was classified within a new protein family defined by ankyrin repeats and a C-terminal SOCS box, establishing it as part of the SOCS box superfamily and predicting a role in protein-protein interaction and possible Elongin-mediated degradation pathways.","evidence":"Database homology search and structural domain classification","pmids":["9419338"],"confidence":"Medium","gaps":["No direct biochemical activity demonstrated for ASB1","Substrates unknown","Expression pattern only partially characterized"]},{"year":2000,"claim":"Molecular cloning of ASB1 confirmed its domain architecture and suggested its SOCS box couples binding partners to Elongin B/C for potential degradation, providing a mechanistic framework before direct biochemical evidence existed.","evidence":"Molecular cloning, expression analysis, and sequence characterization","pmids":["11111040"],"confidence":"Medium","gaps":["Elongin B/C interaction not directly demonstrated for ASB1","No functional assay performed"]},{"year":2001,"claim":"Genetic loss-of-function established that ASB1 is dispensable for hematopoiesis and general development but specifically required for normal spermatogenesis, identifying its principal physiological context.","evidence":"Asb1 knockout and overexpression mouse models with histological analysis of testes and hematopoietic compartments","pmids":["11509662"],"confidence":"High","gaps":["Molecular substrate(s) in the testis not identified","Mechanism linking ASB1 to spermatogenic defect unknown"]},{"year":2005,"claim":"Biochemical demonstration that ASB1 assembles with Cullin5 and Rbx2 via its BC box and Cul5 box to form a functional E3 ubiquitin ligase complex resolved the catalytic mechanism predicted by domain homology.","evidence":"Co-immunoprecipitation, BC box and Cul5 box mutagenesis, and in vitro ubiquitin ligase activity assay","pmids":["16325183"],"confidence":"High","gaps":["No physiological substrate identified for the ASB1-CRL5 complex","Ubiquitin chain linkage type not determined"]},{"year":2013,"claim":"Structural determination of the homologous ASB9-Elongin B/C-Cul5 ternary complex revealed the architecture by which ASB ankyrin repeat domains present substrates toward the E2-ubiquitin active site, providing a generalizable structural model for ASB1.","evidence":"X-ray crystallography of ASB9-ElonginB/C complex with structural modeling","pmids":["23806657"],"confidence":"High","gaps":["No ASB1-specific structure solved","Substrate docking geometry for ASB1 ankyrin repeats not determined"]},{"year":2021,"claim":"Discovery that ASB1 stabilizes TAB2 by inhibiting its K48-linked ubiquitination — rather than promoting degradation — revealed a non-canonical anti-degradative function that activates NF-κB and MAPK inflammatory signaling in vivo.","evidence":"Reciprocal Co-IP; K48-linkage-specific ubiquitination assays; Asb1 KO mice challenged with Salmonella typhimurium, LPS, and DSS colitis model; cycloheximide chase","pmids":["33431678"],"confidence":"High","gaps":["Mechanism by which ASB1 blocks TAB2 ubiquitination (competitive, allosteric, or E3 ligase recruitment inhibition) not defined","Identity of the E3 ligase that ubiquitinates TAB2 in the absence of ASB1 unknown"]},{"year":2024,"claim":"Identification of SQOR as a direct ASB1-CRL5 substrate ubiquitinated at K207 and K344 linked the spermatogenesis defect of Asb1 KO mice to accumulation of SQOR, disrupted H₂S homeostasis, and oxidative stress during spermiogenesis.","evidence":"Co-IP of ASB1-ELOB; K48-linked ubiquitination assay with K207/K344 mutagenesis; Asb1 KO mouse with NaHS rescue; H₂S and oxidative stress measurements","pmids":["39733518"],"confidence":"High","gaps":["Whether SQOR is the sole spermatogenesis-relevant substrate is unknown","Contribution of Cul5/Rbx2 vs. other E3 components not re-examined in testis"]},{"year":2024,"claim":"Identification of CHCHD3 as a second direct ASB1 substrate extended the CRL5-dependent degradation mechanism to a mitochondrial target whose accumulation drives ROS-dependent prostate cancer cell proliferation.","evidence":"Quantitative MS interactome; Co-IP; cycloheximide chase; ubiquitination assay; knockdown/overexpression rescue in prostate cancer cells","pmids":["39113857"],"confidence":"High","gaps":["Specific ubiquitination sites on CHCHD3 not mapped","In vivo tumor suppression by ASB1 not tested","Whether CHCHD3 degradation is relevant outside prostate cancer unknown"]},{"year":null,"claim":"Key unresolved questions include how ASB1 switches between its canonical E3 ligase substrate-degradation mode and its non-canonical TAB2-stabilizing function, whether additional substrates exist, and how ASB1 activity is itself regulated.","evidence":"","pmids":[],"confidence":"Low","gaps":["No structural model of ASB1 itself or ASB1-substrate complexes","Regulatory inputs controlling ASB1 expression or activity (post-translational modification, transcriptional regulation beyond initial cloning data) poorly defined","Mechanism distinguishing degradative vs. stabilizing modes unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3,6,7]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[3,6,7]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[5]}],"localization":[],"pathway":[{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[3,6,7]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[5]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[2,6]}],"complexes":["CRL5 (Cullin5-Rbx2-ElonginB/C-ASB1)"],"partners":["CUL5","RBX2","ELOB","TAB2","SQOR","CHCHD3"],"other_free_text":[]},"mechanistic_narrative":"ASB1 is an ankyrin repeat and SOCS box-containing protein that functions as the substrate-recognition subunit of a Cullin5-Rbx2-Elongin B/C (CRL5) E3 ubiquitin ligase complex, targeting substrates including SQOR and CHCHD3 for K48-linked polyubiquitination and proteasomal degradation [PMID:16325183, PMID:39733518, PMID:39113857]. In the testis, ASB1-mediated degradation of SQOR maintains hydrogen sulfide homeostasis and redox balance during spermiogenesis, and Asb1 knockout mice exhibit diminished spermatogenesis [PMID:11509662, PMID:39733518]. ASB1 also possesses a non-canonical, E3 ligase-independent function in which it binds TAB2 and inhibits its K48-linked ubiquitination, stabilizing TAB2 to promote NF-κB and MAPK inflammatory signaling downstream of cytokine and LPS stimulation [PMID:33431678]. In prostate cancer cells, ASB1-directed ubiquitination and degradation of the mitochondrial protein CHCHD3 suppresses proliferation and migration through modulation of reactive oxygen species [PMID:39113857]."},"prefetch_data":{"uniprot":{"accession":"Q9Y576","full_name":"Ankyrin repeat and SOCS box protein 1","aliases":[],"length_aa":335,"mass_kda":37.0,"function":"Probable substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins (PubMed:16325183). Mediates Notch-induced ubiquitination and degradation of TCF3/E2A and JAK2 (PubMed:21119685). Functions as a tumor suppressor by enhancing CHCHD3 'Lys-48'-linked ubiquitination, leading to inhibition of the CHCHD3/ROS signaling pathway (PubMed:39113857). Suppresses TAB2-linked 'Lys-48' polyubiquitination and consequently facilitates the initiation of NF-kappa-B and MAPK signaling cascades (PubMed:33431678). May play a role in testis development (By similarity)","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9Y576/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ASB1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ASB1","total_profiled":1310},"omim":[{"mim_id":"605758","title":"ANKYRIN REPEAT- AND SOCS BOX-CONTAINING PROTEIN 1; ASB1","url":"https://www.omim.org/entry/605758"},{"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":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ASB1"},"hgnc":{"alias_symbol":["ASB-1"],"prev_symbol":[]},"alphafold":{"accession":"Q9Y576","domains":[{"cath_id":"1.25.40.20","chopping":"37-141","consensus_level":"medium","plddt":90.9433,"start":37,"end":141},{"cath_id":"1.10.750.20","chopping":"298-335","consensus_level":"medium","plddt":93.2855,"start":298,"end":335}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y576","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y576-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y576-F1-predicted_aligned_error_v6.png","plddt_mean":80.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ASB1","jax_strain_url":"https://www.jax.org/strain/search?query=ASB1"},"sequence":{"accession":"Q9Y576","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y576.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y576/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y576"}},"corpus_meta":[{"pmid":"9419338","id":"PMC_9419338","title":"Twenty proteins containing a C-terminal SOCS box form five structural classes.","date":"1998","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/9419338","citation_count":621,"is_preprint":false},{"pmid":"15980261","id":"PMC_15980261","title":"A Link between ethylene and auxin uncovered by the characterization of two root-specific ethylene-insensitive mutants in Arabidopsis.","date":"2005","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/15980261","citation_count":328,"is_preprint":false},{"pmid":"23987513","id":"PMC_23987513","title":"Spatial coordination between stem cell activity and cell differentiation in the root meristem.","date":"2013","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/23987513","citation_count":104,"is_preprint":false},{"pmid":"16325183","id":"PMC_16325183","title":"ASB proteins interact with Cullin5 and Rbx2 to form E3 ubiquitin ligase complexes.","date":"2005","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16325183","citation_count":98,"is_preprint":false},{"pmid":"8400875","id":"PMC_8400875","title":"Suppressors of trp1 fluorescence identify a new arabidopsis gene, TRP4, encoding the anthranilate synthase beta subunit.","date":"1993","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/8400875","citation_count":93,"is_preprint":false},{"pmid":"26588211","id":"PMC_26588211","title":"Conserved piRNA Expression from a Distinct Set of piRNA Cluster Loci in Eutherian Mammals.","date":"2015","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/26588211","citation_count":73,"is_preprint":false},{"pmid":"16308470","id":"PMC_16308470","title":"Identification of differentially expressed genes in metastatic and non-metastatic nasopharyngeal carcinoma cells by suppression subtractive hybridization.","date":"2005","source":"Cellular oncology : the official journal of the International Society for Cellular Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/16308470","citation_count":66,"is_preprint":false},{"pmid":"11509662","id":"PMC_11509662","title":"Functional analysis of Asb-1 using genetic modification in mice.","date":"2001","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11509662","citation_count":54,"is_preprint":false},{"pmid":"28693423","id":"PMC_28693423","title":"Indole-3-butyric acid promotes adventitious rooting in Arabidopsis thaliana thin cell layers by conversion into indole-3-acetic acid and stimulation of anthranilate synthase activity.","date":"2017","source":"BMC plant biology","url":"https://pubmed.ncbi.nlm.nih.gov/28693423","citation_count":50,"is_preprint":false},{"pmid":"11111040","id":"PMC_11111040","title":"Cloning and characterization of the genes encoding the ankyrin repeat and SOCS box-containing proteins Asb-1, Asb-2, Asb-3 and Asb-4.","date":"2000","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/11111040","citation_count":48,"is_preprint":false},{"pmid":"21421932","id":"PMC_21421932","title":"Helicobacter heilmannii sp. nov., isolated from feline gastric mucosa.","date":"2011","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/21421932","citation_count":45,"is_preprint":false},{"pmid":"16188339","id":"PMC_16188339","title":"Expression of the Arabidopsis feedback-insensitive anthranilate synthase holoenzyme and tryptophan decarboxylase genes in Catharanthus roseus hairy roots.","date":"2005","source":"Journal of biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/16188339","citation_count":38,"is_preprint":false},{"pmid":"8620724","id":"PMC_8620724","title":"Clara cell protein (CC-16) and surfactant-associated protein A (SP-A) in asbestos-exposed workers.","date":"1996","source":"Chest","url":"https://pubmed.ncbi.nlm.nih.gov/8620724","citation_count":38,"is_preprint":false},{"pmid":"28540928","id":"PMC_28540928","title":"Anxiety Associated Increased CpG Methylation in the Promoter of Asb1: A Translational Approach Evidenced by Epidemiological and Clinical Studies and a Murine Model.","date":"2017","source":"Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/28540928","citation_count":34,"is_preprint":false},{"pmid":"28028720","id":"PMC_28028720","title":"Liuwei Dihuang Pill () Treats Postmenopausal Osteoporosis with Shen (Kidney) Yin Deficiency via Janus Kinase/Signal Transducer and Activator of Transcription Signal Pathway by Up-regulating Cardiotrophin-Like Cytokine Factor 1 Expression.","date":"2016","source":"Chinese journal of integrative medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28028720","citation_count":33,"is_preprint":false},{"pmid":"23806657","id":"PMC_23806657","title":"Molecular architecture of the ankyrin SOCS box family of Cul5-dependent E3 ubiquitin ligases.","date":"2013","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/23806657","citation_count":30,"is_preprint":false},{"pmid":"36648165","id":"PMC_36648165","title":"Biosynthesis- and transport-mediated dynamic auxin distribution during seed development controls seed size in Arabidopsis.","date":"2023","source":"The Plant journal : for cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/36648165","citation_count":28,"is_preprint":false},{"pmid":"33793921","id":"PMC_33793921","title":"Coordinated cytokinin signaling and auxin biosynthesis mediates arsenate-induced root growth inhibition.","date":"2021","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/33793921","citation_count":25,"is_preprint":false},{"pmid":"33431678","id":"PMC_33431678","title":"An unconventional role of an ASB family protein in NF-κB activation and inflammatory response during microbial infection and colitis.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33431678","citation_count":23,"is_preprint":false},{"pmid":"16465591","id":"PMC_16465591","title":"Two new behavioral QTLs, Emo4 and Reb1, map to mouse Chromosome 1: Congenic strains and candidate gene identification studies.","date":"2006","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/16465591","citation_count":23,"is_preprint":false},{"pmid":"16825652","id":"PMC_16825652","title":"Lactobacillus apodemi sp. nov., a tannase-producing species isolated from wild mouse faeces.","date":"2006","source":"International journal of systematic and evolutionary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/16825652","citation_count":22,"is_preprint":false},{"pmid":"6020287","id":"PMC_6020287","title":"Glutaraldehyde activation of nuclear acid phosphatase in cultured plant cells.","date":"1967","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/6020287","citation_count":19,"is_preprint":false},{"pmid":"39733518","id":"PMC_39733518","title":"ASB1 engages with ELOB to facilitate SQOR ubiquitination and H2S homeostasis during spermiogenesis.","date":"2024","source":"Redox biology","url":"https://pubmed.ncbi.nlm.nih.gov/39733518","citation_count":18,"is_preprint":false},{"pmid":"17223323","id":"PMC_17223323","title":"ASB-1, a germline-specific isoform of mitochondrial ATP synthase b subunit, is required to maintain the rate of germline development in Caenorhabditis elegans.","date":"2006","source":"Mechanisms of development","url":"https://pubmed.ncbi.nlm.nih.gov/17223323","citation_count":17,"is_preprint":false},{"pmid":"29667349","id":"PMC_29667349","title":"ASB1 differential methylation in ischaemic cardiomyopathy: relationship with left ventricular performance in end-stage heart failure patients.","date":"2018","source":"ESC heart failure","url":"https://pubmed.ncbi.nlm.nih.gov/29667349","citation_count":15,"is_preprint":false},{"pmid":"33128317","id":"PMC_33128317","title":"Integrating GWAS and eQTL to predict genes and pathways for non-syndromic cleft lip with or without palate.","date":"2020","source":"Oral diseases","url":"https://pubmed.ncbi.nlm.nih.gov/33128317","citation_count":14,"is_preprint":false},{"pmid":"34568680","id":"PMC_34568680","title":"Comprehensive Analysis of mRNA Expression Profiling and Identification of Potential Diagnostic Biomarkers in Coronary Artery Disease.","date":"2021","source":"ACS omega","url":"https://pubmed.ncbi.nlm.nih.gov/34568680","citation_count":14,"is_preprint":false},{"pmid":"33589721","id":"PMC_33589721","title":"Function of histone H2B monoubiquitination in transcriptional regulation of auxin biosynthesis in Arabidopsis.","date":"2021","source":"Communications biology","url":"https://pubmed.ncbi.nlm.nih.gov/33589721","citation_count":12,"is_preprint":false},{"pmid":"15504594","id":"PMC_15504594","title":"Molecular characterisation and ovine live vaccine 1B evaluation toward a Chlamydophila abortus strain isolated from springbok antelope abortion.","date":"2004","source":"Veterinary microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/15504594","citation_count":10,"is_preprint":false},{"pmid":"2955838","id":"PMC_2955838","title":"Zymograms of Kurloff cell acid phosphatases. Thin layer isoelectric focusing and native polyacrylamide 4-15% gradient gel electrophoresis.","date":"1987","source":"Biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/2955838","citation_count":9,"is_preprint":false},{"pmid":"32397836","id":"PMC_32397836","title":"New aryl Schiff bases of thiadiazole derivative of ibuprofen as DNA binders and potential anticancer drug candidates.","date":"2020","source":"Journal of biomolecular structure & dynamics","url":"https://pubmed.ncbi.nlm.nih.gov/32397836","citation_count":7,"is_preprint":false},{"pmid":"38096826","id":"PMC_38096826","title":"4.5SH RNA counteracts deleterious exonization of SINE B1 in mice.","date":"2023","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/38096826","citation_count":6,"is_preprint":false},{"pmid":"20846475","id":"PMC_20846475","title":"Specific inhibition of protein kinase Cbeta expression by antisense RNA affects the activation of Jurkat T lymphoma cells.","date":"2010","source":"Journal of biological regulators and homeostatic agents","url":"https://pubmed.ncbi.nlm.nih.gov/20846475","citation_count":4,"is_preprint":false},{"pmid":"621376","id":"PMC_621376","title":"The cytochemical demonstration of beta-glucuronidase in colon neoplasms of rats exposed to azoxymethane.","date":"1978","source":"The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society","url":"https://pubmed.ncbi.nlm.nih.gov/621376","citation_count":4,"is_preprint":false},{"pmid":"39113857","id":"PMC_39113857","title":"ASB1 inhibits prostate cancer progression by destabilizing CHCHD3 via K48-linked ubiquitination.","date":"2024","source":"American journal of cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/39113857","citation_count":3,"is_preprint":false},{"pmid":"39895936","id":"PMC_39895936","title":"Characterization of three novel Helicobacter species infecting stomachs of dogs and cats: Helicobacter gastrocanis sp. nov., Helicobacter gastrofelis sp. nov., and Helicobacter felistomachi sp. nov.","date":"2025","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/39895936","citation_count":2,"is_preprint":false},{"pmid":"38132477","id":"PMC_38132477","title":"The Cytotoxicity of Cotyledon orbiculata Aqueous Extract and the Biogenic Silver Nanoparticles Derived from the Extract.","date":"2023","source":"Current issues in molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/38132477","citation_count":2,"is_preprint":false},{"pmid":"36133914","id":"PMC_36133914","title":"Expression and Significance of Cyclin-Dependent Protein Kinase 6 in Diffuse Large B-Cell Lymphoma.","date":"2022","source":"International journal of general medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36133914","citation_count":1,"is_preprint":false},{"pmid":"40465099","id":"PMC_40465099","title":"Identification and validation of a thirteen-gene signature based on ubiquitin related genes in cervical cancer.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40465099","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":21589,"output_tokens":2025,"usd":0.047571},"stage2":{"model":"claude-opus-4-6","input_tokens":5301,"output_tokens":2301,"usd":0.126045},"total_usd":0.173616,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"ASB1 was identified as a member of a new family of proteins containing ankyrin repeats N-terminal of a SOCS box motif, placing it in the SOCS box protein superfamily alongside SOCS, WSB, and SSB families.\",\n      \"method\": \"Database sequence homology search using SOCS box consensus; structural classification\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — foundational classification paper, highly cited, but functional role of ASB1 itself not experimentally defined here\",\n      \"pmids\": [\"9419338\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"ASB1 (Asb-1) was cloned and characterized as an ankyrin repeat and SOCS box-containing protein; the SOCS box was proposed to couple ASB proteins and their binding partners to the elongin B/C complex, potentially targeting them for degradation.\",\n      \"method\": \"Molecular cloning, expression analysis, sequence characterization\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — cloning and expression data with mechanistic inference from SOCS box homology, single lab\",\n      \"pmids\": [\"11111040\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Asb-1 knockout mice develop normally with normal hematopoiesis, but display diminished spermatogenesis with less complete filling of seminiferous tubules, establishing a specific role for Asb-1 in testicular spermatogenesis.\",\n      \"method\": \"Genetic knockout and overexpression mouse models; histological analysis of testes and hematopoietic compartment\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype in vivo, replicated with overexpression controls\",\n      \"pmids\": [\"11509662\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"ASB proteins, including ASB1, interact with Cullin5 (Cul5) and Rbx2 to form E3 ubiquitin ligase complexes; the BC box and Cul5 box sequences within the SOCS box of ASB1 are essential for interaction with Cul5-Rbx2, and the resulting complex has E3 ubiquitin ligase activity.\",\n      \"method\": \"Co-immunoprecipitation in cells; mutational analysis of BC box and Cul5 box; in vitro ubiquitin ligase activity assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal Co-IP, mutagenesis, and in vitro E3 ligase activity assay in a single study\",\n      \"pmids\": [\"16325183\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structures of the related family member ASB9 in ternary complex with Elongin B/C and the N-terminal domain of Cul5 revealed that ASB ankyrin domains are positioned coaxial to the SOCS box-Elongin B/C complex, providing a model for how the ankyrin substrate-binding domain is presented toward the E2-ubiquitin in the complete Cul5-based E3 ligase; this architecture is distinct from other repeat-domain E3 ligases.\",\n      \"method\": \"X-ray crystallography of ASB9-ElonginB/C ternary complex; structural comparison modeling\",\n      \"journal\": \"Journal of molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure of ASB family ternary complex with functional modeling; directly relevant to ASB1 family mechanism\",\n      \"pmids\": [\"23806657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ASB1 positively regulates inflammatory responses by binding TAB2 and inhibiting its K48-linked polyubiquitination, thereby stabilizing TAB2 protein and promoting downstream NF-κB and MAPK signaling upon cytokine and LPS stimulation; this is a non-canonical function distinct from the typical E3 ligase-mediated degradation role of ASB family members.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assays (K48-linkage specific); Asb1 knockout mice challenged with Salmonella typhimurium or LPS; dextran sodium sulfate colitis model; cycloheximide chase; Western blot\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, ubiquitination assays with linkage specificity, multiple in vivo KO models with defined phenotypes\",\n      \"pmids\": [\"33431678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ASB1 acts as the substrate recognition subunit of a CRL5 E3 ubiquitin ligase that interacts with Elongin B (ELOB) and targets sulfide-quinone oxidoreductase (SQOR) for K48-linked ubiquitination at residues K207 and K344, leading to proteasomal degradation of SQOR; this process maintains H2S homeostasis and redox balance during spermiogenesis.\",\n      \"method\": \"Co-immunoprecipitation (ASB1-ELOB interaction); K48-linked ubiquitination assay; site-directed mutagenesis of SQOR ubiquitination sites (K207, K344); Asb1 knockout mouse model; NaHS rescue experiment; oxidative stress and H2S level measurements\",\n      \"journal\": \"Redox biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — Co-IP, in cellulo ubiquitination with mutagenesis of specific sites, KO mouse with rescue, multiple orthogonal methods\",\n      \"pmids\": [\"39733518\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ASB1 interacts with CHCHD3 and promotes its degradation via K48-linked ubiquitination, thereby suppressing prostate cancer cell proliferation, clonogenicity, and migration through the CHCHD3/ROS pathway.\",\n      \"method\": \"Quantitative mass spectrometry interactome analysis; co-immunoprecipitation; cycloheximide chase assay; ubiquitination assay; ASB1 knockdown/overexpression with phenotypic readout; cell rescue experiments\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — MS interactome, Co-IP, ubiquitination assay, and functional rescue with multiple orthogonal methods in single study\",\n      \"pmids\": [\"39113857\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Human/mammalian ASB1 is the substrate-recognition subunit of a Cullin5-Rbx2-ElonginB/C CRL5 E3 ubiquitin ligase complex, where its ankyrin repeats recruit substrates (including SQOR and CHCHD3) for K48-linked ubiquitination and proteasomal degradation; however, ASB1 also has a non-canonical function in which it stabilizes TAB2 by inhibiting its K48-linked ubiquitination, thereby promoting NF-κB and MAPK inflammatory signaling, and in the testis it is specifically required for spermatogenesis and H2S homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ASB1 is an ankyrin repeat and SOCS box-containing protein that functions as the substrate-recognition subunit of a Cullin5-Rbx2-Elongin B/C (CRL5) E3 ubiquitin ligase complex, targeting substrates including SQOR and CHCHD3 for K48-linked polyubiquitination and proteasomal degradation [PMID:16325183, PMID:39733518, PMID:39113857]. In the testis, ASB1-mediated degradation of SQOR maintains hydrogen sulfide homeostasis and redox balance during spermiogenesis, and Asb1 knockout mice exhibit diminished spermatogenesis [PMID:11509662, PMID:39733518]. ASB1 also possesses a non-canonical, E3 ligase-independent function in which it binds TAB2 and inhibits its K48-linked ubiquitination, stabilizing TAB2 to promote NF-κB and MAPK inflammatory signaling downstream of cytokine and LPS stimulation [PMID:33431678]. In prostate cancer cells, ASB1-directed ubiquitination and degradation of the mitochondrial protein CHCHD3 suppresses proliferation and migration through modulation of reactive oxygen species [PMID:39113857].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"ASB1 was classified within a new protein family defined by ankyrin repeats and a C-terminal SOCS box, establishing it as part of the SOCS box superfamily and predicting a role in protein-protein interaction and possible Elongin-mediated degradation pathways.\",\n      \"evidence\": \"Database homology search and structural domain classification\",\n      \"pmids\": [\"9419338\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No direct biochemical activity demonstrated for ASB1\", \"Substrates unknown\", \"Expression pattern only partially characterized\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Molecular cloning of ASB1 confirmed its domain architecture and suggested its SOCS box couples binding partners to Elongin B/C for potential degradation, providing a mechanistic framework before direct biochemical evidence existed.\",\n      \"evidence\": \"Molecular cloning, expression analysis, and sequence characterization\",\n      \"pmids\": [\"11111040\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Elongin B/C interaction not directly demonstrated for ASB1\", \"No functional assay performed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Genetic loss-of-function established that ASB1 is dispensable for hematopoiesis and general development but specifically required for normal spermatogenesis, identifying its principal physiological context.\",\n      \"evidence\": \"Asb1 knockout and overexpression mouse models with histological analysis of testes and hematopoietic compartments\",\n      \"pmids\": [\"11509662\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular substrate(s) in the testis not identified\", \"Mechanism linking ASB1 to spermatogenic defect unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Biochemical demonstration that ASB1 assembles with Cullin5 and Rbx2 via its BC box and Cul5 box to form a functional E3 ubiquitin ligase complex resolved the catalytic mechanism predicted by domain homology.\",\n      \"evidence\": \"Co-immunoprecipitation, BC box and Cul5 box mutagenesis, and in vitro ubiquitin ligase activity assay\",\n      \"pmids\": [\"16325183\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No physiological substrate identified for the ASB1-CRL5 complex\", \"Ubiquitin chain linkage type not determined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Structural determination of the homologous ASB9-Elongin B/C-Cul5 ternary complex revealed the architecture by which ASB ankyrin repeat domains present substrates toward the E2-ubiquitin active site, providing a generalizable structural model for ASB1.\",\n      \"evidence\": \"X-ray crystallography of ASB9-ElonginB/C complex with structural modeling\",\n      \"pmids\": [\"23806657\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No ASB1-specific structure solved\", \"Substrate docking geometry for ASB1 ankyrin repeats not determined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Discovery that ASB1 stabilizes TAB2 by inhibiting its K48-linked ubiquitination — rather than promoting degradation — revealed a non-canonical anti-degradative function that activates NF-κB and MAPK inflammatory signaling in vivo.\",\n      \"evidence\": \"Reciprocal Co-IP; K48-linkage-specific ubiquitination assays; Asb1 KO mice challenged with Salmonella typhimurium, LPS, and DSS colitis model; cycloheximide chase\",\n      \"pmids\": [\"33431678\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which ASB1 blocks TAB2 ubiquitination (competitive, allosteric, or E3 ligase recruitment inhibition) not defined\", \"Identity of the E3 ligase that ubiquitinates TAB2 in the absence of ASB1 unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of SQOR as a direct ASB1-CRL5 substrate ubiquitinated at K207 and K344 linked the spermatogenesis defect of Asb1 KO mice to accumulation of SQOR, disrupted H₂S homeostasis, and oxidative stress during spermiogenesis.\",\n      \"evidence\": \"Co-IP of ASB1-ELOB; K48-linked ubiquitination assay with K207/K344 mutagenesis; Asb1 KO mouse with NaHS rescue; H₂S and oxidative stress measurements\",\n      \"pmids\": [\"39733518\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SQOR is the sole spermatogenesis-relevant substrate is unknown\", \"Contribution of Cul5/Rbx2 vs. other E3 components not re-examined in testis\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identification of CHCHD3 as a second direct ASB1 substrate extended the CRL5-dependent degradation mechanism to a mitochondrial target whose accumulation drives ROS-dependent prostate cancer cell proliferation.\",\n      \"evidence\": \"Quantitative MS interactome; Co-IP; cycloheximide chase; ubiquitination assay; knockdown/overexpression rescue in prostate cancer cells\",\n      \"pmids\": [\"39113857\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific ubiquitination sites on CHCHD3 not mapped\", \"In vivo tumor suppression by ASB1 not tested\", \"Whether CHCHD3 degradation is relevant outside prostate cancer unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how ASB1 switches between its canonical E3 ligase substrate-degradation mode and its non-canonical TAB2-stabilizing function, whether additional substrates exist, and how ASB1 activity is itself regulated.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of ASB1 itself or ASB1-substrate complexes\", \"Regulatory inputs controlling ASB1 expression or activity (post-translational modification, transcriptional regulation beyond initial cloning data) poorly defined\", \"Mechanism distinguishing degradative vs. stabilizing modes unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [3, 6, 7]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"complexes\": [\n      \"CRL5 (Cullin5-Rbx2-ElonginB/C-ASB1)\"\n    ],\n    \"partners\": [\n      \"CUL5\",\n      \"RBX2\",\n      \"ELOB\",\n      \"TAB2\",\n      \"SQOR\",\n      \"CHCHD3\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}