{"gene":"WDR59","run_date":"2026-06-11T09:02:06","timeline":{"discoveries":[{"year":2013,"finding":"WDR59 was identified as a subunit of the GATOR2 complex (along with Mios, WDR24, Seh1L, and Sec13). Inhibition of GATOR2 subunits including WDR59 suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates GATOR1 subunit DEPDC5, placing GATOR2 upstream of GATOR1 in the mTORC1 amino acid sensing pathway.","method":"RNAi knockdown, epistasis analysis, co-immunoprecipitation, mTORC1 activity assays","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP defining complex membership, epistasis analysis placing GATOR2 upstream of GATOR1, replicated across multiple independent studies","pmids":["23723238"],"is_preprint":false},{"year":2017,"finding":"Lysosome-targeted WDR59 (a GATOR2 component) partially corrected hyperactivation of mTORC1 in SZT2-deficient cells under nutrient-deprived conditions, indicating that lysosomal localization of GATOR2 (via SZT2-orchestrated SOG complex) is required for proper mTORC1 suppression and that WDR59/GATOR2 at the lysosome functions to suppress mTORC1 signaling through SESN recruitment.","method":"Overexpression of lysosome-targeted WDR59 in SZT2-deficient cells, mTORC1 activity rescue assays","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional rescue experiment with lysosome-targeted WDR59, single lab, two orthogonal approaches (genetic rescue + localization)","pmids":["28199315"],"is_preprint":false},{"year":2020,"finding":"WDR59 is the GATOR2 component essential for the GATOR2-mTORC2 interaction. Silencing or deleting WDR59 completely ablated Sestrin2-induced AKT activation, establishing WDR59 as the molecular bridge linking GATOR2 to mTORC2 in the Sestrin2→GATOR2→mTORC2→AKT signaling axis.","method":"siRNA knockdown, CRISPR knockout, co-immunoprecipitation, in vitro kinase assay for mTORC2 activity, AKT phosphorylation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP, siRNA and CRISPR KO with defined signaling phenotype, in vitro kinase assay, single lab with multiple orthogonal methods","pmids":["31915252"],"is_preprint":false},{"year":2021,"finding":"In fission yeast, the WDR59 ortholog Sea3 functions physically and functionally proximal to GATOR1 (rather than GATOR2), attenuating TORC1 activity. This is in contrast to the mammalian context, demonstrating that Sea3/WDR59 can function as part of a GATOR1-associated complex to suppress TORC1.","method":"Genetic epistasis, co-immunoprecipitation, TORC1 activity assays in fission yeast","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis and Co-IP in fission yeast ortholog, single lab with multiple orthogonal methods","pmids":["33534698"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of the human GATOR2 complex revealed that WDR59 is one of two WDR59 subunits in the 1.1 MDa cage-like architecture. WDR59 participates in the octagonal scaffold circularized via non-catalytic RING domains and α-solenoids, and its WD40 β-propeller mediates interactions with SESN2, CASTOR1, and GATOR1.","method":"Cryo-electron microscopy structure determination, biochemical interaction assays","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — cryo-EM structure with functional interaction mapping, landmark study defining stoichiometry and architecture","pmids":["35831510"],"is_preprint":false},{"year":2022,"finding":"In Drosophila, Wdr59 has a dual context-dependent function: in the ovary and eye imaginal disc, Wdr59 inhibits TORC1 by opposing GATOR2-dependent inhibition of GATOR1; in the fat body, Wdr59 promotes accumulation of GATOR2 component Mio and is required for TORC1 activation. In mammalian HeLa cells, Wdr59 prevents proteasomal degradation of GATOR2 proteins Mio and Wdr24, and Wdr59 KO reduces TORC1 activity that is restored by proteasome inhibition.","method":"Drosophila genetics (tissue-specific analysis), CRISPR knockout in HeLa cells, proteasome inhibitor rescue, TORC1 activity assays, protein level measurements","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (in vivo Drosophila genetics, mammalian KO, proteasome inhibitor rescue) across two organisms and multiple tissues","pmids":["36577058"],"is_preprint":false},{"year":2022,"finding":"Endogenous GFP-tagging of WDR59 in HeLa cells (using CRISPR) showed that GFP-WDR59 fusion retains proper GATOR2 complex association and downstream mTORC1 signaling, demonstrating that the WD-repeat region of WDR59 is not disrupted by C-terminal tagging and that WDR59 participates in metabolically regulated protein-protein interactions within the GATOR2 complex.","method":"CRISPR endogenous tagging, FACS/MACS selection, Co-IP, mTORC1 signaling assays","journal":"MethodsX","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — endogenous tagging with functional validation of complex association and signaling, single lab, two orthogonal methods","pmids":["36444289"],"is_preprint":false},{"year":2025,"finding":"Cryo-EM structures of GATOR2 bound to amino acid sensors showed that CASTOR1 (arginine sensor) engages the Mios WD40 β-propellers, while Sestrin2 (leucine sensor) interacts with the WDR24-Seh1L subcomplex. HDX-MS revealed that WDR59-containing GATOR2 undergoes dynamic conformational changes upon amino acid sensor binding. These structures clarify the inhibitory mechanism of GATOR2 by amino acid sensors.","method":"Cryo-electron microscopy, hydrogen-deuterium exchange mass spectrometry (HDX-MS)","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-EM structures with HDX-MS validation, single lab, multiple orthogonal structural methods","pmids":["40742811"],"is_preprint":false},{"year":2026,"finding":"Loss-of-function mutations in WDR59 (homozygous p.Gly963Arg founder variant or compound heterozygous splicing variants confirmed by RNA-seq) cause autosomal recessive syndromic dilated cardiomyopathy in humans, implicating dysregulated GATOR2-mTORC1 signaling in cardiomyocyte homeostasis.","method":"Genetic mapping, whole-exome sequencing, RNA-seq splicing validation, familial segregation analysis","journal":"Clinical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetic loss-of-function with RNA-seq confirmation of splicing defect, multi-family evidence, but direct functional rescue not yet demonstrated","pmids":["41715954"],"is_preprint":false}],"current_model":"WDR59 is a core structural subunit of the pentameric GATOR2 complex (with WDR24, MIOS, SEH1L, SEC13), which adopts a 1.1 MDa cage-like architecture; within this complex, WDR59 contributes to scaffold assembly via RING domains and α-solenoids, presents WD40 β-propellers for interactions with amino acid sensors (SESN2, CASTOR1) and GATOR1, serves as the critical bridge linking GATOR2 to mTORC2 (enabling Sestrin2-induced AKT activation), and stabilizes other GATOR2 subunits (MIOS, WDR24) against proteasomal degradation — with the net effect of promoting mTORC1 activation in most contexts, though Drosophila studies reveal tissue-dependent dual roles where WDR59 can instead inhibit TORC1 by opposing GATOR2 function."},"narrative":{"mechanistic_narrative":"WDR59 is a core subunit of the pentameric GATOR2 complex (with MIOS, WDR24, SEH1L, SEC13) that governs amino acid sensing upstream of mTORC1 [PMID:23723238]. Within the 1.1 MDa cage-like GATOR2 architecture, WDR59 is present in two copies and contributes to the octagonal scaffold through non-catalytic RING domains and α-solenoids, while its WD40 β-propeller mediates interactions with the amino acid sensors SESN2 and CASTOR1 and with the downstream regulator GATOR1 [PMID:35831510]. GATOR2 acts as a negative regulator of GATOR1 (DEPDC5), placing it upstream in the pathway, and amino acid sensor binding drives dynamic conformational changes in WDR59-containing GATOR2 that underlie its inhibitory regulation [PMID:23723238, PMID:40742811]. WDR59 is structurally required to stabilize partner subunits MIOS and WDR24 against proteasomal degradation, such that its loss reduces mTORC1 activity in a manner rescued by proteasome inhibition [PMID:36577058]. Beyond mTORC1, WDR59 serves as the essential molecular bridge linking GATOR2 to mTORC2, since its loss ablates Sestrin2-induced AKT activation [PMID:31915252]. Proper lysosomal localization of WDR59/GATOR2 is required for nutrient-dependent mTORC1 suppression [PMID:28199315]. Across organisms WDR59 has context-dependent roles, opposing or promoting TORC1 in a tissue-specific manner in Drosophila and functioning proximal to GATOR1 to attenuate TORC1 in fission yeast [PMID:33534698, PMID:36577058]. Biallelic loss-of-function mutations in WDR59 cause autosomal recessive syndromic dilated cardiomyopathy, implicating dysregulated GATOR2-mTORC1 signaling in cardiomyocyte homeostasis [PMID:41715954].","teleology":[{"year":2013,"claim":"Establishing WDR59 as a GATOR2 subunit answered where it sits in nutrient signaling, placing it upstream of GATOR1 as a positive regulator of mTORC1.","evidence":"RNAi knockdown, epistasis analysis, and Co-IP with mTORC1 activity assays","pmids":["23723238"],"confidence":"High","gaps":["Molecular role of WDR59 within the complex not resolved","No structural basis for GATOR2-GATOR1 regulation"]},{"year":2017,"claim":"Lysosome-targeting experiments showed that subcellular localization of WDR59/GATOR2 is functionally required for nutrient-dependent mTORC1 suppression.","evidence":"Overexpression of lysosome-targeted WDR59 in SZT2-deficient cells with mTORC1 rescue assays","pmids":["28199315"],"confidence":"Medium","gaps":["Endogenous trafficking of WDR59 not directly tracked","Single lab; mechanism of SOG-mediated recruitment of WDR59 not defined"]},{"year":2020,"claim":"Identifying WDR59 as the GATOR2 component required for mTORC2 engagement extended its role beyond mTORC1 to the Sestrin2→GATOR2→mTORC2→AKT axis.","evidence":"siRNA, CRISPR KO, Co-IP, in vitro kinase assay, and AKT phosphorylation assays","pmids":["31915252"],"confidence":"High","gaps":["Structural basis of the WDR59-mTORC2 interface unknown","Whether GATOR2-mTORC2 coupling occurs at the lysosome not addressed"]},{"year":2021,"claim":"The fission yeast ortholog Sea3 revealed evolutionary divergence, functioning proximal to GATOR1 to attenuate TORC1 rather than acting through GATOR2.","evidence":"Genetic epistasis, Co-IP, and TORC1 activity assays in fission yeast","pmids":["33534698"],"confidence":"Medium","gaps":["Relevance of GATOR1-proximal role to mammalian WDR59 unclear","Ortholog-based; not validated in human cells"]},{"year":2022,"claim":"Cryo-EM of human GATOR2 defined WDR59 stoichiometry and architecture, showing two copies contribute RING/α-solenoid scaffolding and a WD40 β-propeller that contacts SESN2, CASTOR1, and GATOR1.","evidence":"Cryo-electron microscopy structure with biochemical interaction mapping","pmids":["35831510"],"confidence":"High","gaps":["Conformational dynamics upon sensor binding not captured","Functional consequence of two WDR59 copies not dissected"]},{"year":2022,"claim":"Dual-organism functional work showed WDR59 stabilizes MIOS and WDR24 against proteasomal degradation in mammalian cells and exerts tissue-dependent dual TORC1 regulation in Drosophila.","evidence":"Drosophila tissue-specific genetics, HeLa CRISPR KO, proteasome inhibitor rescue, and protein level measurements","pmids":["36577058"],"confidence":"High","gaps":["Molecular determinant of the inhibitory versus activating switch unknown","Degradation pathway/E3 ligase acting on destabilized subunits not identified"]},{"year":2022,"claim":"Endogenous GFP-tagging validated that C-terminally tagged WDR59 retains GATOR2 association and signaling, enabling study of metabolically regulated interactions at native expression.","evidence":"CRISPR endogenous tagging with Co-IP and mTORC1 signaling assays","pmids":["36444289"],"confidence":"Medium","gaps":["Methodological validation rather than new mechanism","Dynamics of interactions not quantified"]},{"year":2025,"claim":"Structures of sensor-bound GATOR2 plus HDX-MS demonstrated that WDR59-containing GATOR2 undergoes dynamic conformational changes upon amino acid sensor binding, clarifying the sensor-driven inhibitory mechanism.","evidence":"Cryo-EM structures of sensor-bound GATOR2 and hydrogen-deuterium exchange mass spectrometry","pmids":["40742811"],"confidence":"High","gaps":["Direct allosteric coupling from sensor binding to GATOR1 not fully resolved","WDR59-specific conformational changes not isolated from whole-complex dynamics"]},{"year":2026,"claim":"Human biallelic loss-of-function variants tied WDR59 to autosomal recessive syndromic dilated cardiomyopathy, implicating GATOR2-mTORC1 signaling in cardiomyocyte homeostasis.","evidence":"Genetic mapping, whole-exome sequencing, RNA-seq splicing validation, and familial segregation","pmids":["41715954"],"confidence":"Medium","gaps":["Direct functional rescue not yet demonstrated","Mechanism linking GATOR2 dysregulation to cardiomyocyte pathology unknown"]},{"year":null,"claim":"It remains unresolved what molecular signal determines whether WDR59 promotes or inhibits TORC1 in a context-dependent manner and how this dual function relates to its mTORC2-bridging and disease roles.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No mechanism for the activating-versus-inhibitory switch","Tissue-specific GATOR2 composition not mapped","Functional model of cardiomyopathy-causing mutations not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[4,5]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[0,7]}],"complexes":["GATOR2"],"partners":["WDR24","MIOS","SEH1L","SEC13","SESN2","CASTOR1","DEPDC5"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6PJI9","full_name":"GATOR2 complex protein WDR59","aliases":["WD repeat-containing protein 59"],"length_aa":974,"mass_kda":109.8,"function":"As a component of the GATOR2 complex, functions as an activator of the amino acid-sensing branch of the mTORC1 signaling pathway (PubMed:23723238, PubMed:25457612, PubMed:27487210, PubMed:35831510, PubMed:36528027, PubMed:36577058). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:27487210, PubMed:35831510, PubMed:36528027). GATOR2 probably acts as an E3 ubiquitin-protein ligase toward GATOR1 (PubMed:36528027). In the presence of abundant amino acids, the GATOR2 complex mediates ubiquitination of the NPRL2 core component of the GATOR1 complex, leading to GATOR1 inactivation (PubMed:36528027). In the absence of amino acids, GATOR2 is inhibited, activating the GATOR1 complex (PubMed:25457612, PubMed:27487210)","subcellular_location":"Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q6PJI9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/WDR59","classification":"Not Classified","n_dependent_lines":327,"n_total_lines":1208,"dependency_fraction":0.2706953642384106},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"HSP90B1","stoichiometry":0.2},{"gene":"SEC13","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/WDR59","total_profiled":1310},"omim":[{"mim_id":"620307","title":"WD REPEAT-CONTAINING PROTEIN 24; WDR24","url":"https://www.omim.org/entry/620307"},{"mim_id":"617418","title":"WD REPEAT-CONTAINING PROTEIN 59; WDR59","url":"https://www.omim.org/entry/617418"},{"mim_id":"617034","title":"CELLULAR ARGININE SENSOR FOR MTORC1 PROTEIN 1; CASTOR1","url":"https://www.omim.org/entry/617034"},{"mim_id":"615359","title":"MEIOSIS REGULATOR FOR OOCYTE DEVELOPMENT; MIOS","url":"https://www.omim.org/entry/615359"},{"mim_id":"614191","title":"DEP DOMAIN-CONTAINING PROTEIN 5; DEPDC5","url":"https://www.omim.org/entry/614191"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/WDR59"},"hgnc":{"alias_symbol":["FLJ12270"],"prev_symbol":[]},"alphafold":{"accession":"Q6PJI9","domains":[{"cath_id":"3.10.110.10","chopping":"395-497","consensus_level":"high","plddt":83.9756,"start":395,"end":497},{"cath_id":"-","chopping":"658-757_858-885","consensus_level":"high","plddt":87.723,"start":658,"end":885},{"cath_id":"3.30.40","chopping":"901-974","consensus_level":"medium","plddt":82.523,"start":901,"end":974}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PJI9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PJI9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6PJI9-F1-predicted_aligned_error_v6.png","plddt_mean":72.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=WDR59","jax_strain_url":"https://www.jax.org/strain/search?query=WDR59"},"sequence":{"accession":"Q6PJI9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6PJI9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6PJI9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6PJI9"}},"corpus_meta":[{"pmid":"23723238","id":"PMC_23723238","title":"A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1.","date":"2013","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/23723238","citation_count":888,"is_preprint":false},{"pmid":"28199315","id":"PMC_28199315","title":"SZT2 dictates GATOR control of mTORC1 signalling.","date":"2017","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/28199315","citation_count":159,"is_preprint":false},{"pmid":"27173016","id":"PMC_27173016","title":"Involvement of GATOR complex genes in familial focal epilepsies and focal cortical dysplasia.","date":"2016","source":"Epilepsia","url":"https://pubmed.ncbi.nlm.nih.gov/27173016","citation_count":140,"is_preprint":false},{"pmid":"31917448","id":"PMC_31917448","title":"A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer.","date":"2020","source":"Journal of the National Cancer Institute","url":"https://pubmed.ncbi.nlm.nih.gov/31917448","citation_count":73,"is_preprint":false},{"pmid":"35831510","id":"PMC_35831510","title":"Structure of the nutrient-sensing hub GATOR2.","date":"2022","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/35831510","citation_count":71,"is_preprint":false},{"pmid":"31915252","id":"PMC_31915252","title":"The GATOR2-mTORC2 axis mediates Sestrin2-induced AKT Ser/Thr kinase activation.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/31915252","citation_count":52,"is_preprint":false},{"pmid":"33534698","id":"PMC_33534698","title":"Tripartite suppression of fission yeast TORC1 signaling by the GATOR1-Sea3 complex, the TSC complex, and Gcn2 kinase.","date":"2021","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/33534698","citation_count":28,"is_preprint":false},{"pmid":"35230915","id":"PMC_35230915","title":"The FACT complex facilitates expression of lysosomal and antioxidant genes through binding to TFEB and TFE3.","date":"2022","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/35230915","citation_count":23,"is_preprint":false},{"pmid":"40742811","id":"PMC_40742811","title":"Cryo-EM structures of amino acid sensors bound to the human GATOR2 complex.","date":"2025","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/40742811","citation_count":9,"is_preprint":false},{"pmid":"34085593","id":"PMC_34085593","title":"Multiplexed suppression of TOR complex 1 induces autophagy during starvation.","date":"2021","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/34085593","citation_count":8,"is_preprint":false},{"pmid":"36577058","id":"PMC_36577058","title":"Wdr59 promotes or inhibits TORC1 activity depending on cellular context.","date":"2022","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/36577058","citation_count":7,"is_preprint":false},{"pmid":"38372438","id":"PMC_38372438","title":"New insights into GATOR2-dependent interactions and its conformational changes in amino acid sensing.","date":"2024","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/38372438","citation_count":7,"is_preprint":false},{"pmid":"37194451","id":"PMC_37194451","title":"Integration of GWAS and eGWAS to screen candidate genes underlying green head traits in male ducks.","date":"2023","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/37194451","citation_count":4,"is_preprint":false},{"pmid":"39513902","id":"PMC_39513902","title":"Unveiling GATOR2 Function: Novel Insights from Drosophila Research.","date":"2024","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/39513902","citation_count":3,"is_preprint":false},{"pmid":"37040585","id":"PMC_37040585","title":"Interactions between genetic variants and environmental risk factors are associated with the severity of pelvic organ prolapse.","date":"2023","source":"Menopause (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/37040585","citation_count":3,"is_preprint":false},{"pmid":"41715954","id":"PMC_41715954","title":"WDR59 Is Mutated in Individuals With Autosomal Recessive Syndromic Dilated Cardiomyopathy.","date":"2026","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/41715954","citation_count":0,"is_preprint":false},{"pmid":"36444289","id":"PMC_36444289","title":"Selection-free endogenous tagging of cell lines by bicistronic co-expression of the surface antigen NGFR.","date":"2022","source":"MethodsX","url":"https://pubmed.ncbi.nlm.nih.gov/36444289","citation_count":0,"is_preprint":false},{"pmid":"40887617","id":"PMC_40887617","title":"Comparative genomics of two closely related Acropora coral species with different spawning seasons reveals genomic regions possibly associated with gametogenesis.","date":"2025","source":"BMC ecology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/40887617","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":12150,"output_tokens":2574,"usd":0.03753,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9690,"output_tokens":3241,"usd":0.064738,"stage2_stop_reason":"end_turn"},"total_usd":0.102268,"stage1_batch_id":"msgbatch_01UT1AahFPCAyn2uVweS7A9z","stage2_batch_id":"msgbatch_01HuKWtKNT4Pqj1bc8eEP5RV","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"WDR59 was identified as a subunit of the GATOR2 complex (along with Mios, WDR24, Seh1L, and Sec13). Inhibition of GATOR2 subunits including WDR59 suppresses mTORC1 signaling, and epistasis analysis shows that GATOR2 negatively regulates GATOR1 subunit DEPDC5, placing GATOR2 upstream of GATOR1 in the mTORC1 amino acid sensing pathway.\",\n      \"method\": \"RNAi knockdown, epistasis analysis, co-immunoprecipitation, mTORC1 activity assays\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP defining complex membership, epistasis analysis placing GATOR2 upstream of GATOR1, replicated across multiple independent studies\",\n      \"pmids\": [\"23723238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Lysosome-targeted WDR59 (a GATOR2 component) partially corrected hyperactivation of mTORC1 in SZT2-deficient cells under nutrient-deprived conditions, indicating that lysosomal localization of GATOR2 (via SZT2-orchestrated SOG complex) is required for proper mTORC1 suppression and that WDR59/GATOR2 at the lysosome functions to suppress mTORC1 signaling through SESN recruitment.\",\n      \"method\": \"Overexpression of lysosome-targeted WDR59 in SZT2-deficient cells, mTORC1 activity rescue assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional rescue experiment with lysosome-targeted WDR59, single lab, two orthogonal approaches (genetic rescue + localization)\",\n      \"pmids\": [\"28199315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"WDR59 is the GATOR2 component essential for the GATOR2-mTORC2 interaction. Silencing or deleting WDR59 completely ablated Sestrin2-induced AKT activation, establishing WDR59 as the molecular bridge linking GATOR2 to mTORC2 in the Sestrin2→GATOR2→mTORC2→AKT signaling axis.\",\n      \"method\": \"siRNA knockdown, CRISPR knockout, co-immunoprecipitation, in vitro kinase assay for mTORC2 activity, AKT phosphorylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP, siRNA and CRISPR KO with defined signaling phenotype, in vitro kinase assay, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"31915252\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In fission yeast, the WDR59 ortholog Sea3 functions physically and functionally proximal to GATOR1 (rather than GATOR2), attenuating TORC1 activity. This is in contrast to the mammalian context, demonstrating that Sea3/WDR59 can function as part of a GATOR1-associated complex to suppress TORC1.\",\n      \"method\": \"Genetic epistasis, co-immunoprecipitation, TORC1 activity assays in fission yeast\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis and Co-IP in fission yeast ortholog, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33534698\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of the human GATOR2 complex revealed that WDR59 is one of two WDR59 subunits in the 1.1 MDa cage-like architecture. WDR59 participates in the octagonal scaffold circularized via non-catalytic RING domains and α-solenoids, and its WD40 β-propeller mediates interactions with SESN2, CASTOR1, and GATOR1.\",\n      \"method\": \"Cryo-electron microscopy structure determination, biochemical interaction assays\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — cryo-EM structure with functional interaction mapping, landmark study defining stoichiometry and architecture\",\n      \"pmids\": [\"35831510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Drosophila, Wdr59 has a dual context-dependent function: in the ovary and eye imaginal disc, Wdr59 inhibits TORC1 by opposing GATOR2-dependent inhibition of GATOR1; in the fat body, Wdr59 promotes accumulation of GATOR2 component Mio and is required for TORC1 activation. In mammalian HeLa cells, Wdr59 prevents proteasomal degradation of GATOR2 proteins Mio and Wdr24, and Wdr59 KO reduces TORC1 activity that is restored by proteasome inhibition.\",\n      \"method\": \"Drosophila genetics (tissue-specific analysis), CRISPR knockout in HeLa cells, proteasome inhibitor rescue, TORC1 activity assays, protein level measurements\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (in vivo Drosophila genetics, mammalian KO, proteasome inhibitor rescue) across two organisms and multiple tissues\",\n      \"pmids\": [\"36577058\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Endogenous GFP-tagging of WDR59 in HeLa cells (using CRISPR) showed that GFP-WDR59 fusion retains proper GATOR2 complex association and downstream mTORC1 signaling, demonstrating that the WD-repeat region of WDR59 is not disrupted by C-terminal tagging and that WDR59 participates in metabolically regulated protein-protein interactions within the GATOR2 complex.\",\n      \"method\": \"CRISPR endogenous tagging, FACS/MACS selection, Co-IP, mTORC1 signaling assays\",\n      \"journal\": \"MethodsX\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — endogenous tagging with functional validation of complex association and signaling, single lab, two orthogonal methods\",\n      \"pmids\": [\"36444289\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Cryo-EM structures of GATOR2 bound to amino acid sensors showed that CASTOR1 (arginine sensor) engages the Mios WD40 β-propellers, while Sestrin2 (leucine sensor) interacts with the WDR24-Seh1L subcomplex. HDX-MS revealed that WDR59-containing GATOR2 undergoes dynamic conformational changes upon amino acid sensor binding. These structures clarify the inhibitory mechanism of GATOR2 by amino acid sensors.\",\n      \"method\": \"Cryo-electron microscopy, hydrogen-deuterium exchange mass spectrometry (HDX-MS)\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-EM structures with HDX-MS validation, single lab, multiple orthogonal structural methods\",\n      \"pmids\": [\"40742811\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Loss-of-function mutations in WDR59 (homozygous p.Gly963Arg founder variant or compound heterozygous splicing variants confirmed by RNA-seq) cause autosomal recessive syndromic dilated cardiomyopathy in humans, implicating dysregulated GATOR2-mTORC1 signaling in cardiomyocyte homeostasis.\",\n      \"method\": \"Genetic mapping, whole-exome sequencing, RNA-seq splicing validation, familial segregation analysis\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetic loss-of-function with RNA-seq confirmation of splicing defect, multi-family evidence, but direct functional rescue not yet demonstrated\",\n      \"pmids\": [\"41715954\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"WDR59 is a core structural subunit of the pentameric GATOR2 complex (with WDR24, MIOS, SEH1L, SEC13), which adopts a 1.1 MDa cage-like architecture; within this complex, WDR59 contributes to scaffold assembly via RING domains and α-solenoids, presents WD40 β-propellers for interactions with amino acid sensors (SESN2, CASTOR1) and GATOR1, serves as the critical bridge linking GATOR2 to mTORC2 (enabling Sestrin2-induced AKT activation), and stabilizes other GATOR2 subunits (MIOS, WDR24) against proteasomal degradation — with the net effect of promoting mTORC1 activation in most contexts, though Drosophila studies reveal tissue-dependent dual roles where WDR59 can instead inhibit TORC1 by opposing GATOR2 function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"WDR59 is a core subunit of the pentameric GATOR2 complex (with MIOS, WDR24, SEH1L, SEC13) that governs amino acid sensing upstream of mTORC1 [#0]. Within the 1.1 MDa cage-like GATOR2 architecture, WDR59 is present in two copies and contributes to the octagonal scaffold through non-catalytic RING domains and α-solenoids, while its WD40 β-propeller mediates interactions with the amino acid sensors SESN2 and CASTOR1 and with the downstream regulator GATOR1 [#4]. GATOR2 acts as a negative regulator of GATOR1 (DEPDC5), placing it upstream in the pathway, and amino acid sensor binding drives dynamic conformational changes in WDR59-containing GATOR2 that underlie its inhibitory regulation [#0, #7]. WDR59 is structurally required to stabilize partner subunits MIOS and WDR24 against proteasomal degradation, such that its loss reduces mTORC1 activity in a manner rescued by proteasome inhibition [#5]. Beyond mTORC1, WDR59 serves as the essential molecular bridge linking GATOR2 to mTORC2, since its loss ablates Sestrin2-induced AKT activation [#2]. Proper lysosomal localization of WDR59/GATOR2 is required for nutrient-dependent mTORC1 suppression [#1]. Across organisms WDR59 has context-dependent roles, opposing or promoting TORC1 in a tissue-specific manner in Drosophila and functioning proximal to GATOR1 to attenuate TORC1 in fission yeast [#3, #5]. Biallelic loss-of-function mutations in WDR59 cause autosomal recessive syndromic dilated cardiomyopathy, implicating dysregulated GATOR2-mTORC1 signaling in cardiomyocyte homeostasis [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Establishing WDR59 as a GATOR2 subunit answered where it sits in nutrient signaling, placing it upstream of GATOR1 as a positive regulator of mTORC1.\",\n      \"evidence\": \"RNAi knockdown, epistasis analysis, and Co-IP with mTORC1 activity assays\",\n      \"pmids\": [\"23723238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular role of WDR59 within the complex not resolved\", \"No structural basis for GATOR2-GATOR1 regulation\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Lysosome-targeting experiments showed that subcellular localization of WDR59/GATOR2 is functionally required for nutrient-dependent mTORC1 suppression.\",\n      \"evidence\": \"Overexpression of lysosome-targeted WDR59 in SZT2-deficient cells with mTORC1 rescue assays\",\n      \"pmids\": [\"28199315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endogenous trafficking of WDR59 not directly tracked\", \"Single lab; mechanism of SOG-mediated recruitment of WDR59 not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying WDR59 as the GATOR2 component required for mTORC2 engagement extended its role beyond mTORC1 to the Sestrin2→GATOR2→mTORC2→AKT axis.\",\n      \"evidence\": \"siRNA, CRISPR KO, Co-IP, in vitro kinase assay, and AKT phosphorylation assays\",\n      \"pmids\": [\"31915252\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the WDR59-mTORC2 interface unknown\", \"Whether GATOR2-mTORC2 coupling occurs at the lysosome not addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"The fission yeast ortholog Sea3 revealed evolutionary divergence, functioning proximal to GATOR1 to attenuate TORC1 rather than acting through GATOR2.\",\n      \"evidence\": \"Genetic epistasis, Co-IP, and TORC1 activity assays in fission yeast\",\n      \"pmids\": [\"33534698\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance of GATOR1-proximal role to mammalian WDR59 unclear\", \"Ortholog-based; not validated in human cells\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cryo-EM of human GATOR2 defined WDR59 stoichiometry and architecture, showing two copies contribute RING/α-solenoid scaffolding and a WD40 β-propeller that contacts SESN2, CASTOR1, and GATOR1.\",\n      \"evidence\": \"Cryo-electron microscopy structure with biochemical interaction mapping\",\n      \"pmids\": [\"35831510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational dynamics upon sensor binding not captured\", \"Functional consequence of two WDR59 copies not dissected\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Dual-organism functional work showed WDR59 stabilizes MIOS and WDR24 against proteasomal degradation in mammalian cells and exerts tissue-dependent dual TORC1 regulation in Drosophila.\",\n      \"evidence\": \"Drosophila tissue-specific genetics, HeLa CRISPR KO, proteasome inhibitor rescue, and protein level measurements\",\n      \"pmids\": [\"36577058\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular determinant of the inhibitory versus activating switch unknown\", \"Degradation pathway/E3 ligase acting on destabilized subunits not identified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Endogenous GFP-tagging validated that C-terminally tagged WDR59 retains GATOR2 association and signaling, enabling study of metabolically regulated interactions at native expression.\",\n      \"evidence\": \"CRISPR endogenous tagging with Co-IP and mTORC1 signaling assays\",\n      \"pmids\": [\"36444289\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Methodological validation rather than new mechanism\", \"Dynamics of interactions not quantified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Structures of sensor-bound GATOR2 plus HDX-MS demonstrated that WDR59-containing GATOR2 undergoes dynamic conformational changes upon amino acid sensor binding, clarifying the sensor-driven inhibitory mechanism.\",\n      \"evidence\": \"Cryo-EM structures of sensor-bound GATOR2 and hydrogen-deuterium exchange mass spectrometry\",\n      \"pmids\": [\"40742811\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct allosteric coupling from sensor binding to GATOR1 not fully resolved\", \"WDR59-specific conformational changes not isolated from whole-complex dynamics\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Human biallelic loss-of-function variants tied WDR59 to autosomal recessive syndromic dilated cardiomyopathy, implicating GATOR2-mTORC1 signaling in cardiomyocyte homeostasis.\",\n      \"evidence\": \"Genetic mapping, whole-exome sequencing, RNA-seq splicing validation, and familial segregation\",\n      \"pmids\": [\"41715954\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct functional rescue not yet demonstrated\", \"Mechanism linking GATOR2 dysregulation to cardiomyocyte pathology unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved what molecular signal determines whether WDR59 promotes or inhibits TORC1 in a context-dependent manner and how this dual function relates to its mTORC2-bridging and disease roles.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No mechanism for the activating-versus-inhibitory switch\", \"Tissue-specific GATOR2 composition not mapped\", \"Functional model of cardiomyopathy-causing mutations not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"complexes\": [\"GATOR2\"],\n    \"partners\": [\"WDR24\", \"MIOS\", \"SEH1L\", \"SEC13\", \"SESN2\", \"CASTOR1\", \"DEPDC5\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}