{"gene":"ATXN1L","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2007,"finding":"ATXN1L (BOAT1) competes with polyglutamine-expanded ATXN1 for incorporation into the native ATXN1-Capicua (CIC) complex; elevated ATXN1L levels suppress SCA1 neuropathology by displacing mutant ATXN1 from this complex.","method":"Targeted duplication of mouse Atxn1l locus; knock-in SCA1 mouse model; genetic epistasis demonstrating suppression of neuropathology by Atxn1l overexpression","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis in knock-in mouse model with clear phenotypic rescue, multiple assays demonstrating complex displacement, replicated in subsequent studies","pmids":["17322884"],"is_preprint":false},{"year":2011,"finding":"ATXN1L forms a complex with the transcriptional repressor CIC; loss of ATXN1L destabilizes CIC protein, leading to derepression of ETV4 and subsequent upregulation of MMP genes (including MMP9), mediating extracellular matrix remodeling during lung alveolarization.","method":"Atxn1L knockout and Atxn1/Atxn1L double-knockout mouse generation; gene expression analysis showing Mmp overexpression; CIC protein stability assays; genetic epistasis with Cic-deficient mice","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse models, genetic epistasis, protein stability assays, replicated across multiple subsequent studies","pmids":["22014525"],"is_preprint":false},{"year":2011,"finding":"ATXN1L (BOAT1) and ATXN1 are components of the Notch signalling pathway; both proteins bind to the Hey1 promoter and inhibit Notch transcriptional output through direct interactions with CBF1 (a key Notch pathway transcription factor). In Drosophila, BOAT1 compromises Notch activity.","method":"Drosophila genetic analysis; mammalian cell-based promoter binding assays; direct protein interaction assays with CBF1; analysis of Hey1 transcriptional output","journal":"EMBO reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding and protein interaction assays in mammalian cells plus Drosophila genetic data, single lab","pmids":["21475249"],"is_preprint":false},{"year":2017,"finding":"ATXN1L deletion reduces CIC protein levels and modulates sensitivity to MEK inhibitor trametinib; the ATXN1L-CIC-ETS transcription factor axis mediates resistance to MAPK pathway inhibition, with ectopic ETV1, ETV4, or ETV5 expression phenocopying ATXN1L loss.","method":"Genome-scale CRISPR-Cas9 loss-of-function screens in KRAS-mutant pancreatic cancer cell lines; ectopic expression of ETS factors; ATXN1L deletion with MAPKi sensitivity assays","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR screens with functional follow-up, epistasis through ETS overexpression, multiple cell lines, corroborated by clinical data","pmids":["28178529"],"is_preprint":false},{"year":2018,"finding":"ATXN1L and CIC have a reciprocal functional relationship: ATXN1LKO and CICKO human cell lines show convergent transcriptomic changes related to mitotic cell cycle and division, indicating the CIC-ATXN1-ATXN1L axis regulates cell cycle progression.","method":"ATXN1LKO and CICKO human cell line generation; transcriptomic analysis; functional in vitro studies","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout cell lines with transcriptomic readout, single lab, two orthogonal approaches (KO + transcriptomics)","pmids":["30093628"],"is_preprint":false},{"year":2020,"finding":"ATXN1L promotes post-translational stability of CIC by preventing its polyubiquitination and proteasomal degradation; loss of ATXN1L leads to accumulation of polyubiquitinated CIC and its degradation via the proteasome, mediated by the E3 ubiquitin ligase TRIM25, independently of ERK activity.","method":"ATXN1LKO human cell lines; ubiquitination assays detecting polyubiquitinated CIC; proteasome inhibition experiments; TRIM25 functional assays; validation in glioma cell lines","journal":"BMC biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO cell lines, ubiquitination assays, identification of E3 ligase TRIM25, validated in multiple cell line models, multiple orthogonal methods","pmids":["33115448"],"is_preprint":false},{"year":2013,"finding":"ATXN1L (Atxn1L) is a regulator of hematopoietic stem cell (HSC) quiescence; mice lacking Atxn1L have greater numbers of HSCs with elevated proliferation, indicating Atxn1L maintains HSC quiescence.","method":"Atxn1L knockout mice; in vitro and in vivo HSC assays; molecular gene expression analyses of null HSCs","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse model with in vivo and in vitro functional assays, single lab, defined cellular phenotype","pmids":["23555280"],"is_preprint":false},{"year":2022,"finding":"ATXN1L binds to CIC and suppresses PYDC1 expression; miR-136-5p targets ATXN1L mRNA, and overexpression of miR-136-5p suppresses pyroptosis by inhibiting ATXN1L-CIC binding and thereby promoting PYDC1 expression in cardiomyocytes.","method":"Dual-luciferase reporter assay confirming miR-136-5p targeting of ATXN1L; co-immunoprecipitation of ATXN1L and CIC; cell transfection and pyroptosis assays in cardiomyocytes","journal":"Apoptosis","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — co-IP plus luciferase reporter, functional pyroptosis assay, single lab, context is cardiomyocyte injury model","pmids":["35084609"],"is_preprint":false},{"year":2022,"finding":"ATXN1L promotes deacetylation of histone H3 through HDAC3, thereby inhibiting NOL3 promoter activity and expression; ChIP confirmed ATXN1L and HDAC3 binding to the NOL3 promoter, promoting cardiomyocyte apoptosis and pyroptosis.","method":"ChIP assay for ATXN1L and HDAC3 binding to NOL3 promoter; HDAC3 inhibition experiments; ATXN1L knockout adenoviral vectors in rats; immunofluorescence for HDAC3 localization","journal":"Journal of molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP assay plus functional rescue experiments, in vivo and in vitro validation, single lab","pmids":["35414011"],"is_preprint":false},{"year":2024,"finding":"ATXN1L, as part of the CIC-ATXN1L complex, is required for marginal zone B (MZB) cell development; ATXN1L deficiency specifically disrupts Notch signaling in MZB cells through ETV4 de-repression, which inhibits Notch1 and Notch2 transcription; this pathway also controls humoral immune responses and LPS-induced sepsis progression.","method":"B cell-specific Atxn1l conditional knockout mice (Atxn1lf/f;Cd19-Cre); Notch signaling analysis; Etv4 deletion epistasis rescue experiments; LPS-induced sepsis model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout mice with epistasis (Etv4 deletion rescue), multiple phenotypic readouts, defined molecular mechanism via Notch pathway","pmids":["39632849"],"is_preprint":false},{"year":2025,"finding":"The CIC-ATXN1L complex binds to an 8-nucleotide motif near IFN and ISG promoters and represses their expression under homeostatic conditions; during respiratory viral infection, MAPK pathway activation leads to rapid degradation of the CIC-ATXN1L complex, relieving repression and enabling robust IFN and ISG induction.","method":"DNA-binding assays identifying 8-nt promoter motif; CIC-ATXN1L complex degradation assays during viral infection; MAPK pathway activation experiments; loss-of-function studies in human and mouse cells","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — promoter binding identification, complex degradation mechanistic assays, functional IFN/ISG induction assays, validated in both human and mouse systems","pmids":["40132591"],"is_preprint":false},{"year":2025,"finding":"CIC-S isoform preferentially interacts with ATXN1L, while CIC-L isoform preferentially interacts with ATXN1; loss of CIC-S causes perinatal lethality phenocopying ATXN1L knockout, whereas loss of CIC-L causes cognitive deficits phenocopying ATXN1 knockout, demonstrating isoform-specific paralog interactions.","method":"Generation of CIC isoform-specific knockout mice (CIC-L or CIC-S only); behavioral and phenotypic characterization; co-immunoprecipitation to determine isoform-paralog binding preferences","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific knockout mice plus Co-IP for binding preference, preprint not yet peer-reviewed","pmids":["41279815"],"is_preprint":true}],"current_model":"ATXN1L (BOAT1) functions primarily as a stabilizer of the transcriptional repressor CIC: it forms a complex with CIC to repress ETS transcription factors (ETV1/4/5), Notch target genes, and IFN/ISG promoters, prevents CIC polyubiquitination and TRIM25-mediated proteasomal degradation, competes with ATXN1 for CIC binding (with CIC-S isoform preferentially binding ATXN1L), and thereby regulates developmental processes (lung alveolarization, MZB cell development, HSC quiescence), cancer cell sensitivity to MAPK inhibitors, and antiviral interferon responses."},"narrative":{"mechanistic_narrative":"ATXN1L (BOAT1) functions as a stabilizing partner of the transcriptional repressor CIC, and through this complex governs developmental, immune, and oncogenic gene-expression programs [PMID:22014525, PMID:33115448]. It binds CIC and prevents its polyubiquitination and TRIM25-mediated proteasomal degradation independently of ERK activity, so loss of ATXN1L destabilizes CIC and derepresses CIC target genes including the ETS factors ETV1/4/5 [PMID:33115448, PMID:28178529]. ETV4 derepression in turn drives downstream programs: MMP gene induction and extracellular matrix remodeling during lung alveolarization [PMID:22014525], and suppression of Notch1/Notch2 transcription that disrupts marginal zone B cell development and humoral immunity [PMID:39632849]. The CIC-ATXN1L complex also binds an 8-nucleotide motif near interferon and ISG promoters to repress them under homeostasis, with MAPK-driven complex degradation during respiratory viral infection relieving this repression to permit robust IFN/ISG induction [PMID:40132591]. ATXN1L competes with its paralog ATXN1 for incorporation into the CIC complex, and CIC isoforms partition between them, the CIC-S isoform preferentially binding ATXN1L; elevated ATXN1L displaces polyglutamine-expanded ATXN1 and suppresses SCA1 neuropathology [PMID:17322884, PMID:41279815]. Through the CIC-ETS axis, ATXN1L also modulates cancer-cell sensitivity to MAPK pathway inhibitors [PMID:28178529] and maintains hematopoietic stem cell quiescence [PMID:23555280].","teleology":[{"year":2007,"claim":"Established that ATXN1L is a native component of the ATXN1-CIC complex and that it competes with ATXN1, reframing it from a paralog of unknown role into a dose-dependent modifier of an established complex.","evidence":"Targeted Atxn1l duplication and genetic epistasis in a knock-in SCA1 mouse model","pmids":["17322884"],"confidence":"High","gaps":["Did not define the biochemical determinants of competition with ATXN1","Did not establish CIC target genes regulated by ATXN1L"]},{"year":2011,"claim":"Defined ATXN1L's core mechanism as a CIC stabilizer whose loss derepresses ETV4 and downstream MMPs, linking the complex to a concrete developmental output (lung alveolarization).","evidence":"Atxn1l and Atxn1/Atxn1l double-knockout mice, CIC protein stability assays, and genetic epistasis with Cic-deficient mice","pmids":["22014525"],"confidence":"High","gaps":["Mechanism of CIC destabilization not yet identified","E3 ligase mediating CIC turnover unknown"]},{"year":2011,"claim":"Tested whether ATXN1L acts beyond CIC by probing Notch output, showing ATXN1L and ATXN1 bind the Hey1 promoter and interact with CBF1 to inhibit Notch transcription.","evidence":"Drosophila genetics plus mammalian promoter-binding and CBF1 interaction assays","pmids":["21475249"],"confidence":"Medium","gaps":["Single-lab data","Relationship between CBF1-dependent Notch repression and the CIC-dependent mechanism not reconciled"]},{"year":2013,"claim":"Extended ATXN1L function to adult stem cell biology, showing it maintains hematopoietic stem cell quiescence.","evidence":"Atxn1l knockout mice with in vitro and in vivo HSC assays and expression profiling","pmids":["23555280"],"confidence":"Medium","gaps":["Did not establish whether the quiescence phenotype is CIC-dependent","Downstream transcriptional effectors not defined"]},{"year":2017,"claim":"Connected the ATXN1L-CIC-ETS axis to therapy response, showing ATXN1L loss reduces CIC and modulates MEK inhibitor sensitivity, with ETS overexpression phenocopying the loss.","evidence":"Genome-scale CRISPR screens in KRAS-mutant pancreatic cancer lines plus ectopic ETS factor expression and MAPKi sensitivity assays","pmids":["28178529"],"confidence":"High","gaps":["Did not resolve the molecular step linking ATXN1L to CIC stability","Clinical generalizability across tumor types not established"]},{"year":2018,"claim":"Demonstrated convergent CIC and ATXN1L function at the transcriptome level, implicating the axis in mitotic cell cycle and division control.","evidence":"ATXN1LKO and CICKO human cell lines with transcriptomic profiling","pmids":["30093628"],"confidence":"Medium","gaps":["Correlative transcriptomics without direct cell-cycle mechanistic dissection","Single lab"]},{"year":2020,"claim":"Resolved the biochemical mechanism of CIC stabilization, identifying TRIM25 as the E3 ligase whose ATXN1L-blocked polyubiquitination targets CIC for proteasomal degradation, independent of ERK.","evidence":"ATXN1LKO cell lines, polyubiquitination and proteasome-inhibition assays, TRIM25 functional assays, validated in glioma lines","pmids":["33115448"],"confidence":"High","gaps":["How ATXN1L binding sterically or allosterically blocks TRIM25 not defined","Whether other ligases contribute under ERK-active conditions unknown"]},{"year":2022,"claim":"Implicated ATXN1L in cardiomyocyte cell death regulation, both via CIC-dependent suppression of PYDC1 (controlled by miR-136-5p) and via HDAC3-mediated histone deacetylation repressing NOL3.","evidence":"Luciferase reporter and co-IP for the miR-136-5p/ATXN1L/CIC axis, plus ChIP and HDAC3 inhibition for the NOL3 mechanism in cardiomyocytes and rats","pmids":["35084609","35414011"],"confidence":"Medium","gaps":["Co-IP without reciprocal validation for the ATXN1L-CIC pyroptosis link","Whether HDAC3 recruitment is CIC-dependent not established","Single disease-model context"]},{"year":2024,"claim":"Showed the CIC-ATXN1L complex is required for marginal zone B cell development and humoral immunity, with ETV4 derepression repressing Notch1/Notch2 as the operative mechanism.","evidence":"B cell-specific conditional Atxn1l knockout mice with Etv4 deletion epistasis rescue and an LPS sepsis model","pmids":["39632849"],"confidence":"High","gaps":["How ETV4 represses Notch receptor transcription mechanistically not detailed","Generalizability to other B cell subsets unclear"]},{"year":2025,"claim":"Defined an antiviral function: the CIC-ATXN1L complex represses IFN/ISG promoters via an 8-nt motif at homeostasis, and MAPK-triggered complex degradation during viral infection unleashes interferon responses.","evidence":"DNA-binding motif identification, complex degradation assays during infection, and loss-of-function studies in human and mouse cells","pmids":["40132591"],"confidence":"High","gaps":["Whether TRIM25 mediates the infection-triggered complex degradation not established","Kinetics relative to other IFN-regulatory layers unresolved"]},{"year":2025,"claim":"Resolved paralog/isoform specificity, showing CIC-S preferentially binds ATXN1L and CIC-L binds ATXN1, with isoform-specific knockouts phenocopying the respective paralog knockouts.","evidence":"CIC isoform-specific knockout mice and co-immunoprecipitation binding-preference assays (preprint)","pmids":["41279815"],"confidence":"Medium","gaps":["Preprint not yet peer-reviewed","Structural basis of isoform-paralog selectivity not defined"]},{"year":null,"claim":"How ATXN1L binding mechanistically blocks TRIM25-mediated CIC ubiquitination, and how this is reversed during MAPK-driven signaling, remains undefined at the structural level.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the ATXN1L-CIC interface","Signal that triggers complex degradation during infection vs homeostasis not biochemically mapped"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,9,10]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[5]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[2,8,10]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1,10]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,5,9,10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9,10]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,3,9]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[5]}],"complexes":["CIC-ATXN1L complex"],"partners":["CIC","ATXN1","TRIM25","CBF1","HDAC3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P0C7T5","full_name":"Ataxin-1-like","aliases":["Brother of ataxin-1","Brother of ATXN1"],"length_aa":689,"mass_kda":73.3,"function":"Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor. Binds to the HEY promoter and might assist, along with NCOR2, RBPJ-mediated repression (PubMed:21475249). Can suppress ATXN1 cytotoxicity in spinocerebellar ataxia type 1 (SCA1). In concert with CIC and ATXN1, involved in brain development (By similarity)","subcellular_location":"Nucleus; Cell projection, dendrite","url":"https://www.uniprot.org/uniprotkb/P0C7T5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATXN1L","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATXN1L","total_profiled":1310},"omim":[{"mim_id":"614301","title":"ATAXIN 1-LIKE; ATXN1L","url":"https://www.omim.org/entry/614301"},{"mim_id":"612082","title":"CAPICUA TRANSCRIPTIONAL REPRESSOR; CIC","url":"https://www.omim.org/entry/612082"},{"mim_id":"601556","title":"ATAXIN 1; ATXN1","url":"https://www.omim.org/entry/601556"},{"mim_id":"147183","title":"RECOMBINATION SIGNAL-BINDING PROTEIN FOR IMMUNOGLOBULIN KAPPA J REGION; RBPJ","url":"https://www.omim.org/entry/147183"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/ATXN1L"},"hgnc":{"alias_symbol":["BOAT1"],"prev_symbol":[]},"alphafold":{"accession":"P0C7T5","domains":[{"cath_id":"-","chopping":"468-583","consensus_level":"medium","plddt":94.054,"start":468,"end":583}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P0C7T5","model_url":"https://alphafold.ebi.ac.uk/files/AF-P0C7T5-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P0C7T5-F1-predicted_aligned_error_v6.png","plddt_mean":50.47},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATXN1L","jax_strain_url":"https://www.jax.org/strain/search?query=ATXN1L"},"sequence":{"accession":"P0C7T5","fasta_url":"https://rest.uniprot.org/uniprotkb/P0C7T5.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P0C7T5/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P0C7T5"}},"corpus_meta":[{"pmid":"28178529","id":"PMC_28178529","title":"ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition.","date":"2017","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/28178529","citation_count":98,"is_preprint":false},{"pmid":"22014525","id":"PMC_22014525","title":"ATXN1 protein family and CIC regulate extracellular matrix remodeling and lung alveolarization.","date":"2011","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/22014525","citation_count":90,"is_preprint":false},{"pmid":"17322884","id":"PMC_17322884","title":"Duplication of Atxn1l suppresses SCA1 neuropathology by decreasing incorporation of polyglutamine-expanded ataxin-1 into native complexes.","date":"2007","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/17322884","citation_count":67,"is_preprint":false},{"pmid":"21475249","id":"PMC_21475249","title":"Ataxin-1 and Brother of ataxin-1 are components of the Notch signalling pathway.","date":"2011","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/21475249","citation_count":65,"is_preprint":false},{"pmid":"33782651","id":"PMC_33782651","title":"Perspectives on plant flavonoid quercetin-based drugs for novel SARS-CoV-2.","date":"2021","source":"Beni-Suef University journal of basic and applied sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33782651","citation_count":38,"is_preprint":false},{"pmid":"30093628","id":"PMC_30093628","title":"Transcriptomic analysis of CIC and ATXN1L reveal a functional relationship exploited by cancer.","date":"2018","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/30093628","citation_count":30,"is_preprint":false},{"pmid":"32073140","id":"PMC_32073140","title":"Making heads or tails - the emergence of capicua (CIC) as an important multifunctional tumour suppressor.","date":"2020","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32073140","citation_count":23,"is_preprint":false},{"pmid":"19085187","id":"PMC_19085187","title":"Characterization of the zebrafish atxn1/axh gene family.","date":"2008","source":"Journal of neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/19085187","citation_count":17,"is_preprint":false},{"pmid":"26639094","id":"PMC_26639094","title":"The Relevance of JAK2 in the Regulation of Cellular Transport.","date":"2016","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26639094","citation_count":16,"is_preprint":false},{"pmid":"34498878","id":"PMC_34498878","title":"New Two-Dimensional Wide Band Gap Hydrocarbon Insulator by Hydrogenation of a Biphenylene Sheet.","date":"2021","source":"The journal of physical chemistry letters","url":"https://pubmed.ncbi.nlm.nih.gov/34498878","citation_count":16,"is_preprint":false},{"pmid":"35084609","id":"PMC_35084609","title":"MicroRNA-136-5p protects cardiomyocytes from coronary microembolization through the inhibition of pyroptosis.","date":"2022","source":"Apoptosis : an international journal on programmed cell death","url":"https://pubmed.ncbi.nlm.nih.gov/35084609","citation_count":15,"is_preprint":false},{"pmid":"35573049","id":"PMC_35573049","title":"Combined overexpression of ATXN1L and mutant ATXN1 knockdown by AAV rescue motor phenotypes and gene signatures in SCA1 mice.","date":"2022","source":"Molecular therapy. 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elevated ATXN1L levels suppress SCA1 neuropathology by displacing mutant ATXN1 from this complex.\",\n      \"method\": \"Targeted duplication of mouse Atxn1l locus; knock-in SCA1 mouse model; genetic epistasis demonstrating suppression of neuropathology by Atxn1l overexpression\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis in knock-in mouse model with clear phenotypic rescue, multiple assays demonstrating complex displacement, replicated in subsequent studies\",\n      \"pmids\": [\"17322884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ATXN1L forms a complex with the transcriptional repressor CIC; loss of ATXN1L destabilizes CIC protein, leading to derepression of ETV4 and subsequent upregulation of MMP genes (including MMP9), mediating extracellular matrix remodeling during lung alveolarization.\",\n      \"method\": \"Atxn1L knockout and Atxn1/Atxn1L double-knockout mouse generation; gene expression analysis showing Mmp overexpression; CIC protein stability assays; genetic epistasis with Cic-deficient mice\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse models, genetic epistasis, protein stability assays, replicated across multiple subsequent studies\",\n      \"pmids\": [\"22014525\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"ATXN1L (BOAT1) and ATXN1 are components of the Notch signalling pathway; both proteins bind to the Hey1 promoter and inhibit Notch transcriptional output through direct interactions with CBF1 (a key Notch pathway transcription factor). In Drosophila, BOAT1 compromises Notch activity.\",\n      \"method\": \"Drosophila genetic analysis; mammalian cell-based promoter binding assays; direct protein interaction assays with CBF1; analysis of Hey1 transcriptional output\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding and protein interaction assays in mammalian cells plus Drosophila genetic data, single lab\",\n      \"pmids\": [\"21475249\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATXN1L deletion reduces CIC protein levels and modulates sensitivity to MEK inhibitor trametinib; the ATXN1L-CIC-ETS transcription factor axis mediates resistance to MAPK pathway inhibition, with ectopic ETV1, ETV4, or ETV5 expression phenocopying ATXN1L loss.\",\n      \"method\": \"Genome-scale CRISPR-Cas9 loss-of-function screens in KRAS-mutant pancreatic cancer cell lines; ectopic expression of ETS factors; ATXN1L deletion with MAPKi sensitivity assays\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR screens with functional follow-up, epistasis through ETS overexpression, multiple cell lines, corroborated by clinical data\",\n      \"pmids\": [\"28178529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATXN1L and CIC have a reciprocal functional relationship: ATXN1LKO and CICKO human cell lines show convergent transcriptomic changes related to mitotic cell cycle and division, indicating the CIC-ATXN1-ATXN1L axis regulates cell cycle progression.\",\n      \"method\": \"ATXN1LKO and CICKO human cell line generation; transcriptomic analysis; functional in vitro studies\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout cell lines with transcriptomic readout, single lab, two orthogonal approaches (KO + transcriptomics)\",\n      \"pmids\": [\"30093628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"ATXN1L promotes post-translational stability of CIC by preventing its polyubiquitination and proteasomal degradation; loss of ATXN1L leads to accumulation of polyubiquitinated CIC and its degradation via the proteasome, mediated by the E3 ubiquitin ligase TRIM25, independently of ERK activity.\",\n      \"method\": \"ATXN1LKO human cell lines; ubiquitination assays detecting polyubiquitinated CIC; proteasome inhibition experiments; TRIM25 functional assays; validation in glioma cell lines\",\n      \"journal\": \"BMC biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO cell lines, ubiquitination assays, identification of E3 ligase TRIM25, validated in multiple cell line models, multiple orthogonal methods\",\n      \"pmids\": [\"33115448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ATXN1L (Atxn1L) is a regulator of hematopoietic stem cell (HSC) quiescence; mice lacking Atxn1L have greater numbers of HSCs with elevated proliferation, indicating Atxn1L maintains HSC quiescence.\",\n      \"method\": \"Atxn1L knockout mice; in vitro and in vivo HSC assays; molecular gene expression analyses of null HSCs\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse model with in vivo and in vitro functional assays, single lab, defined cellular phenotype\",\n      \"pmids\": [\"23555280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATXN1L binds to CIC and suppresses PYDC1 expression; miR-136-5p targets ATXN1L mRNA, and overexpression of miR-136-5p suppresses pyroptosis by inhibiting ATXN1L-CIC binding and thereby promoting PYDC1 expression in cardiomyocytes.\",\n      \"method\": \"Dual-luciferase reporter assay confirming miR-136-5p targeting of ATXN1L; co-immunoprecipitation of ATXN1L and CIC; cell transfection and pyroptosis assays in cardiomyocytes\",\n      \"journal\": \"Apoptosis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — co-IP plus luciferase reporter, functional pyroptosis assay, single lab, context is cardiomyocyte injury model\",\n      \"pmids\": [\"35084609\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ATXN1L promotes deacetylation of histone H3 through HDAC3, thereby inhibiting NOL3 promoter activity and expression; ChIP confirmed ATXN1L and HDAC3 binding to the NOL3 promoter, promoting cardiomyocyte apoptosis and pyroptosis.\",\n      \"method\": \"ChIP assay for ATXN1L and HDAC3 binding to NOL3 promoter; HDAC3 inhibition experiments; ATXN1L knockout adenoviral vectors in rats; immunofluorescence for HDAC3 localization\",\n      \"journal\": \"Journal of molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP assay plus functional rescue experiments, in vivo and in vitro validation, single lab\",\n      \"pmids\": [\"35414011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATXN1L, as part of the CIC-ATXN1L complex, is required for marginal zone B (MZB) cell development; ATXN1L deficiency specifically disrupts Notch signaling in MZB cells through ETV4 de-repression, which inhibits Notch1 and Notch2 transcription; this pathway also controls humoral immune responses and LPS-induced sepsis progression.\",\n      \"method\": \"B cell-specific Atxn1l conditional knockout mice (Atxn1lf/f;Cd19-Cre); Notch signaling analysis; Etv4 deletion epistasis rescue experiments; LPS-induced sepsis model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout mice with epistasis (Etv4 deletion rescue), multiple phenotypic readouts, defined molecular mechanism via Notch pathway\",\n      \"pmids\": [\"39632849\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The CIC-ATXN1L complex binds to an 8-nucleotide motif near IFN and ISG promoters and represses their expression under homeostatic conditions; during respiratory viral infection, MAPK pathway activation leads to rapid degradation of the CIC-ATXN1L complex, relieving repression and enabling robust IFN and ISG induction.\",\n      \"method\": \"DNA-binding assays identifying 8-nt promoter motif; CIC-ATXN1L complex degradation assays during viral infection; MAPK pathway activation experiments; loss-of-function studies in human and mouse cells\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — promoter binding identification, complex degradation mechanistic assays, functional IFN/ISG induction assays, validated in both human and mouse systems\",\n      \"pmids\": [\"40132591\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CIC-S isoform preferentially interacts with ATXN1L, while CIC-L isoform preferentially interacts with ATXN1; loss of CIC-S causes perinatal lethality phenocopying ATXN1L knockout, whereas loss of CIC-L causes cognitive deficits phenocopying ATXN1 knockout, demonstrating isoform-specific paralog interactions.\",\n      \"method\": \"Generation of CIC isoform-specific knockout mice (CIC-L or CIC-S only); behavioral and phenotypic characterization; co-immunoprecipitation to determine isoform-paralog binding preferences\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific knockout mice plus Co-IP for binding preference, preprint not yet peer-reviewed\",\n      \"pmids\": [\"41279815\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"ATXN1L (BOAT1) functions primarily as a stabilizer of the transcriptional repressor CIC: it forms a complex with CIC to repress ETS transcription factors (ETV1/4/5), Notch target genes, and IFN/ISG promoters, prevents CIC polyubiquitination and TRIM25-mediated proteasomal degradation, competes with ATXN1 for CIC binding (with CIC-S isoform preferentially binding ATXN1L), and thereby regulates developmental processes (lung alveolarization, MZB cell development, HSC quiescence), cancer cell sensitivity to MAPK inhibitors, and antiviral interferon responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATXN1L (BOAT1) functions as a stabilizing partner of the transcriptional repressor CIC, and through this complex governs developmental, immune, and oncogenic gene-expression programs [#1, #5]. It binds CIC and prevents its polyubiquitination and TRIM25-mediated proteasomal degradation independently of ERK activity, so loss of ATXN1L destabilizes CIC and derepresses CIC target genes including the ETS factors ETV1/4/5 [#5, #3]. ETV4 derepression in turn drives downstream programs: MMP gene induction and extracellular matrix remodeling during lung alveolarization [#1], and suppression of Notch1/Notch2 transcription that disrupts marginal zone B cell development and humoral immunity [#9]. The CIC-ATXN1L complex also binds an 8-nucleotide motif near interferon and ISG promoters to repress them under homeostasis, with MAPK-driven complex degradation during respiratory viral infection relieving this repression to permit robust IFN/ISG induction [#10]. ATXN1L competes with its paralog ATXN1 for incorporation into the CIC complex, and CIC isoforms partition between them, the CIC-S isoform preferentially binding ATXN1L; elevated ATXN1L displaces polyglutamine-expanded ATXN1 and suppresses SCA1 neuropathology [#0, #11]. Through the CIC-ETS axis, ATXN1L also modulates cancer-cell sensitivity to MAPK pathway inhibitors [#3] and maintains hematopoietic stem cell quiescence [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that ATXN1L is a native component of the ATXN1-CIC complex and that it competes with ATXN1, reframing it from a paralog of unknown role into a dose-dependent modifier of an established complex.\",\n      \"evidence\": \"Targeted Atxn1l duplication and genetic epistasis in a knock-in SCA1 mouse model\",\n      \"pmids\": [\"17322884\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the biochemical determinants of competition with ATXN1\", \"Did not establish CIC target genes regulated by ATXN1L\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined ATXN1L's core mechanism as a CIC stabilizer whose loss derepresses ETV4 and downstream MMPs, linking the complex to a concrete developmental output (lung alveolarization).\",\n      \"evidence\": \"Atxn1l and Atxn1/Atxn1l double-knockout mice, CIC protein stability assays, and genetic epistasis with Cic-deficient mice\",\n      \"pmids\": [\"22014525\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CIC destabilization not yet identified\", \"E3 ligase mediating CIC turnover unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Tested whether ATXN1L acts beyond CIC by probing Notch output, showing ATXN1L and ATXN1 bind the Hey1 promoter and interact with CBF1 to inhibit Notch transcription.\",\n      \"evidence\": \"Drosophila genetics plus mammalian promoter-binding and CBF1 interaction assays\",\n      \"pmids\": [\"21475249\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab data\", \"Relationship between CBF1-dependent Notch repression and the CIC-dependent mechanism not reconciled\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Extended ATXN1L function to adult stem cell biology, showing it maintains hematopoietic stem cell quiescence.\",\n      \"evidence\": \"Atxn1l knockout mice with in vitro and in vivo HSC assays and expression profiling\",\n      \"pmids\": [\"23555280\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish whether the quiescence phenotype is CIC-dependent\", \"Downstream transcriptional effectors not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Connected the ATXN1L-CIC-ETS axis to therapy response, showing ATXN1L loss reduces CIC and modulates MEK inhibitor sensitivity, with ETS overexpression phenocopying the loss.\",\n      \"evidence\": \"Genome-scale CRISPR screens in KRAS-mutant pancreatic cancer lines plus ectopic ETS factor expression and MAPKi sensitivity assays\",\n      \"pmids\": [\"28178529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular step linking ATXN1L to CIC stability\", \"Clinical generalizability across tumor types not established\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated convergent CIC and ATXN1L function at the transcriptome level, implicating the axis in mitotic cell cycle and division control.\",\n      \"evidence\": \"ATXN1LKO and CICKO human cell lines with transcriptomic profiling\",\n      \"pmids\": [\"30093628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Correlative transcriptomics without direct cell-cycle mechanistic dissection\", \"Single lab\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Resolved the biochemical mechanism of CIC stabilization, identifying TRIM25 as the E3 ligase whose ATXN1L-blocked polyubiquitination targets CIC for proteasomal degradation, independent of ERK.\",\n      \"evidence\": \"ATXN1LKO cell lines, polyubiquitination and proteasome-inhibition assays, TRIM25 functional assays, validated in glioma lines\",\n      \"pmids\": [\"33115448\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ATXN1L binding sterically or allosterically blocks TRIM25 not defined\", \"Whether other ligases contribute under ERK-active conditions unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated ATXN1L in cardiomyocyte cell death regulation, both via CIC-dependent suppression of PYDC1 (controlled by miR-136-5p) and via HDAC3-mediated histone deacetylation repressing NOL3.\",\n      \"evidence\": \"Luciferase reporter and co-IP for the miR-136-5p/ATXN1L/CIC axis, plus ChIP and HDAC3 inhibition for the NOL3 mechanism in cardiomyocytes and rats\",\n      \"pmids\": [\"35084609\", \"35414011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP without reciprocal validation for the ATXN1L-CIC pyroptosis link\", \"Whether HDAC3 recruitment is CIC-dependent not established\", \"Single disease-model context\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed the CIC-ATXN1L complex is required for marginal zone B cell development and humoral immunity, with ETV4 derepression repressing Notch1/Notch2 as the operative mechanism.\",\n      \"evidence\": \"B cell-specific conditional Atxn1l knockout mice with Etv4 deletion epistasis rescue and an LPS sepsis model\",\n      \"pmids\": [\"39632849\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ETV4 represses Notch receptor transcription mechanistically not detailed\", \"Generalizability to other B cell subsets unclear\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined an antiviral function: the CIC-ATXN1L complex represses IFN/ISG promoters via an 8-nt motif at homeostasis, and MAPK-triggered complex degradation during viral infection unleashes interferon responses.\",\n      \"evidence\": \"DNA-binding motif identification, complex degradation assays during infection, and loss-of-function studies in human and mouse cells\",\n      \"pmids\": [\"40132591\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TRIM25 mediates the infection-triggered complex degradation not established\", \"Kinetics relative to other IFN-regulatory layers unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolved paralog/isoform specificity, showing CIC-S preferentially binds ATXN1L and CIC-L binds ATXN1, with isoform-specific knockouts phenocopying the respective paralog knockouts.\",\n      \"evidence\": \"CIC isoform-specific knockout mice and co-immunoprecipitation binding-preference assays (preprint)\",\n      \"pmids\": [\"41279815\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint not yet peer-reviewed\", \"Structural basis of isoform-paralog selectivity not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ATXN1L binding mechanistically blocks TRIM25-mediated CIC ubiquitination, and how this is reversed during MAPK-driven signaling, remains undefined at the structural level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural model of the ATXN1L-CIC interface\", \"Signal that triggers complex degradation during infection vs homeostasis not biochemically mapped\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 9, 10]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [2, 8, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1, 10]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 5, 9, 10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 3, 9]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"complexes\": [\"CIC-ATXN1L complex\"],\n    \"partners\": [\"CIC\", \"ATXN1\", \"TRIM25\", \"CBF1\", \"HDAC3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}