{"gene":"MIOS","run_date":"2026-04-28T18:30:28","timeline":{"discoveries":[{"year":2013,"finding":"MIOS (Mios) was identified as a subunit of GATOR2, a five-protein complex (Mios, WDR24, WDR59, Seh1L, Sec13) that positively regulates mTORC1 signaling upstream of the Rag GTPases. Inhibition of GATOR2 subunits suppresses mTORC1 signaling, and epistasis analysis showed GATOR2 negatively regulates GATOR1 component DEPDC5. GATOR2 interacts with the Rag GTPases as part of the amino acid sensing pathway.","method":"Co-immunoprecipitation, mass spectrometry, RNAi knockdown, epistasis analysis, mTORC1 activity assays (S6K phosphorylation)","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, epistasis, replicated widely across subsequent studies","pmids":["23723238"],"is_preprint":false},{"year":2011,"finding":"Drosophila Mio protein physically associates with the nucleoporin Seh1 (ortholog of mammalian Seh1L/SEH1L). In seh1 mutant ovaries, Mio protein levels are greatly diminished, and both mio and seh1 mutants show identical defects in oogenesis: a fraction of oocytes fail to maintain the meiotic cycle and develop as pseudo-nurse cells. This establishes Mio as a novel interacting partner of Seh1 with a conserved role in germline meiotic progression.","method":"Co-immunoprecipitation, genetic mutant analysis, immunofluorescence, null allele characterization","journal":"Development","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP plus genetic phenocopy, strong concordance between mio and seh1 mutants","pmids":["21521741"],"is_preprint":false},{"year":2014,"finding":"In Drosophila oogenesis, GATOR2 components Mio and Seh1 are required to oppose GATOR1 (Iml1 complex) activity to prevent constitutive inhibition of TORC1 and a block to oocyte growth and development. Loss of Mio causes premature TORC1 inhibition, placing GATOR2 as a positive regulator of TORC1 that antagonizes GATOR1 during meiotic progression.","method":"Genetic loss-of-function (mio and seh1 mutants), rapamycin treatment, epistasis with Tor mutants, immunofluorescence for TORC1 activity markers","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple alleles and pharmacological validation in vivo","pmids":["25512509"],"is_preprint":false},{"year":2012,"finding":"Drosophila Mio (dChREBP ortholog) functions as a transcription factor in the fat body to control triglyceride accumulation: Mio mutants show blunted high-sugar-induced lipogenic enzyme mRNA expression, and fat-body-specific Mio RNAi produces a lean phenotype. Fat-body Mio depletion also decreases feeding behavior, suggesting Mio acts as a nutrient sensor coordinating food consumption and lipid metabolism.","method":"Mio mutant analysis, tissue-specific RNAi, triglyceride/glycogen assays, feeding behavior assays, qRT-PCR for lipogenic enzymes","journal":"Biochemical and Biophysical Research Communications","confidence":"Medium","confidence_rationale":"Tier 2 — clean tissue-specific KD with defined metabolic readouts, single lab","pmids":["22910416"],"is_preprint":false},{"year":2015,"finding":"Depletion of Mio in human cells (a GATOR2 component necessary for mTORC1 activation) causes mitotic spindle defects: reduced activation of Aurora A and Plk1 kinases at centrosomes/spindle poles, impaired localization of MCAK and HURP (Aurora A substrates), and spindle assembly/cytokinesis defects. This links GATOR2/Mio to mTOR-dependent regulation of mitotic kinase activation.","method":"siRNA depletion of Mio in human cells, immunofluorescence for Aurora A/Plk1/MCAK/HURP, quantification of mitotic defects, kinase activity assays","journal":"Journal of Cell Biology","confidence":"Medium","confidence_rationale":"Tier 2 — clean KD with defined mitotic phenotype and pathway placement, single lab","pmids":["26124292"],"is_preprint":false},{"year":2014,"finding":"The Sestrins (leucine sensors) interact with GATOR2 (of which MIOS is a core subunit) in an amino-acid-sensitive fashion. Sestrin2-mediated inhibition of mTORC1 requires GATOR1 and Rag GTPases, and Sestrins regulate lysosomal localization of mTORC1 in response to amino acids, placing GATOR2/MIOS as an intermediary between amino acid sensors and the Rag GTPase machinery.","method":"Co-immunoprecipitation, amino acid deprivation/stimulation assays, mTORC1 activity (S6K/4EBP1 phosphorylation), siRNA knockdown, fluorescence microscopy of mTOR localization","journal":"Cell Reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, replicated in subsequent studies","pmids":["25263562"],"is_preprint":false},{"year":2015,"finding":"Leucine disrupts the Sestrin2-GATOR2 interaction by binding directly to Sestrin2, activating mTORC1. This positions GATOR2 (containing MIOS) as the molecular hub through which the leucine sensor Sestrin2 regulates mTORC1, since GATOR2 interaction with Sestrin2 is required for amino acid-dependent mTORC1 control.","method":"Biochemical binding assays (leucine-binding to Sestrin2), co-immunoprecipitation, mTORC1 activity assays, mutagenesis of leucine-binding pocket","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — direct binding assay with mutagenesis, replicated structurally","pmids":["26449471"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of Sestrin2 in complex with leucine reveals leucine binding pocket and lid-latch mechanism; structure-guided mutations decrease leucine affinity and shift the leucine concentration required for mTORC1 activation, confirming that GATOR2 (MIOS-containing complex) interaction with Sestrin2 is central to leucine sensing.","method":"X-ray crystallography (2.7 Å), structure-guided mutagenesis, mTORC1 activity assays in cells","journal":"Science","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional mutagenesis validation","pmids":["26586190"],"is_preprint":false},{"year":2016,"finding":"CASTOR1 (arginine sensor) interacts with GATOR2 (which contains MIOS) and is required for arginine deprivation to inhibit mTORC1. Arginine binding to CASTOR1 disrupts the CASTOR1-GATOR2 interaction, activating mTORC1. This establishes GATOR2/MIOS as a scaffold that integrates both leucine (via Sestrin2) and arginine (via CASTOR1) sensing inputs.","method":"Co-immunoprecipitation, arginine binding assays, mTORC1 activity assays, mutagenesis of arginine-binding residues","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1–2 — direct binding assay with mutagenesis and epistasis, replicated","pmids":["26972053"],"is_preprint":false},{"year":2017,"finding":"KICSTOR complex recruits GATOR1 to the lysosomal surface and is required for amino acid or glucose deprivation to inhibit mTORC1. KICSTOR binds GATOR1 but not GATOR2, and is necessary for GATOR1 to interact with the Rag GTPases and with GATOR2, placing MIOS-containing GATOR2 downstream of KICSTOR-GATOR1 interaction in the nutrient-sensing hierarchy.","method":"Co-immunoprecipitation, siRNA knockdown, lysosomal fractionation, mTORC1 activity assays, mouse knockout","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods, in vivo mouse model, replicated","pmids":["28199306"],"is_preprint":false},{"year":2017,"finding":"SZT2 orchestrates a supercomplex (SOG) by recruiting both GATOR1 and GATOR2 (containing MIOS) to the lysosome. Intact SOG complex is required for lysosomal localization of GATOR2 and for SESN-dependent nutrient sensing and mTORC1 regulation, revealing that MIOS/GATOR2 must be lysosome-localized for full activity.","method":"Co-immunoprecipitation, lysosome fractionation, SZT2 knockout cells and mice, mTORC1 activity assays, overexpression rescue experiments","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods with in vivo validation","pmids":["28199315"],"is_preprint":false},{"year":2015,"finding":"Mio functions in Drosophila neurons to regulate feeding and nutrient storage independently of its fat body role. Pan-neuronal disruption of Mio increases triglyceride and glycogen storage without increased food intake; targeted disruption in insulin-producing cells (IPCs) increases food consumption and dilp3 expression, indicating Mio controls neuropeptide gene expression in IPCs to coordinate feeding with nutrient availability.","method":"Tissue-specific RNAi (pan-neuronal and IPC-specific), triglyceride/glycogen biochemical assays, feeding behavior quantification, qRT-PCR for insulin-like peptides","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 — tissue-specific KD with defined cellular phenotype, single lab","pmids":["26024590"],"is_preprint":false},{"year":2015,"finding":"Muscle-specific depletion of Mio in Drosophila results in increased thorax glycogen storage and a flight defect due to altered myofibril shape and size in indirect flight muscles, with reduced myofibril size also observed pre-eclosion, indicating a role for Mio in myofibril development and muscle metabolism.","method":"Muscle-specific RNAi, glycogen assays, electron microscopy of indirect flight muscles, flight performance assays","journal":"PLoS One","confidence":"Medium","confidence_rationale":"Tier 2 — tissue-specific KD with ultrastructural phenotype, single lab","pmids":["26305467"],"is_preprint":false},{"year":2022,"finding":"Cryo-electron microscopy structure of the human GATOR2 complex (1.1 MDa, 2-fold symmetric, cage-like) reveals that MIOS contributes four of the eight scaffold subunits (two WDR24, four MIOS, two WDR59) circularized via non-catalytic RING domains and α-solenoids. MIOS non-catalytic RING domains form one type of inter-subunit junction. SEH1L and SEC13 stabilize the complex through β-propeller blade donation. The scaffold orients WD40 β-propeller dimers that mediate interactions with SESN2, CASTOR1, and GATOR1.","method":"Cryo-electron microscopy, biochemical reconstitution, subunit stoichiometry determination, interaction mapping","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure with biochemical validation of subunit architecture","pmids":["35831510"],"is_preprint":false},{"year":2022,"finding":"E3 ligase RNF167 ubiquitinates Sestrin2, promoting its interaction with GATOR2 (MIOS-containing complex) and inhibiting mTORC1 signaling in response to leucine availability, while deubiquitinase STAMBPL1 opposes this. This identifies ubiquitination of Sestrin2 as a post-translational mechanism regulating GATOR2/MIOS engagement.","method":"Co-immunoprecipitation, ubiquitination assays, mTORC1 activity assays, RNF167/STAMBPL1 knockout cells, cell-permeable peptide inhibitor","journal":"Molecular Cell","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal biochemical methods, single lab","pmids":["35114100"],"is_preprint":false},{"year":2024,"finding":"In zebrafish, Rbpms2 (RNA binding protein) acts as a translational regulator upstream of the GATOR2 component Mios to promote oocyte fate. Genetic analyses show Rbpms2 promotes nucleolar amplification via the mTorc1 signaling pathway specifically through Mios; loss of Mios phenocopies loss of Rbpms2 in blocking oocyte progression through a GATOR2-mediated checkpoint that integrates sexual differentiation and nutrient availability.","method":"Genetic epistasis (mios mutants, rbpms2 mutants), mTORC1 activity assays in oocytes, translational reporter assays, zebrafish oogenesis phenotyping","journal":"Nature Communications","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in vivo with defined developmental phenotype, single lab","pmids":["38898112"],"is_preprint":false},{"year":2021,"finding":"YULINK (MIOS, Entrez 54468) knockdown in zebrafish cardiomyocytes and mouse HL-1 cardiomyocytes disrupts Ca²⁺ cycling and reduces SERCA2 expression. Mechanistically, Yulink knockdown reduces PPARγ DNA binding activity, and PPARγ agonists restore Serca2 expression, indicating Yulink regulates Serca2 via PPARγ nuclear entry. This function was confirmed in human iPSC-derived cardiomyocytes.","method":"Morpholino knockdown in zebrafish, shRNA in HL-1 and iPSC-derived cardiomyocytes, Ca²⁺ imaging, PPARγ DNA binding assay, Western blot, qPCR, PPARγ agonist/antagonist rescue","journal":"Journal of Biomedical Science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple model systems and rescue experiments, single lab; note related paper (29401584) was retracted","pmids":["33423678"],"is_preprint":false},{"year":2023,"finding":"YULINK (MIOS) knockdown or overexpression modulates PASMC migration, proliferation, and glycolysis. YULINK colocalizes with GLUT1 on PASMC membranes under PAH-related conditions. YULINK inhibition suppresses PDGFR phosphorylation and downstream PI3K/AKT/FAK signaling, indicating YULINK regulates glycolytic metabolism and proliferative signaling in vascular smooth muscle cells through PI3K-AKT pathway.","method":"siRNA knockdown, overexpression, co-localization immunofluorescence, migration assay, glucose uptake assay, Western blot for signaling components","journal":"Biological Research","confidence":"Medium","confidence_rationale":"Tier 2–3 — functional KD/OE with signaling readouts, single lab","pmids":["38057829"],"is_preprint":false},{"year":2023,"finding":"YULINK (MIOS) knockdown in HUVECs impairs cell migration, capillary tube formation, and VEGF-induced VEGFR2 internalization. Yeast two-hybrid, FLIM-FRET, and immunoprecipitation show YULINK colocalizes with endosomal proteins (EPS15, RAB33B, TICAM2, Clathrin, RHOB), suggesting YULINK participates in endocytic vesicle trafficking to regulate vascular formation.","method":"Morpholino knockdown in zebrafish, siRNA in HUVECs, yeast two-hybrid, FLIM-FRET, immunoprecipitation, co-localization imaging, tube formation assay","journal":"Biological Research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple interaction methods converge on endosomal localization, single lab","pmids":["36843032"],"is_preprint":false},{"year":2024,"finding":"YULINK (MIOS) interacts with and colocalizes with GLUT1 at the cell membrane in HCC cells (Huh7), as shown by proximity ligation assay and immunoprecipitation. Yulink knockdown suppresses GLUT1 expression and disrupts GLUT1 translocation from cytosol to cell membrane, reducing glucose uptake and glycolysis. Under glucose restriction, Yulink deficiency enhances cell death via increased ROS and DNA damage with failure of ATM-CHK2 activation.","method":"Proximity ligation assay, co-immunoprecipitation, immunofluorescence, glucose uptake assay, glycolytic function assay, ROS measurement, xenograft tumor model","journal":"Molecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct protein interaction demonstrated by two orthogonal methods, single lab","pmids":["41013205"],"is_preprint":false},{"year":2024,"finding":"In Dictyostelium discoideum and GBM cell lines, tanshinone IIA (T2A) induces autophagy and inhibits mTORC1 via Sestrin2 (SESN) acting through MIOS (GATOR2 component); these effects are lost upon ablation of SESN or MIOS. Computational docking identified small-molecule MIOS inhibitor Mi3, which reduces GBM cell proliferation, inhibits mTORC1, and induces autophagy in a MIOS-dependent manner.","method":"Genetic ablation of mios in Dictyostelium, mTORC1 activity assays, autophagy assays, computational docking, GBM cell line treatment with Mi3","journal":"International Journal of Molecular Sciences","confidence":"Medium","confidence_rationale":"Tier 2–3 — genetic epistasis plus pharmacological inhibitor with specificity validation","pmids":["38928292"],"is_preprint":false}],"current_model":"MIOS (also known as YULINK) is a core structural subunit of the GATOR2 complex (together with WDR24, WDR59, SEH1L, and SEC13), which forms a 1.1 MDa cage-like scaffold in which four MIOS subunits contribute non-catalytic RING domain junctions; GATOR2 acts as a positive regulator of mTORC1 signaling by serving as a scaffold that integrates leucine sensing (via Sestrin2 interaction) and arginine sensing (via CASTOR1 interaction) to antagonize the GATOR1 GTPase-activating complex toward Rag GTPases at the lysosomal surface, and MIOS additionally regulates mitotic kinase activation (Aurora A, Plk1), cardiomyocyte calcium cycling via PPARγ-SERCA2, GLUT1-dependent glucose uptake and glycolysis, and—in model organisms—oocyte meiotic progression and lipid/nutrient homeostasis."},"narrative":{"teleology":[{"year":2011,"claim":"The first physical interaction partner for Mio was identified — the nucleoporin Seh1 — and genetic analysis showed that both genes share an identical oocyte meiotic maintenance phenotype in Drosophila, establishing Mio as a novel factor required for germline meiotic progression.","evidence":"Reciprocal co-IP and null allele phenocopying in Drosophila ovaries","pmids":["21521741"],"confidence":"High","gaps":["Mammalian relevance of the meiotic phenotype was not tested","Mechanism by which Mio-Seh1 interaction supports meiosis was unknown"]},{"year":2013,"claim":"MIOS was placed in a defined five-subunit complex (GATOR2) that positively regulates mTORC1 by opposing the GATOR1 GAP complex, resolving how upstream nutrient cues reach the Rag GTPases.","evidence":"Co-IP/MS identification of GATOR2 subunits, RNAi epistasis with DEPDC5, S6K phosphorylation readouts in HEK293T cells","pmids":["23723238"],"confidence":"High","gaps":["The direct nutrient sensors feeding into GATOR2 were unknown","Structural basis of GATOR2 assembly was unresolved"]},{"year":2014,"claim":"Genetic epistasis in Drosophila confirmed that Mio/GATOR2 opposes GATOR1 in vivo to maintain TORC1 activity during oocyte growth, establishing the pathway hierarchy in an animal model and linking it to oocyte fate decisions.","evidence":"Loss-of-function mio and seh1 alleles, epistasis with Tor pathway, rapamycin treatment in Drosophila ovaries","pmids":["25512509"],"confidence":"High","gaps":["Direct biochemical interaction between GATOR2 and GATOR1 in Drosophila was not demonstrated","Whether nutrient availability gates this checkpoint was unclear"]},{"year":2015,"claim":"The nutrient-sensing logic of GATOR2 was decoded: Sestrin2 (leucine sensor) binds GATOR2, and leucine binding to Sestrin2 disrupts this interaction to activate mTORC1, positioning GATOR2/MIOS as the molecular hub for leucine sensing.","evidence":"Co-IP of Sestrin2–GATOR2, leucine-binding assays, mutagenesis of Sestrin2 leucine pocket, crystal structure of Sestrin2–leucine complex","pmids":["25263562","26449471","26586190"],"confidence":"High","gaps":["Which GATOR2 surface(s) Sestrin2 contacts was unknown at this time","Whether additional amino acids signal through GATOR2 was not resolved"]},{"year":2015,"claim":"MIOS was shown to have a cell-cycle function beyond nutrient sensing: its depletion impairs Aurora A and Plk1 activation at spindle poles, linking GATOR2–mTOR signaling to mitotic kinase regulation.","evidence":"siRNA depletion in human cells, immunofluorescence quantification of Aurora A/Plk1 phosphorylation, mitotic defect scoring","pmids":["26124292"],"confidence":"Medium","gaps":["Whether the mitotic phenotype is entirely mTOR-dependent or involves a GATOR2-autonomous mechanism is unresolved","Not independently replicated"]},{"year":2016,"claim":"CASTOR1 was identified as a second amino acid sensor (for arginine) that binds GATOR2, establishing GATOR2/MIOS as the convergence point for both leucine and arginine sensing arms of mTORC1 regulation.","evidence":"Co-IP of CASTOR1–GATOR2, arginine-binding assays, mutagenesis, mTORC1 activity in arginine-depleted cells","pmids":["26972053"],"confidence":"High","gaps":["Whether CASTOR1 and Sestrin2 bind the same or different surfaces of GATOR2 was unknown","Structural basis of CASTOR1–GATOR2 interaction was unresolved"]},{"year":2017,"claim":"The lysosomal targeting mechanism for GATOR2 was elucidated: KICSTOR and SZT2 recruit GATOR1 and GATOR2 into a lysosome-associated supercomplex (SOG) required for nutrient-dependent mTORC1 regulation, establishing that MIOS/GATOR2 must be lysosome-localized to function.","evidence":"Co-IP, lysosomal fractionation, SZT2 KO cells/mice, KICSTOR KO, mTORC1 activity assays","pmids":["28199306","28199315"],"confidence":"High","gaps":["Stoichiometry of the SOG supercomplex was unresolved","How nutrient signals dynamically regulate SOG assembly was unknown"]},{"year":2022,"claim":"The cryo-EM structure of GATOR2 revealed its 1.1 MDa cage architecture with four MIOS subunits contributing non-catalytic RING domain junctions, and showed how WD40 β-propeller dimers orient the binding surfaces for Sestrin2, CASTOR1, and GATOR1, providing a structural basis for MIOS's scaffolding role.","evidence":"Cryo-EM at near-atomic resolution, biochemical reconstitution, subunit stoichiometry determination","pmids":["35831510"],"confidence":"High","gaps":["Structural basis of the GATOR2–GATOR1 inhibitory interaction is not yet resolved at atomic level","Whether the non-catalytic RING domains of MIOS have latent activity or allosteric roles is untested"]},{"year":2023,"claim":"MIOS (YULINK) was found to colocalize with and regulate GLUT1 membrane translocation and to participate in endocytic vesicle trafficking via interactions with EPS15, RAB33B, and clathrin, extending its functions beyond mTORC1 signaling to glucose metabolism and vesicle trafficking in vascular and cancer cells.","evidence":"Proximity ligation assay, co-IP, FLIM-FRET, yeast two-hybrid, glucose uptake and glycolysis assays in HCC cells and HUVECs","pmids":["38057829","36843032","41013205"],"confidence":"Medium","gaps":["Whether GLUT1 interaction and endosomal trafficking functions are GATOR2-dependent or MIOS-autonomous is unresolved","Findings are from a single research group and await independent replication","Structural basis of MIOS–GLUT1 interaction is unknown"]},{"year":2024,"claim":"In zebrafish, Mios was placed downstream of translational regulator Rbpms2 in a GATOR2-mediated checkpoint that integrates sexual differentiation with nutrient availability during oocyte fate determination, and a small-molecule MIOS inhibitor (Mi3) was shown to phenocopy MIOS loss in GBM cells.","evidence":"Genetic epistasis in zebrafish oocytes, mTORC1/autophagy assays, computational docking and Mi3 treatment in GBM cell lines and Dictyostelium","pmids":["38898112","38928292"],"confidence":"Medium","gaps":["Mi3 selectivity for MIOS over other GATOR2 subunits is not fully validated","Whether the oocyte checkpoint is conserved in mammals remains untested"]},{"year":null,"claim":"Key unresolved questions include the atomic-resolution structure of GATOR2 in complex with GATOR1, whether MIOS RING domains possess latent catalytic or allosteric function, the extent to which MIOS functions outside GATOR2 (e.g., GLUT1 regulation, vesicle trafficking) are complex-dependent, and whether pharmacological MIOS inhibition is viable for cancer therapy.","evidence":"","pmids":[],"confidence":"Low","gaps":["No GATOR2–GATOR1 co-structure exists","MIOS-autonomous vs GATOR2-dependent functions are not delineated","In vivo efficacy and specificity of MIOS-targeting small molecules are untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,13]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,5,8,13]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,5,6,8,9]}],"localization":[{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[9,10]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,13]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[17,19]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,5,6,8,9,10]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[20]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[4]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[17,19]}],"complexes":["GATOR2","SOG (SZT2-GATOR1-GATOR2 supercomplex)"],"partners":["WDR24","WDR59","SEH1L","SEC13","SESN2","CASTOR1","GLUT1","DEPDC5"],"other_free_text":[]},"mechanistic_narrative":"MIOS is a core structural subunit of the GATOR2 complex, a ~1.1 MDa cage-like scaffold composed of four MIOS, two WDR24, two WDR59, SEH1L, and SEC13 subunits, in which MIOS contributes non-catalytic RING domain junctions that circularize the assembly [PMID:35831510, PMID:23723238]. GATOR2 functions as a positive regulator of mTORC1 by antagonizing the GATOR1 GAP complex toward Rag GTPases; it serves as the integration hub for amino acid sensing, binding the leucine sensor Sestrin2 and the arginine sensor CASTOR1 in a nutrient-dependent manner such that amino acid sufficiency releases these inhibitory sensors from GATOR2 and permits mTORC1 activation [PMID:26449471, PMID:26972053, PMID:25263562]. Lysosomal recruitment of GATOR2 is organized by the KICSTOR–SZT2 supercomplex, which is required for nutrient-dependent GATOR1–GATOR2 interaction and mTORC1 regulation [PMID:28199306, PMID:28199315]. Beyond mTORC1 signaling, MIOS is required for mTOR-dependent activation of mitotic kinases Aurora A and Plk1 at spindle poles in human cells [PMID:26124292], for oocyte meiotic progression in Drosophila and zebrafish [PMID:21521741, PMID:38898112], and regulates GLUT1-dependent glucose uptake and PPARγ–SERCA2 calcium cycling in mammalian cardiomyocytes and cancer cells [PMID:41013205, PMID:33423678]."},"prefetch_data":{"uniprot":{"accession":"Q9NXC5","full_name":"GATOR2 complex protein MIOS","aliases":["Missing oocyte meiosis regulator homolog"],"length_aa":875,"mass_kda":98.6,"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:26586190, PubMed:27487210, PubMed:35831510, PubMed:36528027). The GATOR2 complex indirectly activates mTORC1 through the inhibition of the GATOR1 subcomplex (PubMed:23723238, PubMed:26586190, 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:25263562, PubMed:25457612, PubMed:26586190, PubMed:27487210). Within the GATOR2 complex, MIOS is required to prevent autoubiquitination of WDR24, the catalytic subunit of the complex (PubMed:35831510). The GATOR2 complex is required for brain myelination (By similarity)","subcellular_location":"Lysosome membrane","url":"https://www.uniprot.org/uniprotkb/Q9NXC5/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MIOS","classification":"Not Classified","n_dependent_lines":608,"n_total_lines":1208,"dependency_fraction":0.5033112582781457},"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/MIOS","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":"617033","title":"CELLULAR ARGININE SENSOR FOR MTORC1 PROTEIN 2; CASTOR2","url":"https://www.omim.org/entry/617033"},{"mim_id":"615359","title":"MEIOSIS REGULATOR FOR OOCYTE DEVELOPMENT; MIOS","url":"https://www.omim.org/entry/615359"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"skeletal 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signaling","url":"https://pubmed.ncbi.nlm.nih.gov/25921289","citation_count":61,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25512509","id":"PMC_25512509","title":"TORC1 regulators Iml1/GATOR1 and GATOR2 control meiotic entry and oocyte development in Drosophila.","date":"2014","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/25512509","citation_count":54,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":25627,"output_tokens":3250,"usd":0.062815},"stage2":{"model":"claude-opus-4-6","input_tokens":6613,"output_tokens":3050,"usd":0.163972},"total_usd":0.526873,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":38452,"output_tokens":6416,"usd":0.105798},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":9395,"output_tokens":3302,"usd":0.194288}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"MIOS (Mio), a conserved member of the SEACAT/GATOR2 complex, is required for mTORC1 kinase activation and plays a critical role in mitotic spindle formation and chromosome segregation by regulating the concentration of active Plk1 and Aurora A kinases at centrosomes and spindle poles. Mio-depleted cells showed reduced activation of Plk1 and Aurora A at spindle poles and impaired localization of MCAK and HURP (two Aurora A substrates and key regulators of mitotic spindle formation), resulting in spindle assembly and cytokinesis defects.\",\n      \"method\": \"siRNA depletion with immunofluorescence, kinase activity assays, and live-cell imaging; substrate localization rescue experiments\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype plus multiple orthogonal methods (IF, kinase assays, substrate tracking)\",\n      \"pmids\": [\"26124292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Drosophila Mio (ortholog of human MIOS) physically associates with the nucleoporin Seh1 (a component of the Nup107-160 NPC subcomplex). Loss of Seh1 drastically reduces Mio protein accumulation in the germline, and both mio and seh1 mutants share the same oogenesis defect whereby oocytes fail to maintain the meiotic cycle and develop as pseudo-nurse cells, placing Mio and Seh1 in the same functional pathway during Drosophila oogenesis.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), genetic null allele analysis, immunofluorescence of protein levels in mutant backgrounds\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic and biochemical evidence (Co-IP + null mutant phenocopy + protein level dependence)\",\n      \"pmids\": [\"21521741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In zebrafish, the RNA-binding protein Rbpms2 acts as a translational regulator upstream of the GATOR2 complex component Mios (ortholog of human MIOS) to promote nucleolar amplification via the mTORC1 signaling pathway. Genetic analyses place Mios downstream of Rbpms2 in a pathway that controls oocyte progression through an mTORC1-dependent checkpoint during sex determination and oogenesis.\",\n      \"method\": \"Genetic epistasis (rbpms2 and mios mutant/knockdown zebrafish), ribosome profiling/RNA-binding analysis, mTORC1 pathway readouts\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in zebrafish with multiple pathway readouts, single lab\",\n      \"pmids\": [\"38898112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MIOS (YULINK) interacts physically with glucose transporter 1 (GLUT1) in HCC cells, as demonstrated by proximity ligation assay and immunoprecipitation. Knockdown of YULINK suppresses GLUT1 expression and disrupts GLUT1 translocation from cytosol to the cell membrane, resulting in downregulated glucose uptake and glycolysis. YULINK deficiency under glucose restriction enhances cell death associated with increased ROS, DNA damage, and failure of ATM-CHK2 activation.\",\n      \"method\": \"Proximity ligation assay, co-immunoprecipitation, glucose uptake assay, glycolytic function assay, Western blotting, xenograft model\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct interaction shown by two orthogonal methods (PLA + co-IP), functional consequence confirmed by multiple assays; single lab\",\n      \"pmids\": [\"41013205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YULINK (MIOS) regulates PASMC migration, proliferation, and glycolysis (glucose uptake, GLUT1 expression, hexokinase II expression, pyruvate production). YULINK inhibition suppresses PDGFR signaling and the phosphorylation of FAK, PI3K, and AKT, suggesting YULINK acts through the PI3K-AKT pathway. YULINK and GLUT1 were observed to colocalize on PASMC membranes under PAH-related pathogenic conditions.\",\n      \"method\": \"siRNA knockdown and overexpression in PASMCs, Western blotting, glucose uptake assays, co-localization imaging\",\n      \"journal\": \"Biological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, multiple functional readouts with KD/OE and colocalization but no direct binding assay for YULINK-PI3K interaction\",\n      \"pmids\": [\"38057829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YULINK (MIOS) is required for cardiac function in zebrafish and cardiomyocytes. In mouse HL-1 cardiomyocytes, YULINK knockdown disrupts Ca2+ cycling, reduces PPARγ DNA binding activity, and reduces SERCA2 expression. PPARγ agonists rescue SERCA2 expression while PPARγ knockdown reduces it, placing YULINK upstream of PPARγ in a pathway regulating SERCA2 expression in cardiomyocytes.\",\n      \"method\": \"Morpholino knockdown in zebrafish, shRNA in mouse HL-1 cardiomyocytes and human iPSC-derived cardiomyocytes, Ca2+ imaging, PPARγ DNA-binding assay, Western blotting, rescue experiments with PPARγ agonists\",\n      \"journal\": \"Journal of biomedical science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods across multiple model systems; single lab; note a related FASEB paper was retracted\",\n      \"pmids\": [\"33423678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YULINK (MIOS) is involved in vasculogenesis in zebrafish and HUVECs, specifically in venous formation. YULINK knockdown in HUVECs impairs cell migration, tube formation, and reduces phosphorylated EPHB4. Yeast two-hybrid, FLIM-FRET, and immunoprecipitation showed YULINK colocalizes and interacts with endosome-related proteins EPS15, RAB33B, TICAM2, Clathrin, and RHOB. VEGF-induced VEGFR2 internalization is compromised upon YULINK knockdown, implicating YULINK in endocytic trafficking.\",\n      \"method\": \"Zebrafish morpholino knockdown, yeast two-hybrid, FLIM-FRET, co-immunoprecipitation, migration assay, tube formation assay, Western blotting\",\n      \"journal\": \"Biological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interactions confirmed by three orthogonal methods (yeast 2-hybrid, FLIM-FRET, co-IP); single lab\",\n      \"pmids\": [\"36843032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MIOS functions as a component of the GATOR2 complex to activate mTORC1 and regulate autophagy in glioblastoma cells. Treatment with Tanshinone IIA (T2A) inhibits mTORC1 and induces autophagy through sestrin 2 (SESN2) and MIOS; both effects are lost upon ablation of SESN or MIOS in Dictyostelium discoideum, placing MIOS downstream of SESN2 and upstream of mTORC1/autophagy. Pharmacological inhibition of MIOS (compound Mi3) reduced cell proliferation in GBM cell lines and induced autophagy in a MIOS-dependent manner.\",\n      \"method\": \"Genetic knockout (mios-) in Dictyostelium, GBM cell lines with MIOS inhibitor treatment, mTORC1 activity assays, autophagy assays, computational docking\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with null mutants combined with pharmacological inhibition and functional pathway readouts; single lab\",\n      \"pmids\": [\"38928292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila Mio (ortholog of human MIOS/ChREBP) acts as a transcription factor in the fat body to regulate lipogenic enzyme mRNA expression in response to high sugar. RNAi-mediated knockdown of Mio specifically in the fat body produces a lean phenotype with blunted high-sugar-induced lipogenic enzyme mRNA expression and decreased feeding behavior. Bigmax (fly Mlx homolog), the binding partner of Mio, shows a similar lean phenotype when knocked down in the fat body.\",\n      \"method\": \"RNAi knockdown in Drosophila fat body, triglyceride measurements, mRNA expression analysis, feeding behavior assays\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KD with defined metabolic phenotype and gene expression readouts; single lab\",\n      \"pmids\": [\"22910416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Drosophila Mio (ortholog of human MIOS) functions in neurons to regulate feeding and nutrient storage. Pan-neuronal disruption of Mio leads to increased triglyceride and glycogen storage without increased food consumption. Targeted knockdown specifically in insulin-producing cells (IPCs) increases feeding and dilp3 expression, indicating Mio regulates neuropeptide gene expression in IPCs to coordinate feeding behavior with nutrient availability.\",\n      \"method\": \"UAS-RNAi neuronal and IPC-specific knockdown in Drosophila, triglyceride/glycogen measurements, qPCR of dilp gene expression, feeding behavior assay\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific KD with defined phenotypic readouts and molecular mechanism (neuropeptide gene expression); single lab\",\n      \"pmids\": [\"26024590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Drosophila Mio (ortholog of human MIOS) functions in muscle to regulate glycogen storage and myofibril development. Muscle-specific RNAi knockdown of Mio results in increased thorax glycogen storage and a flight defect associated with altered myofibril shape and size in indirect flight muscles, with myofibril size also decreased in pre-eclosion pupae.\",\n      \"method\": \"Muscle-specific UAS-RNAi in Drosophila, glycogen measurements, electron microscopy of myofibrils, flight assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KD with structural (EM) and biochemical phenotypic readouts; single lab\",\n      \"pmids\": [\"26305467\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MIOS is a conserved WD40-repeat-containing subunit of the GATOR2 complex that positively regulates mTORC1 kinase activity; in mitosis, MIOS depletion impairs Aurora A and Plk1 activation at centrosomes/spindle poles, causing spindle assembly and cytokinesis defects; MIOS also interacts physically with GLUT1 to regulate glucose uptake and glycolysis, associates with endosomal proteins to support VEGFR2 internalization and vasculogenesis, and in cardiac cells acts upstream of PPARγ to regulate SERCA2 expression and Ca²⁺ cycling, while Drosophila ortholog studies establish its role as a nutrient-responsive transcription factor controlling lipid synthesis, feeding behavior, and muscle metabolism downstream of carbohydrate signaling.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEPT papers only.\n\n**Classification:**\n- Papers about MIO-M1 (Müller cell line), MIO cells (poliovirus), MIO (cofactor for ammonia lyases), MIO (imaging method), MIO (bladder cancer model), MIO (snail clade), MIO (microRNA tool), MiO/Mio-hBC model → EXCLUDE (alias collisions)\n- Papers about MIOS/Mio as GATOR2 component, mTORC1 pathway, ChREBP homolog in Drosophila/zebrafish, or YULINK (same gene, Entrez 54468) → KEEP\n\n**KEPT papers:**\n- PMID:23723238 (Bar-Peled GATOR1/GATOR2)\n- PMID:25512509 (Wei GATOR2/Mio Drosophila)\n- PMID:21521741 (Senger Seh1/Mio Drosophila)\n- PMID:26124292 (Platani Mio/mitosis)\n- PMID:22910416 (Sassu Mio/ChREBP Drosophila)\n- PMID:26024590 (Docherty Mio brain Drosophila)\n- PMID:26305467 (Polak Mio muscle Drosophila)\n- PMID:35831510 (Valenstein GATOR2 structure)\n- PMID:38898112 (Wilson Rbpms2/Mios zebrafish)\n- PMID:38328218 (Wilson preprint, same as above)\n- PMID:38057829 (Wu YULINK/PAH)\n- PMID:33423678 (Kuo YULINK cardiac)\n- PMID:29401584 (Tsai YULINK heart failure - RETRACTED)\n- PMID:36843032 (Lin YULINK vascular)\n- PMID:41013205 (Wu YULINK HCC)\n- PMID:38928292 (Shinhmar MIOS/GBM)\n- PMID:26449471 (Wolfson Sestrin2/GATOR2)\n- PMID:26586190 (Saxton Sestrin2 structure)\n- PMID:25263562 (Chantranupong Sestrins/GATOR2)\n- PMID:26972053 (Chantranupong CASTOR/GATOR2)\n- PMID:28199306 (Wolfson KICSTOR)\n- PMID:28199315 (Peng SZT2/GATOR)\n- PMID:35114100 (Wang RNF167/Sestrin2)\n- PMID:19615732 (Sowa DUB interactome - MIOS as interactor, minor)\n- PMID:26186194 (BioPlex - interactome, minor)\n- PMID:28514442 (BioPlex 2.0 - minor)\n- PMID:33961781 (BioPlex 3.0 - minor)\n- PMID:35271311 (OpenCell - localization)\n- PMID:34079125 (BioID map)\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2013,\n      \"finding\": \"MIOS (Mios) was identified as a subunit of GATOR2, a five-protein complex (Mios, WDR24, WDR59, Seh1L, Sec13) that positively regulates mTORC1 signaling upstream of the Rag GTPases. Inhibition of GATOR2 subunits suppresses mTORC1 signaling, and epistasis analysis showed GATOR2 negatively regulates GATOR1 component DEPDC5. GATOR2 interacts with the Rag GTPases as part of the amino acid sensing pathway.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, RNAi knockdown, epistasis analysis, mTORC1 activity assays (S6K phosphorylation)\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, epistasis, replicated widely across subsequent studies\",\n      \"pmids\": [\"23723238\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Drosophila Mio protein physically associates with the nucleoporin Seh1 (ortholog of mammalian Seh1L/SEH1L). In seh1 mutant ovaries, Mio protein levels are greatly diminished, and both mio and seh1 mutants show identical defects in oogenesis: a fraction of oocytes fail to maintain the meiotic cycle and develop as pseudo-nurse cells. This establishes Mio as a novel interacting partner of Seh1 with a conserved role in germline meiotic progression.\",\n      \"method\": \"Co-immunoprecipitation, genetic mutant analysis, immunofluorescence, null allele characterization\",\n      \"journal\": \"Development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP plus genetic phenocopy, strong concordance between mio and seh1 mutants\",\n      \"pmids\": [\"21521741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In Drosophila oogenesis, GATOR2 components Mio and Seh1 are required to oppose GATOR1 (Iml1 complex) activity to prevent constitutive inhibition of TORC1 and a block to oocyte growth and development. Loss of Mio causes premature TORC1 inhibition, placing GATOR2 as a positive regulator of TORC1 that antagonizes GATOR1 during meiotic progression.\",\n      \"method\": \"Genetic loss-of-function (mio and seh1 mutants), rapamycin treatment, epistasis with Tor mutants, immunofluorescence for TORC1 activity markers\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple alleles and pharmacological validation in vivo\",\n      \"pmids\": [\"25512509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Drosophila Mio (dChREBP ortholog) functions as a transcription factor in the fat body to control triglyceride accumulation: Mio mutants show blunted high-sugar-induced lipogenic enzyme mRNA expression, and fat-body-specific Mio RNAi produces a lean phenotype. Fat-body Mio depletion also decreases feeding behavior, suggesting Mio acts as a nutrient sensor coordinating food consumption and lipid metabolism.\",\n      \"method\": \"Mio mutant analysis, tissue-specific RNAi, triglyceride/glycogen assays, feeding behavior assays, qRT-PCR for lipogenic enzymes\",\n      \"journal\": \"Biochemical and Biophysical Research Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean tissue-specific KD with defined metabolic readouts, single lab\",\n      \"pmids\": [\"22910416\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Depletion of Mio in human cells (a GATOR2 component necessary for mTORC1 activation) causes mitotic spindle defects: reduced activation of Aurora A and Plk1 kinases at centrosomes/spindle poles, impaired localization of MCAK and HURP (Aurora A substrates), and spindle assembly/cytokinesis defects. This links GATOR2/Mio to mTOR-dependent regulation of mitotic kinase activation.\",\n      \"method\": \"siRNA depletion of Mio in human cells, immunofluorescence for Aurora A/Plk1/MCAK/HURP, quantification of mitotic defects, kinase activity assays\",\n      \"journal\": \"Journal of Cell Biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined mitotic phenotype and pathway placement, single lab\",\n      \"pmids\": [\"26124292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"The Sestrins (leucine sensors) interact with GATOR2 (of which MIOS is a core subunit) in an amino-acid-sensitive fashion. Sestrin2-mediated inhibition of mTORC1 requires GATOR1 and Rag GTPases, and Sestrins regulate lysosomal localization of mTORC1 in response to amino acids, placing GATOR2/MIOS as an intermediary between amino acid sensors and the Rag GTPase machinery.\",\n      \"method\": \"Co-immunoprecipitation, amino acid deprivation/stimulation assays, mTORC1 activity (S6K/4EBP1 phosphorylation), siRNA knockdown, fluorescence microscopy of mTOR localization\",\n      \"journal\": \"Cell Reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, replicated in subsequent studies\",\n      \"pmids\": [\"25263562\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Leucine disrupts the Sestrin2-GATOR2 interaction by binding directly to Sestrin2, activating mTORC1. This positions GATOR2 (containing MIOS) as the molecular hub through which the leucine sensor Sestrin2 regulates mTORC1, since GATOR2 interaction with Sestrin2 is required for amino acid-dependent mTORC1 control.\",\n      \"method\": \"Biochemical binding assays (leucine-binding to Sestrin2), co-immunoprecipitation, mTORC1 activity assays, mutagenesis of leucine-binding pocket\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding assay with mutagenesis, replicated structurally\",\n      \"pmids\": [\"26449471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of Sestrin2 in complex with leucine reveals leucine binding pocket and lid-latch mechanism; structure-guided mutations decrease leucine affinity and shift the leucine concentration required for mTORC1 activation, confirming that GATOR2 (MIOS-containing complex) interaction with Sestrin2 is central to leucine sensing.\",\n      \"method\": \"X-ray crystallography (2.7 Å), structure-guided mutagenesis, mTORC1 activity assays in cells\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with functional mutagenesis validation\",\n      \"pmids\": [\"26586190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"CASTOR1 (arginine sensor) interacts with GATOR2 (which contains MIOS) and is required for arginine deprivation to inhibit mTORC1. Arginine binding to CASTOR1 disrupts the CASTOR1-GATOR2 interaction, activating mTORC1. This establishes GATOR2/MIOS as a scaffold that integrates both leucine (via Sestrin2) and arginine (via CASTOR1) sensing inputs.\",\n      \"method\": \"Co-immunoprecipitation, arginine binding assays, mTORC1 activity assays, mutagenesis of arginine-binding residues\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — direct binding assay with mutagenesis and epistasis, replicated\",\n      \"pmids\": [\"26972053\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"KICSTOR complex recruits GATOR1 to the lysosomal surface and is required for amino acid or glucose deprivation to inhibit mTORC1. KICSTOR binds GATOR1 but not GATOR2, and is necessary for GATOR1 to interact with the Rag GTPases and with GATOR2, placing MIOS-containing GATOR2 downstream of KICSTOR-GATOR1 interaction in the nutrient-sensing hierarchy.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, lysosomal fractionation, mTORC1 activity assays, mouse knockout\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods, in vivo mouse model, replicated\",\n      \"pmids\": [\"28199306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SZT2 orchestrates a supercomplex (SOG) by recruiting both GATOR1 and GATOR2 (containing MIOS) to the lysosome. Intact SOG complex is required for lysosomal localization of GATOR2 and for SESN-dependent nutrient sensing and mTORC1 regulation, revealing that MIOS/GATOR2 must be lysosome-localized for full activity.\",\n      \"method\": \"Co-immunoprecipitation, lysosome fractionation, SZT2 knockout cells and mice, mTORC1 activity assays, overexpression rescue experiments\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods with in vivo validation\",\n      \"pmids\": [\"28199315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Mio functions in Drosophila neurons to regulate feeding and nutrient storage independently of its fat body role. Pan-neuronal disruption of Mio increases triglyceride and glycogen storage without increased food intake; targeted disruption in insulin-producing cells (IPCs) increases food consumption and dilp3 expression, indicating Mio controls neuropeptide gene expression in IPCs to coordinate feeding with nutrient availability.\",\n      \"method\": \"Tissue-specific RNAi (pan-neuronal and IPC-specific), triglyceride/glycogen biochemical assays, feeding behavior quantification, qRT-PCR for insulin-like peptides\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KD with defined cellular phenotype, single lab\",\n      \"pmids\": [\"26024590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Muscle-specific depletion of Mio in Drosophila results in increased thorax glycogen storage and a flight defect due to altered myofibril shape and size in indirect flight muscles, with reduced myofibril size also observed pre-eclosion, indicating a role for Mio in myofibril development and muscle metabolism.\",\n      \"method\": \"Muscle-specific RNAi, glycogen assays, electron microscopy of indirect flight muscles, flight performance assays\",\n      \"journal\": \"PLoS One\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KD with ultrastructural phenotype, single lab\",\n      \"pmids\": [\"26305467\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-electron microscopy structure of the human GATOR2 complex (1.1 MDa, 2-fold symmetric, cage-like) reveals that MIOS contributes four of the eight scaffold subunits (two WDR24, four MIOS, two WDR59) circularized via non-catalytic RING domains and α-solenoids. MIOS non-catalytic RING domains form one type of inter-subunit junction. SEH1L and SEC13 stabilize the complex through β-propeller blade donation. The scaffold orients WD40 β-propeller dimers that mediate interactions with SESN2, CASTOR1, and GATOR1.\",\n      \"method\": \"Cryo-electron microscopy, biochemical reconstitution, subunit stoichiometry determination, interaction mapping\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure with biochemical validation of subunit architecture\",\n      \"pmids\": [\"35831510\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"E3 ligase RNF167 ubiquitinates Sestrin2, promoting its interaction with GATOR2 (MIOS-containing complex) and inhibiting mTORC1 signaling in response to leucine availability, while deubiquitinase STAMBPL1 opposes this. This identifies ubiquitination of Sestrin2 as a post-translational mechanism regulating GATOR2/MIOS engagement.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assays, mTORC1 activity assays, RNF167/STAMBPL1 knockout cells, cell-permeable peptide inhibitor\",\n      \"journal\": \"Molecular Cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal biochemical methods, single lab\",\n      \"pmids\": [\"35114100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In zebrafish, Rbpms2 (RNA binding protein) acts as a translational regulator upstream of the GATOR2 component Mios to promote oocyte fate. Genetic analyses show Rbpms2 promotes nucleolar amplification via the mTorc1 signaling pathway specifically through Mios; loss of Mios phenocopies loss of Rbpms2 in blocking oocyte progression through a GATOR2-mediated checkpoint that integrates sexual differentiation and nutrient availability.\",\n      \"method\": \"Genetic epistasis (mios mutants, rbpms2 mutants), mTORC1 activity assays in oocytes, translational reporter assays, zebrafish oogenesis phenotyping\",\n      \"journal\": \"Nature Communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in vivo with defined developmental phenotype, single lab\",\n      \"pmids\": [\"38898112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"YULINK (MIOS, Entrez 54468) knockdown in zebrafish cardiomyocytes and mouse HL-1 cardiomyocytes disrupts Ca²⁺ cycling and reduces SERCA2 expression. Mechanistically, Yulink knockdown reduces PPARγ DNA binding activity, and PPARγ agonists restore Serca2 expression, indicating Yulink regulates Serca2 via PPARγ nuclear entry. This function was confirmed in human iPSC-derived cardiomyocytes.\",\n      \"method\": \"Morpholino knockdown in zebrafish, shRNA in HL-1 and iPSC-derived cardiomyocytes, Ca²⁺ imaging, PPARγ DNA binding assay, Western blot, qPCR, PPARγ agonist/antagonist rescue\",\n      \"journal\": \"Journal of Biomedical Science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple model systems and rescue experiments, single lab; note related paper (29401584) was retracted\",\n      \"pmids\": [\"33423678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YULINK (MIOS) knockdown or overexpression modulates PASMC migration, proliferation, and glycolysis. YULINK colocalizes with GLUT1 on PASMC membranes under PAH-related conditions. YULINK inhibition suppresses PDGFR phosphorylation and downstream PI3K/AKT/FAK signaling, indicating YULINK regulates glycolytic metabolism and proliferative signaling in vascular smooth muscle cells through PI3K-AKT pathway.\",\n      \"method\": \"siRNA knockdown, overexpression, co-localization immunofluorescence, migration assay, glucose uptake assay, Western blot for signaling components\",\n      \"journal\": \"Biological Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — functional KD/OE with signaling readouts, single lab\",\n      \"pmids\": [\"38057829\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"YULINK (MIOS) knockdown in HUVECs impairs cell migration, capillary tube formation, and VEGF-induced VEGFR2 internalization. Yeast two-hybrid, FLIM-FRET, and immunoprecipitation show YULINK colocalizes with endosomal proteins (EPS15, RAB33B, TICAM2, Clathrin, RHOB), suggesting YULINK participates in endocytic vesicle trafficking to regulate vascular formation.\",\n      \"method\": \"Morpholino knockdown in zebrafish, siRNA in HUVECs, yeast two-hybrid, FLIM-FRET, immunoprecipitation, co-localization imaging, tube formation assay\",\n      \"journal\": \"Biological Research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple interaction methods converge on endosomal localization, single lab\",\n      \"pmids\": [\"36843032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"YULINK (MIOS) interacts with and colocalizes with GLUT1 at the cell membrane in HCC cells (Huh7), as shown by proximity ligation assay and immunoprecipitation. Yulink knockdown suppresses GLUT1 expression and disrupts GLUT1 translocation from cytosol to cell membrane, reducing glucose uptake and glycolysis. Under glucose restriction, Yulink deficiency enhances cell death via increased ROS and DNA damage with failure of ATM-CHK2 activation.\",\n      \"method\": \"Proximity ligation assay, co-immunoprecipitation, immunofluorescence, glucose uptake assay, glycolytic function assay, ROS measurement, xenograft tumor model\",\n      \"journal\": \"Molecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct protein interaction demonstrated by two orthogonal methods, single lab\",\n      \"pmids\": [\"41013205\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In Dictyostelium discoideum and GBM cell lines, tanshinone IIA (T2A) induces autophagy and inhibits mTORC1 via Sestrin2 (SESN) acting through MIOS (GATOR2 component); these effects are lost upon ablation of SESN or MIOS. Computational docking identified small-molecule MIOS inhibitor Mi3, which reduces GBM cell proliferation, inhibits mTORC1, and induces autophagy in a MIOS-dependent manner.\",\n      \"method\": \"Genetic ablation of mios in Dictyostelium, mTORC1 activity assays, autophagy assays, computational docking, GBM cell line treatment with Mi3\",\n      \"journal\": \"International Journal of Molecular Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — genetic epistasis plus pharmacological inhibitor with specificity validation\",\n      \"pmids\": [\"38928292\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MIOS (also known as YULINK) is a core structural subunit of the GATOR2 complex (together with WDR24, WDR59, SEH1L, and SEC13), which forms a 1.1 MDa cage-like scaffold in which four MIOS subunits contribute non-catalytic RING domain junctions; GATOR2 acts as a positive regulator of mTORC1 signaling by serving as a scaffold that integrates leucine sensing (via Sestrin2 interaction) and arginine sensing (via CASTOR1 interaction) to antagonize the GATOR1 GTPase-activating complex toward Rag GTPases at the lysosomal surface, and MIOS additionally regulates mitotic kinase activation (Aurora A, Plk1), cardiomyocyte calcium cycling via PPARγ-SERCA2, GLUT1-dependent glucose uptake and glycolysis, and—in model organisms—oocyte meiotic progression and lipid/nutrient homeostasis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"MIOS is a conserved WD40-repeat protein that serves as a core subunit of the GATOR2 complex, functioning as a positive regulator of mTORC1 signaling with additional roles in mitotic spindle assembly, glucose metabolism, endocytic trafficking, and nutrient-responsive transcriptional control. As a GATOR2 component, MIOS activates mTORC1 and regulates autophagy; genetic ablation of MIOS in Dictyostelium and pharmacological inhibition in glioblastoma cells block mTORC1 activity and induce autophagy downstream of sestrin 2 [PMID:38928292], while in zebrafish oogenesis MIOS mediates an mTORC1-dependent checkpoint controlling nucleolar amplification [PMID:38898112]. Beyond mTORC1, MIOS depletion in human cells impairs activation of Aurora A and Plk1 at centrosomes, causing spindle assembly and cytokinesis defects [PMID:26124292], and MIOS physically interacts with GLUT1 to promote its membrane translocation and support glycolysis [PMID:41013205, PMID:38057829]. MIOS also associates with endosomal proteins (EPS15, RAB33B, Clathrin, RHOB) to facilitate VEGFR2 internalization during vasculogenesis [PMID:36843032], and its Drosophila ortholog functions as a sugar-responsive transcription factor partnering with Bigmax/Mlx to drive lipogenic gene expression in the fat body and regulate feeding behavior and muscle metabolism [PMID:22910416, PMID:26024590, PMID:26305467].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Establishing that MIOS functions in a protein complex with the nucleoporin Seh1 resolved how Mio protein stability is maintained and linked it to a specific developmental process—oocyte meiotic maintenance—providing the first biochemical and genetic framework for Mio function in vivo.\",\n      \"evidence\": \"Co-IP of Mio–Seh1 and genetic null allele analysis in Drosophila oogenesis\",\n      \"pmids\": [\"21521741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the Mio–Seh1 interaction is direct or bridged by additional GATOR2/SEA subunits\",\n        \"Mechanism by which Seh1 stabilizes Mio protein\",\n        \"Whether this interaction is conserved in mammalian systems\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrating that Drosophila Mio acts as a nutrient-responsive transcription factor in the fat body—partnering with Bigmax/Mlx to drive lipogenic gene expression on a high-sugar diet—established MIOS as a carbohydrate-sensing transcriptional regulator of lipid metabolism.\",\n      \"evidence\": \"Tissue-specific RNAi in Drosophila fat body with triglyceride quantification, lipogenic mRNA expression, and feeding behavior assays\",\n      \"pmids\": [\"22910416\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether human MIOS retains direct transcription factor activity or this is a Drosophila-specific function\",\n        \"Direct DNA-binding evidence for Mio\",\n        \"Chromatin occupancy data for Mio at lipogenic gene promoters\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extending Mio's tissue-specific roles to neurons and muscle showed it regulates feeding behavior, neuropeptide expression in insulin-producing cells, glycogen storage, and myofibril development, broadening the functional scope from fat body lipogenesis to systemic metabolic and structural regulation.\",\n      \"evidence\": \"Neuron- and muscle-specific UAS-RNAi in Drosophila with metabolic, behavioral, and ultrastructural (EM) readouts\",\n      \"pmids\": [\"26024590\", \"26305467\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether these phenotypes are mTORC1-dependent or reflect transcription-factor-specific functions\",\n        \"Identity of direct Mio transcriptional targets in neurons and muscle\",\n        \"Relevance of these tissue-specific roles in mammalian physiology\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Showing that MIOS depletion in human cells impairs Aurora A and Plk1 activation at spindle poles—causing spindle assembly and cytokinesis defects—revealed an unexpected mitotic function for a GATOR2 subunit, linking nutrient signaling machinery to cell division control.\",\n      \"evidence\": \"siRNA knockdown in human cells with immunofluorescence, kinase activity assays, live-cell imaging, and substrate localization rescue\",\n      \"pmids\": [\"26124292\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the mitotic role depends on mTORC1 activity or is mTORC1-independent\",\n        \"Direct physical link between MIOS and Aurora A/Plk1 activation machinery\",\n        \"Whether other GATOR2 subunits share this mitotic function\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placing MIOS upstream of PPARγ-dependent SERCA2 expression in cardiomyocytes revealed a cardiac-specific signaling axis where MIOS loss disrupts Ca²⁺ cycling, expanding its functional repertoire to heart physiology.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish and shRNA in mouse HL-1/human iPSC-derived cardiomyocytes with Ca²⁺ imaging and PPARγ rescue experiments\",\n      \"pmids\": [\"33423678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which MIOS regulates PPARγ DNA-binding activity\",\n        \"Whether this pathway operates via mTORC1 or is an independent function\",\n        \"A related publication from this group was retracted, warranting independent replication\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identifying MIOS interactions with endosomal trafficking proteins (EPS15, RAB33B, Clathrin, RHOB) and showing that MIOS is required for VEGFR2 internalization established a role in endocytic trafficking during vasculogenesis.\",\n      \"evidence\": \"Yeast two-hybrid, FLIM-FRET, co-IP in HUVECs; zebrafish morpholino knockdown; migration and tube formation assays\",\n      \"pmids\": [\"36843032\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MIOS participates in endocytic trafficking independently of GATOR2\",\n        \"Structural basis for MIOS interaction with clathrin-coated pit components\",\n        \"Whether MIOS regulates internalization of receptors beyond VEGFR2\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrating that MIOS physically interacts with GLUT1 and is required for GLUT1 membrane translocation, glucose uptake, and glycolysis provided a direct mechanistic link between MIOS and cellular glucose metabolism, validated across PASMCs and HCC cells.\",\n      \"evidence\": \"Proximity ligation assay, co-IP, glucose uptake assays, glycolysis measurements, and xenograft models in HCC and PASMC systems\",\n      \"pmids\": [\"38057829\", \"41013205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether MIOS–GLUT1 interaction is direct or mediated by an intermediate\",\n        \"Structural determinants of the interaction\",\n        \"Relationship between MIOS–GLUT1 regulation and GATOR2/mTORC1 function\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Genetic epistasis placing MIOS downstream of sestrin 2 and upstream of mTORC1/autophagy—combined with pharmacological inhibition by compound Mi3—confirmed MIOS as a druggable node in the GATOR2–mTORC1–autophagy axis with therapeutic relevance to glioblastoma.\",\n      \"evidence\": \"Genetic knockout in Dictyostelium, GBM cell treatment with MIOS inhibitor Mi3, mTORC1 and autophagy readouts\",\n      \"pmids\": [\"38928292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Selectivity and binding mode of Mi3 for MIOS\",\n        \"Whether Mi3 effects are fully MIOS-dependent in mammalian cells\",\n        \"In vivo efficacy data in animal tumor models\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Zebrafish genetic epistasis positioned MIOS downstream of the RNA-binding protein Rbpms2 in a translational regulatory pathway controlling oocyte progression through an mTORC1-dependent checkpoint, linking MIOS to translational control of oogenesis.\",\n      \"evidence\": \"Genetic epistasis in rbpms2 and mios mutant zebrafish with ribosome profiling and mTORC1 readouts\",\n      \"pmids\": [\"38898112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether Rbpms2 directly binds MIOS mRNA or acts indirectly\",\n        \"Conservation of this translational regulatory axis in mammals\",\n        \"Whether MIOS protein levels are limiting for mTORC1 activation in oocytes\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unresolved how MIOS's multiple reported functions—mTORC1 activation, mitotic kinase regulation, GLUT1 trafficking, endocytic trafficking, and transcription factor activity—are mechanistically integrated or compartmentalized, and whether they all operate through a unified GATOR2-dependent mechanism or represent separable functions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No structural model of MIOS within the GATOR2 complex at atomic resolution\",\n        \"No separation-of-function mutants distinguishing mTORC1-dependent from mTORC1-independent roles\",\n        \"No systematic interactome study in mammalian cells under defined nutrient conditions\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 7]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [3, 4, 8]}\n    ],\n    \"complexes\": [\n      \"GATOR2\"\n    ],\n    \"partners\": [\n      \"SEH1L\",\n      \"GLUT1\",\n      \"EPS15\",\n      \"RAB33B\",\n      \"RHOB\",\n      \"SESN2\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"MIOS is a core structural subunit of the GATOR2 complex, a ~1.1 MDa cage-like scaffold composed of four MIOS, two WDR24, two WDR59, SEH1L, and SEC13 subunits, in which MIOS contributes non-catalytic RING domain junctions that circularize the assembly [PMID:35831510, PMID:23723238]. GATOR2 functions as a positive regulator of mTORC1 by antagonizing the GATOR1 GAP complex toward Rag GTPases; it serves as the integration hub for amino acid sensing, binding the leucine sensor Sestrin2 and the arginine sensor CASTOR1 in a nutrient-dependent manner such that amino acid sufficiency releases these inhibitory sensors from GATOR2 and permits mTORC1 activation [PMID:26449471, PMID:26972053, PMID:25263562]. Lysosomal recruitment of GATOR2 is organized by the KICSTOR–SZT2 supercomplex, which is required for nutrient-dependent GATOR1–GATOR2 interaction and mTORC1 regulation [PMID:28199306, PMID:28199315]. Beyond mTORC1 signaling, MIOS is required for mTOR-dependent activation of mitotic kinases Aurora A and Plk1 at spindle poles in human cells [PMID:26124292], for oocyte meiotic progression in Drosophila and zebrafish [PMID:21521741, PMID:38898112], and regulates GLUT1-dependent glucose uptake and PPARγ–SERCA2 calcium cycling in mammalian cardiomyocytes and cancer cells [PMID:41013205, PMID:33423678].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"The first physical interaction partner for Mio was identified — the nucleoporin Seh1 — and genetic analysis showed that both genes share an identical oocyte meiotic maintenance phenotype in Drosophila, establishing Mio as a novel factor required for germline meiotic progression.\",\n      \"evidence\": \"Reciprocal co-IP and null allele phenocopying in Drosophila ovaries\",\n      \"pmids\": [\"21521741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mammalian relevance of the meiotic phenotype was not tested\",\n        \"Mechanism by which Mio-Seh1 interaction supports meiosis was unknown\"\n      ]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"MIOS was placed in a defined five-subunit complex (GATOR2) that positively regulates mTORC1 by opposing the GATOR1 GAP complex, resolving how upstream nutrient cues reach the Rag GTPases.\",\n      \"evidence\": \"Co-IP/MS identification of GATOR2 subunits, RNAi epistasis with DEPDC5, S6K phosphorylation readouts in HEK293T cells\",\n      \"pmids\": [\"23723238\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The direct nutrient sensors feeding into GATOR2 were unknown\",\n        \"Structural basis of GATOR2 assembly was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Genetic epistasis in Drosophila confirmed that Mio/GATOR2 opposes GATOR1 in vivo to maintain TORC1 activity during oocyte growth, establishing the pathway hierarchy in an animal model and linking it to oocyte fate decisions.\",\n      \"evidence\": \"Loss-of-function mio and seh1 alleles, epistasis with Tor pathway, rapamycin treatment in Drosophila ovaries\",\n      \"pmids\": [\"25512509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct biochemical interaction between GATOR2 and GATOR1 in Drosophila was not demonstrated\",\n        \"Whether nutrient availability gates this checkpoint was unclear\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The nutrient-sensing logic of GATOR2 was decoded: Sestrin2 (leucine sensor) binds GATOR2, and leucine binding to Sestrin2 disrupts this interaction to activate mTORC1, positioning GATOR2/MIOS as the molecular hub for leucine sensing.\",\n      \"evidence\": \"Co-IP of Sestrin2–GATOR2, leucine-binding assays, mutagenesis of Sestrin2 leucine pocket, crystal structure of Sestrin2–leucine complex\",\n      \"pmids\": [\"25263562\", \"26449471\", \"26586190\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Which GATOR2 surface(s) Sestrin2 contacts was unknown at this time\",\n        \"Whether additional amino acids signal through GATOR2 was not resolved\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"MIOS was shown to have a cell-cycle function beyond nutrient sensing: its depletion impairs Aurora A and Plk1 activation at spindle poles, linking GATOR2–mTOR signaling to mitotic kinase regulation.\",\n      \"evidence\": \"siRNA depletion in human cells, immunofluorescence quantification of Aurora A/Plk1 phosphorylation, mitotic defect scoring\",\n      \"pmids\": [\"26124292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether the mitotic phenotype is entirely mTOR-dependent or involves a GATOR2-autonomous mechanism is unresolved\",\n        \"Not independently replicated\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"CASTOR1 was identified as a second amino acid sensor (for arginine) that binds GATOR2, establishing GATOR2/MIOS as the convergence point for both leucine and arginine sensing arms of mTORC1 regulation.\",\n      \"evidence\": \"Co-IP of CASTOR1–GATOR2, arginine-binding assays, mutagenesis, mTORC1 activity in arginine-depleted cells\",\n      \"pmids\": [\"26972053\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether CASTOR1 and Sestrin2 bind the same or different surfaces of GATOR2 was unknown\",\n        \"Structural basis of CASTOR1–GATOR2 interaction was unresolved\"\n      ]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The lysosomal targeting mechanism for GATOR2 was elucidated: KICSTOR and SZT2 recruit GATOR1 and GATOR2 into a lysosome-associated supercomplex (SOG) required for nutrient-dependent mTORC1 regulation, establishing that MIOS/GATOR2 must be lysosome-localized to function.\",\n      \"evidence\": \"Co-IP, lysosomal fractionation, SZT2 KO cells/mice, KICSTOR KO, mTORC1 activity assays\",\n      \"pmids\": [\"28199306\", \"28199315\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry of the SOG supercomplex was unresolved\",\n        \"How nutrient signals dynamically regulate SOG assembly was unknown\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The cryo-EM structure of GATOR2 revealed its 1.1 MDa cage architecture with four MIOS subunits contributing non-catalytic RING domain junctions, and showed how WD40 β-propeller dimers orient the binding surfaces for Sestrin2, CASTOR1, and GATOR1, providing a structural basis for MIOS's scaffolding role.\",\n      \"evidence\": \"Cryo-EM at near-atomic resolution, biochemical reconstitution, subunit stoichiometry determination\",\n      \"pmids\": [\"35831510\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis of the GATOR2–GATOR1 inhibitory interaction is not yet resolved at atomic level\",\n        \"Whether the non-catalytic RING domains of MIOS have latent activity or allosteric roles is untested\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"MIOS (YULINK) was found to colocalize with and regulate GLUT1 membrane translocation and to participate in endocytic vesicle trafficking via interactions with EPS15, RAB33B, and clathrin, extending its functions beyond mTORC1 signaling to glucose metabolism and vesicle trafficking in vascular and cancer cells.\",\n      \"evidence\": \"Proximity ligation assay, co-IP, FLIM-FRET, yeast two-hybrid, glucose uptake and glycolysis assays in HCC cells and HUVECs\",\n      \"pmids\": [\"38057829\", \"36843032\", \"41013205\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether GLUT1 interaction and endosomal trafficking functions are GATOR2-dependent or MIOS-autonomous is unresolved\",\n        \"Findings are from a single research group and await independent replication\",\n        \"Structural basis of MIOS–GLUT1 interaction is unknown\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"In zebrafish, Mios was placed downstream of translational regulator Rbpms2 in a GATOR2-mediated checkpoint that integrates sexual differentiation with nutrient availability during oocyte fate determination, and a small-molecule MIOS inhibitor (Mi3) was shown to phenocopy MIOS loss in GBM cells.\",\n      \"evidence\": \"Genetic epistasis in zebrafish oocytes, mTORC1/autophagy assays, computational docking and Mi3 treatment in GBM cell lines and Dictyostelium\",\n      \"pmids\": [\"38898112\", \"38928292\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mi3 selectivity for MIOS over other GATOR2 subunits is not fully validated\",\n        \"Whether the oocyte checkpoint is conserved in mammals remains untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the atomic-resolution structure of GATOR2 in complex with GATOR1, whether MIOS RING domains possess latent catalytic or allosteric function, the extent to which MIOS functions outside GATOR2 (e.g., GLUT1 regulation, vesicle trafficking) are complex-dependent, and whether pharmacological MIOS inhibition is viable for cancer therapy.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No GATOR2–GATOR1 co-structure exists\",\n        \"MIOS-autonomous vs GATOR2-dependent functions are not delineated\",\n        \"In vivo efficacy and specificity of MIOS-targeting small molecules are untested\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 5, 8, 13]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 5, 6, 8, 9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [9, 10]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 13]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [17, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 5, 6, 8, 9, 10]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [17, 19]}\n    ],\n    \"complexes\": [\n      \"GATOR2\",\n      \"SOG (SZT2-GATOR1-GATOR2 supercomplex)\"\n    ],\n    \"partners\": [\n      \"WDR24\",\n      \"WDR59\",\n      \"SEH1L\",\n      \"SEC13\",\n      \"SESN2\",\n      \"CASTOR1\",\n      \"GLUT1\",\n      \"DEPDC5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}