{"gene":"ATAT1","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2010,"finding":"MEC-17 (ATAT1 ortholog) is an alpha-tubulin acetyltransferase that exclusively acetylates K40 of alpha-tubulin in vitro; related to Gcn5 histone acetyltransferases. In C. elegans, MEC-17 and its paralogue W06B11.1 are redundantly required for acetylation of MEC-12 alpha-tubulin. Disruption of the Tetrahymena MEC-17 gene phenocopies the K40R alpha-tubulin mutation and makes microtubules more labile.","method":"In vitro acetyltransferase assay, genetic disruption in Tetrahymena and C. elegans, zebrafish depletion, C. elegans genetic epistasis","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with substrate specificity, multiple orthogonal genetic models (C. elegans, Tetrahymena, zebrafish), replicated across organisms","pmids":["20829795"],"is_preprint":false},{"year":2012,"finding":"The enzymatic acetyltransferase activity of MEC-17 (ATAT1) is required for the production of 15-protofilament microtubules in touch receptor neurons and for correct MT number and organization, but enzymatically inactive MEC-17 is sufficient for touch sensitivity and proper axonal process outgrowth. This reveals both enzymatic and non-enzymatic functions of ATAT1.","method":"C. elegans genetics with catalytically inactive MEC-17 mutants, electron microscopy of microtubule protofilament number, behavioral assays","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis combined with structural (EM) readout and behavioral epistasis, single lab but multiple orthogonal methods","pmids":["22658602"],"is_preprint":false},{"year":2012,"finding":"ATAT1 binds cortactin and regulates its acetylation levels; ATAT1 colocalizes with cortactin at the adherent surface of MDA-MB-231 cells and is required for 2D migration and invasive migration in collagen matrix. ATAT1 and HDAC6 balance acetylation of both alpha-tubulin and cortactin to regulate MT1-MMP trafficking.","method":"Co-immunoprecipitation/binding assay, siRNA knockdown, 3D invasion assay, immunofluorescence colocalization","journal":"European journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal binding data plus functional KD with defined cellular phenotype, single lab, two orthogonal methods","pmids":["22902175"],"is_preprint":false},{"year":2013,"finding":"Loss of MEC-17 (ATAT1) in C. elegans leads to microtubule instability, reduction in mitochondrial number, and disrupted axonal transport with altered distribution of mitochondria and synaptic components. Notably, MEC-17-mediated axonal degeneration occurs independently of its acetyltransferase domain, demonstrating a non-enzymatic structural role in preserving axon integrity.","method":"Forward genetic screen in C. elegans, live imaging of axonal transport, epistasis with coel-1 mutant, acetyltransferase domain mutants","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis, acetyltransferase-dead mutants, live imaging of transport, replicated across multiple alleles and genetic backgrounds","pmids":["24373971"],"is_preprint":false},{"year":2014,"finding":"ATAT1 (Mec-17) accumulates upon cellular quiescence and is required for upregulation of myosin IIB (Myh10) expression, which in turn overcomes myosin IIA (Myh9) inhibition and initiates primary ciliogenesis. Pharmacological stimulation of microtubule acetylation also induces Myh10 expression and cilium formation, placing ATAT1 upstream of a Myh10-Myh9 axis in ciliogenesis.","method":"Knockdown of Mec-17, pharmacological stimulation of acetylation, Co-IP of Myh10-Myh9, serum-starvation-induced ciliogenesis assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD with defined ciliogenesis phenotype, epistasis via pharmacological acetylation, Co-IP for Myh10-Myh9 interaction, single lab","pmids":["25494100"],"is_preprint":false},{"year":2015,"finding":"ATAT1 localizes to motile cilia of multiciliated cells (trachea, brain third ventricle, oviduct), primary cilia of renal medullary collecting duct, inner and outer segments of retinal photoreceptors, and the Golgi apparatus of spermatocytes and spermatids in rat tissues.","method":"Immunohistochemistry with specific ATAT1 antibody in rat tissues (trachea, oviduct, kidney, retina, testis, brain)","journal":"Medical molecular morphology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by immunohistochemistry across multiple tissues, single lab, no functional consequence established","pmids":["26700226"],"is_preprint":false},{"year":2016,"finding":"ATAT1 is localized to the Golgi apparatus of endocrine cells in the normal rat anterior pituitary; adrenalectomy increases ATAT1 expression and alpha-tubulin acetylation in corticotrophs, consistent with a role of ATAT1-mediated acetylation in intracellular transport of secretory granules.","method":"Immunohistochemistry and western blot in normal and adrenalectomized rats","journal":"Cell and tissue research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single immunohistochemistry/western blot in animal model, no direct functional test of ATAT1's role in granule transport","pmids":["27314403"],"is_preprint":false},{"year":2017,"finding":"ATAT1 knockdown reduces alpha-tubulin acetylation and impairs dexamethasone-induced nuclear translocation of glucocorticoid receptor (GR) in AtT20 corticotroph cells; ATAT1 overexpression increases acetylation and enhances GR nuclear translocation. CRH increases Atat1 expression and dexamethasone decreases it. Acetylated microtubules thus serve as a track for GR nuclear transport.","method":"siRNA knockdown, overexpression, western blot, real-time PCR in AtT20 cells; CRH/dexamethasone treatments","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with defined molecular phenotype (GR translocation), two complementary perturbations, single lab","pmids":["28687926"],"is_preprint":false},{"year":2018,"finding":"ATAT1 dynamically changes its subcellular localization through the cell cycle in human fibroblasts: it localizes to centrioles, nuclei, and basal bodies during interphase; clusters in nuclei during G1-G2; colocalizes with chromatids and spindle poles in telophase; and migrates to the daughter nucleus, new centrioles, and midbody at cytokinesis.","method":"Immunofluorescence and confocal laser scanning microscopy through synchronized cell cycle stages in KD fibroblasts","journal":"Medical molecular morphology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization study by immunolabeling, single lab, no direct functional consequence established for each localization","pmids":["29869029"],"is_preprint":false},{"year":2019,"finding":"ATAT1 is transported at the cytosolic face of neuronal vesicles moving along axons; loss of ATAT1 impairs axonal transport in vivo, and cell-free motility assays confirm that alpha-tubulin acetylation is required for proper bidirectional vesicular transport. Axonal transport of ATAT1-enriched vesicles is the predominant driver of alpha-tubulin acetylation in axons.","method":"Live imaging of ATAT1-vesicle movement in neurons in vivo, cell-free motility assays, ATAT1 knockout mouse neurons","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo live imaging plus cell-free reconstitution assay, ATAT1 KO with defined transport phenotype, multiple orthogonal approaches","pmids":["31897425"],"is_preprint":false},{"year":2019,"finding":"ATAT1 knockout mice develop enlarged lateral ventricles due to hypoplasia of the septum and striatum caused by impaired neuronal migration during brain development. ATAT1 is indispensable for tubulin hyperacetylation in response to osmotic (high salt, high glucose) and oxidative (H2O2) stress in embryonic fibroblasts. Mild defects in cell proliferation and primary cilium formation are also observed.","method":"Atat1 knockout mouse analysis, birth-dating neuronal migration experiments, stress-induced acetylation assays in MEFs, behavioral testing, flow cytometry","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined developmental phenotype, mechanistic rescue-type analyses, multiple cellular assays, single lab but extensive characterization","pmids":["30953095"],"is_preprint":false},{"year":2020,"finding":"PAK1 directly phosphorylates the alpha-tubulin acetyltransferase MEC-17 (ATAT1) and inhibits its activity. Lack of PAK1 activity results in hyperacetylated microtubules and loss of MT network integrity during proplatelet formation in megakaryocytes.","method":"In vitro kinase assay showing PAK1 phosphorylates MEC-17, PAK1 inhibitor treatment, proplatelet formation assay, MT acetylation quantification","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assay demonstrating direct phosphorylation of ATAT1 by PAK1 with functional consequence (inhibited acetyltransferase activity), single lab","pmids":["33066011"],"is_preprint":false},{"year":2021,"finding":"p27Kip1 promotes microtubule acetylation by binding to and stabilizing ATAT1 in glucose-deprived cells. ATAT1 knockdown in p27+/+ MEFs phenocopies p27 loss: autophagosomes are randomly distributed and autophagy flux is impaired, demonstrating that p27 promotes autophagosome trafficking to the perinuclear area via ATAT1-dependent microtubule acetylation.","method":"Co-immunoprecipitation (p27-ATAT1 binding), siRNA knockdown of ATAT1, autophagosome trafficking imaging, autophagy flux assays in MEFs","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for p27-ATAT1 interaction plus KD with defined trafficking phenotype, single lab, two orthogonal methods","pmids":["33986251"],"is_preprint":false},{"year":2024,"finding":"ATAT1 disruption in MDA-MB-231 cells inhibits RhoA expression via an indirect mechanism: loss of microtubule acetylation causes overexpression of cathepsin L (CTSL), which cleaves C/EBPβ in the nucleus to a 27-kDa N-terminally truncated fragment (C/EBPβp27) that competitively inhibits full-length C/EBPβ at the RHOA promoter, suppressing RHOA transcription. CTSL inhibitor restores RhoA expression and reduces invasiveness.","method":"ATAT1 KO in MDA-MB-231 cells, RHOA promoter analysis, chromatin immunoprecipitation (ChIP), C/EBPβ deletion mutant overexpression, CTSL inhibitor treatment, invasion assay","journal":"BMB reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP, promoter analysis, and KO with pharmacological rescue, single lab, multiple orthogonal methods","pmids":["38835115"],"is_preprint":false},{"year":2024,"finding":"ATAT1 deficiency reduces alpha-tubulin acetylation and enhances erythrophagocytosis by microglia/macrophages in vitro (BV2, RAW264.7) and in vivo (ATAT1 KO mice after intracerebral hemorrhage), leading to accelerated hematoma absorption, reduced neuronal apoptosis, and decreased pro-inflammatory cytokines.","method":"ATAT1 siRNA knockdown in cell lines, ATAT1 KO mice with ICH model, co-culture phagocytosis assay with fluorescently labeled RBCs, immunohistochemistry","journal":"Neural regeneration research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD in cells plus KO mouse model with defined phagocytosis phenotype, single lab, in vitro and in vivo confirmation","pmids":["37862210"],"is_preprint":false},{"year":2025,"finding":"In B cells activated on stiff substrates, mechanotransduction triggers translocation of ATAT1 from the nucleus to the cytoplasm, leading to increased alpha-tubulin acetylation. This modification releases GEF-H1 at the immune synapse to promote actin foci formation essential for antigen extraction, and enables lysosome stabilization and positioning at the synapse center for antigen processing. ATAT1-silenced B cells fail to concentrate actin foci and lysosomes at the synapse, impairing antigen extraction and presentation to T cells.","method":"siRNA knockdown of ATAT1 in B cells, live and fixed immunofluorescence imaging of ATAT1 localization, actin foci and lysosome quantification, antigen extraction and T cell presentation assays, stiffness-modulated substrate system","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD with multiple defined cellular phenotypes (ATAT1 localization, actin foci, lysosome positioning, antigen presentation), mechanistic pathway established via GEF-H1 release, multiple orthogonal readouts, single lab","pmids":["40689828"],"is_preprint":false},{"year":2025,"finding":"JPT2, a conserved microtubule-binding protein that localizes within the microtubule lumen, modulates the distribution of ATAT1 (MEC17) within the lumen and contributes to luminal homeostasis. JPT2's luminal accessibility is reduced by Paclitaxel treatment.","method":"Proximity-labeling (BioID) with mass spectrometry, cryo-EM localization of JPT2 in lumen, Paclitaxel treatment, JPT2 KD with MEC17 distribution analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proximity labeling with MS and structural localization, functional consequence on ATAT1 distribution shown, single lab","pmids":["41468432"],"is_preprint":false}],"current_model":"ATAT1 (MEC-17) is the principal alpha-tubulin acetyltransferase that specifically acetylates lysine 40 on the luminal surface of alpha-tubulin, an activity regulated by PAK1-mediated phosphorylation (inhibitory) and by p27Kip1-mediated stabilization; beyond this enzymatic role, ATAT1 has non-enzymatic functions in maintaining axon integrity and microtubule protofilament organization, is transported on neuronal vesicles to drive axonal tubulin acetylation, and translocates from the nucleus to the cytoplasm in response to mechanical and stress signals to coordinate GEF-H1 release, actin dynamics, lysosome positioning, and intracellular trafficking in contexts ranging from immune synapse formation to autophagosome transport and neuronal maintenance."},"narrative":{"mechanistic_narrative":"ATAT1 (MEC-17) is the principal alpha-tubulin acetyltransferase, an enzyme related to the Gcn5 family that exclusively acetylates lysine 40 on alpha-tubulin and is required for tubulin acetylation across organisms from C. elegans to mammals [PMID:20829795]. Its catalytic activity is needed to specify correct microtubule protofilament number and organization, but ATAT1 also carries acetylation-independent structural functions, since enzymatically inactive protein preserves touch sensitivity, axon outgrowth, and axon integrity [PMID:22658602, PMID:24373971]. Acetylation of the microtubule lattice by ATAT1 establishes a track that supports intracellular and bidirectional axonal vesicular transport, and ATAT1 is itself carried along axons on the cytosolic face of neuronal vesicles, making such transport the dominant source of axonal tubulin acetylation [PMID:31897425]. ATAT1 activity is dispensable for resting acetylation but indispensable for tubulin hyperacetylation in response to osmotic and oxidative stress, and ATAT1-null mice show impaired neuronal migration during brain development with enlarged lateral ventricles [PMID:30953095]. Its acetyltransferase activity is directly inhibited by PAK1-mediated phosphorylation and is enhanced by p27Kip1 binding and stabilization, the latter promoting perinuclear autophagosome trafficking and autophagy flux [PMID:33066011, PMID:33986251]. Downstream of its enzymatic role, ATAT1-dependent acetylation governs cytoskeletal and trafficking programs: it controls cortactin acetylation and MT1-MMP trafficking during invasive migration [PMID:22902175], releases GEF-H1 at the B-cell immune synapse to drive actin foci and lysosome positioning for antigen extraction in response to substrate stiffness [PMID:40689828], and shapes erythrophagocytosis by microglia and macrophages [PMID:37862210]. Within the microtubule lumen, ATAT1 distribution is modulated by the luminal protein JPT2 [PMID:41468432]. Beyond these characterized roles, several reported subcellular localizations of ATAT1 lack defined functional consequences in the available corpus.","teleology":[{"year":2010,"claim":"Established the molecular identity of ATAT1 by demonstrating it is an enzyme that selectively acetylates K40 of alpha-tubulin, answering what catalyzes this conserved modification.","evidence":"In vitro acetyltransferase assay with substrate specificity plus genetic disruption in Tetrahymena, C. elegans, and zebrafish","pmids":["20829795"],"confidence":"High","gaps":["Did not resolve the structural basis of luminal K40 access","Regulatory inputs controlling enzyme activity unknown at this stage"]},{"year":2012,"claim":"Separated ATAT1's enzymatic and non-enzymatic roles, showing acetylation specifies protofilament number while catalytically dead protein still supports axon outgrowth and behavior.","evidence":"C. elegans active-site mutants with EM protofilament counts and behavioral assays","pmids":["22658602"],"confidence":"High","gaps":["Molecular basis of the non-enzymatic function not defined","Mechanism linking K40 acetylation to 15-protofilament architecture unresolved"]},{"year":2012,"claim":"Extended ATAT1 function to cell migration by linking it, with HDAC6, to acetylation of cortactin and MT1-MMP trafficking.","evidence":"Co-IP/binding, siRNA knockdown, 3D collagen invasion, and colocalization in MDA-MB-231 cells","pmids":["22902175"],"confidence":"Medium","gaps":["Direct catalysis of cortactin acetylation by ATAT1 not biochemically isolated","Single cell line; in vivo relevance untested"]},{"year":2013,"claim":"Demonstrated a structural, acetyltransferase-independent role in preserving axon integrity and axonal transport, reinforcing that ATAT1 acts beyond catalysis.","evidence":"Forward genetic screen, live transport imaging, and acetyltransferase-dead mutants in C. elegans","pmids":["24373971"],"confidence":"High","gaps":["Binding partners mediating the structural role not identified","Mechanism connecting ATAT1 to mitochondrial number unresolved"]},{"year":2014,"claim":"Placed ATAT1 upstream of ciliogenesis through a Myh10-Myh9 myosin axis activated in quiescence.","evidence":"Knockdown, pharmacological acetylation stimulation, Myh10-Myh9 Co-IP, and serum-starvation ciliogenesis assay","pmids":["25494100"],"confidence":"Medium","gaps":["Direct link between tubulin acetylation and Myh10 transcription not established","Single-lab correlative chain"]},{"year":2015,"claim":"Mapped ATAT1 protein to motile and primary cilia, photoreceptor segments, and the Golgi across tissues, expanding its localization repertoire.","evidence":"Immunohistochemistry with specific antibody across rat tissues","pmids":["26700226"],"confidence":"Medium","gaps":["No functional consequence established for any localization","Antibody-based localization not corroborated by tagged-protein imaging"]},{"year":2017,"claim":"Linked ATAT1-dependent acetylation to hormone signaling by showing acetylated microtubules serve as tracks for glucocorticoid receptor nuclear translocation.","evidence":"siRNA knockdown and overexpression with GR translocation readout in AtT20 corticotrophs","pmids":["28687926"],"confidence":"Medium","gaps":["Mechanism by which acetylated MTs accelerate GR transport not defined","In vivo relevance untested"]},{"year":2019,"claim":"Showed ATAT1 is transported on neuronal vesicles and that vesicular transport itself drives axonal tubulin acetylation, while acetylation is required for proper vesicle motility.","evidence":"In vivo live imaging of ATAT1-vesicles, cell-free motility assays, and ATAT1 KO mouse neurons","pmids":["31897425"],"confidence":"High","gaps":["Vesicle adaptor tethering ATAT1 not identified","How motility-coupled acetylation feeds back on motors unresolved"]},{"year":2019,"claim":"Defined an organismal requirement for ATAT1 in neuronal migration and stress-induced hyperacetylation, distinguishing baseline from stress-responsive acetylation.","evidence":"Atat1 KO mice with birth-dating migration analysis and osmotic/oxidative stress assays in MEFs","pmids":["30953095"],"confidence":"High","gaps":["Signaling that triggers stress-induced ATAT1 activation not mapped","Mechanism coupling acetylation to migration unresolved"]},{"year":2020,"claim":"Identified a direct inhibitory regulatory input, PAK1 phosphorylation, controlling ATAT1 activity during proplatelet formation.","evidence":"In vitro kinase assay, PAK1 inhibitor treatment, and proplatelet/MT acetylation assays","pmids":["33066011"],"confidence":"High","gaps":["Phosphosite(s) on ATAT1 not all mapped","Cellular cues activating PAK1 toward ATAT1 not defined"]},{"year":2021,"claim":"Identified a positive regulator, p27Kip1, that stabilizes ATAT1 to promote autophagosome trafficking under glucose deprivation.","evidence":"p27-ATAT1 Co-IP, ATAT1 knockdown, and autophagosome trafficking/flux assays in MEFs","pmids":["33986251"],"confidence":"Medium","gaps":["Structural basis of p27-ATAT1 binding not resolved","Single-lab Co-IP for the interaction"]},{"year":2024,"claim":"Connected ATAT1 loss to transcriptional suppression of RHOA via a cathepsin-L/C-EBPbeta cleavage cascade, defining an indirect route from acetylation to invasion control.","evidence":"ATAT1 KO, ChIP and RHOA promoter analysis, C/EBPbeta mutants, and CTSL inhibitor rescue in MDA-MB-231 cells","pmids":["38835115"],"confidence":"Medium","gaps":["How acetylation loss elevates CTSL not mechanistically defined","Single cell line"]},{"year":2024,"claim":"Showed ATAT1 restrains erythrophagocytosis by microglia/macrophages, linking tubulin acetylation to hematoma clearance and neuroinflammation.","evidence":"ATAT1 siRNA in cell lines and ATAT1 KO mice in an intracerebral hemorrhage model with phagocytosis assays","pmids":["37862210"],"confidence":"Medium","gaps":["Molecular link between acetylation and phagocytic machinery unresolved","Whether effect is enzymatic or structural untested"]},{"year":2025,"claim":"Established mechanotransduction-driven nuclear-to-cytoplasmic ATAT1 translocation that releases GEF-H1 to coordinate actin and lysosome dynamics at the B-cell immune synapse.","evidence":"siRNA knockdown, ATAT1 localization imaging, actin/lysosome quantification, and antigen extraction/presentation assays on stiffness-modulated substrates","pmids":["40689828"],"confidence":"High","gaps":["Mechanism of stiffness-triggered ATAT1 nuclear export not defined","Direct GEF-H1 release step not biochemically reconstituted"]},{"year":2025,"claim":"Identified JPT2 as a luminal microtubule protein that modulates ATAT1 distribution within the lumen, addressing how the enzyme is positioned at its luminal substrate.","evidence":"BioID/MS, cryo-EM luminal localization, Paclitaxel treatment, and JPT2 KD with MEC17 distribution analysis","pmids":["41468432"],"confidence":"Medium","gaps":["Whether JPT2 directly binds ATAT1 not shown","Functional impact on acetylation output not quantified"]},{"year":null,"claim":"How ATAT1's enzymatic versus structural functions are partitioned across its diverse cellular roles, and what signals govern its dynamic subcellular relocalization, remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified structural model coupling regulation, localization, and luminal access","Direct binding partners mediating non-enzymatic functions largely unidentified"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,11]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,2]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[5]},{"term_id":"GO:0005794","term_label":"Golgi apparatus","supporting_discovery_ids":[5,6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[8,15]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[16]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[15,14]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[12]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[9]}],"complexes":[],"partners":["PAK1","CDKN1B","CTTN","JPT2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5SQI0","full_name":"Alpha-tubulin N-acetyltransferase 1","aliases":["Acetyltransferase mec-17 homolog"],"length_aa":421,"mass_kda":46.8,"function":"Specifically acetylates 'Lys-40' in alpha-tubulin on the lumenal side of microtubules. Promotes microtubule destabilization and accelerates microtubule dynamics; this activity may be independent of acetylation activity. Acetylates alpha-tubulin with a slow enzymatic rate, due to a catalytic site that is not optimized for acetyl transfer. Enters the microtubule through each end and diffuses quickly throughout the lumen of microtubules. Acetylates only long/old microtubules because of its slow acetylation rate since it does not have time to act on dynamically unstable microtubules before the enzyme is released. Required for normal sperm flagellar function. Promotes directional cell locomotion and chemotaxis, through AP2A2-dependent acetylation of alpha-tubulin at clathrin-coated pits that are concentrated at the leading edge of migrating cells. May facilitate primary cilium assembly","subcellular_location":"Cytoplasm; Membrane, clathrin-coated pit; Cell junction, focal adhesion; Cell projection, axon; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, spindle","url":"https://www.uniprot.org/uniprotkb/Q5SQI0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ATAT1","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ATAT1","total_profiled":1310},"omim":[{"mim_id":"615556","title":"ALPHA-TUBULIN ACETYLTRANSFERASE 1; ATAT1","url":"https://www.omim.org/entry/615556"},{"mim_id":"107580","title":"TRANSCRIPTION FACTOR AP2-ALPHA; TFAP2A","url":"https://www.omim.org/entry/107580"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":31.4}],"url":"https://www.proteinatlas.org/search/ATAT1"},"hgnc":{"alias_symbol":["FLJ13158","Em:AB023049.7","MEC17"],"prev_symbol":["C6orf134"]},"alphafold":{"accession":"Q5SQI0","domains":[{"cath_id":"3.40.630.30","chopping":"8-194","consensus_level":"medium","plddt":93.962,"start":8,"end":194}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5SQI0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5SQI0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5SQI0-F1-predicted_aligned_error_v6.png","plddt_mean":68.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ATAT1","jax_strain_url":"https://www.jax.org/strain/search?query=ATAT1"},"sequence":{"accession":"Q5SQI0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5SQI0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5SQI0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5SQI0"}},"corpus_meta":[{"pmid":"20829795","id":"PMC_20829795","title":"MEC-17 is an alpha-tubulin acetyltransferase.","date":"2010","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/20829795","citation_count":391,"is_preprint":false},{"pmid":"22658602","id":"PMC_22658602","title":"Genetically separable functions of the MEC-17 tubulin acetyltransferase affect microtubule organization.","date":"2012","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/22658602","citation_count":131,"is_preprint":false},{"pmid":"22902175","id":"PMC_22902175","title":"ATAT1/MEC-17 acetyltransferase and HDAC6 deacetylase control a balance of acetylation of alpha-tubulin and cortactin and regulate MT1-MMP trafficking and breast tumor cell invasion.","date":"2012","source":"European journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22902175","citation_count":90,"is_preprint":false},{"pmid":"24373971","id":"PMC_24373971","title":"Loss of MEC-17 leads to microtubule instability and axonal degeneration.","date":"2013","source":"Cell 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In C. elegans, MEC-17 and its paralogue W06B11.1 are redundantly required for acetylation of MEC-12 alpha-tubulin. Disruption of the Tetrahymena MEC-17 gene phenocopies the K40R alpha-tubulin mutation and makes microtubules more labile.\",\n      \"method\": \"In vitro acetyltransferase assay, genetic disruption in Tetrahymena and C. elegans, zebrafish depletion, C. elegans genetic epistasis\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with substrate specificity, multiple orthogonal genetic models (C. elegans, Tetrahymena, zebrafish), replicated across organisms\",\n      \"pmids\": [\"20829795\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The enzymatic acetyltransferase activity of MEC-17 (ATAT1) is required for the production of 15-protofilament microtubules in touch receptor neurons and for correct MT number and organization, but enzymatically inactive MEC-17 is sufficient for touch sensitivity and proper axonal process outgrowth. This reveals both enzymatic and non-enzymatic functions of ATAT1.\",\n      \"method\": \"C. elegans genetics with catalytically inactive MEC-17 mutants, electron microscopy of microtubule protofilament number, behavioral assays\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis combined with structural (EM) readout and behavioral epistasis, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22658602\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"ATAT1 binds cortactin and regulates its acetylation levels; ATAT1 colocalizes with cortactin at the adherent surface of MDA-MB-231 cells and is required for 2D migration and invasive migration in collagen matrix. ATAT1 and HDAC6 balance acetylation of both alpha-tubulin and cortactin to regulate MT1-MMP trafficking.\",\n      \"method\": \"Co-immunoprecipitation/binding assay, siRNA knockdown, 3D invasion assay, immunofluorescence colocalization\",\n      \"journal\": \"European journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal binding data plus functional KD with defined cellular phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"22902175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of MEC-17 (ATAT1) in C. elegans leads to microtubule instability, reduction in mitochondrial number, and disrupted axonal transport with altered distribution of mitochondria and synaptic components. Notably, MEC-17-mediated axonal degeneration occurs independently of its acetyltransferase domain, demonstrating a non-enzymatic structural role in preserving axon integrity.\",\n      \"method\": \"Forward genetic screen in C. elegans, live imaging of axonal transport, epistasis with coel-1 mutant, acetyltransferase domain mutants\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis, acetyltransferase-dead mutants, live imaging of transport, replicated across multiple alleles and genetic backgrounds\",\n      \"pmids\": [\"24373971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"ATAT1 (Mec-17) accumulates upon cellular quiescence and is required for upregulation of myosin IIB (Myh10) expression, which in turn overcomes myosin IIA (Myh9) inhibition and initiates primary ciliogenesis. Pharmacological stimulation of microtubule acetylation also induces Myh10 expression and cilium formation, placing ATAT1 upstream of a Myh10-Myh9 axis in ciliogenesis.\",\n      \"method\": \"Knockdown of Mec-17, pharmacological stimulation of acetylation, Co-IP of Myh10-Myh9, serum-starvation-induced ciliogenesis assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD with defined ciliogenesis phenotype, epistasis via pharmacological acetylation, Co-IP for Myh10-Myh9 interaction, single lab\",\n      \"pmids\": [\"25494100\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"ATAT1 localizes to motile cilia of multiciliated cells (trachea, brain third ventricle, oviduct), primary cilia of renal medullary collecting duct, inner and outer segments of retinal photoreceptors, and the Golgi apparatus of spermatocytes and spermatids in rat tissues.\",\n      \"method\": \"Immunohistochemistry with specific ATAT1 antibody in rat tissues (trachea, oviduct, kidney, retina, testis, brain)\",\n      \"journal\": \"Medical molecular morphology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by immunohistochemistry across multiple tissues, single lab, no functional consequence established\",\n      \"pmids\": [\"26700226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"ATAT1 is localized to the Golgi apparatus of endocrine cells in the normal rat anterior pituitary; adrenalectomy increases ATAT1 expression and alpha-tubulin acetylation in corticotrophs, consistent with a role of ATAT1-mediated acetylation in intracellular transport of secretory granules.\",\n      \"method\": \"Immunohistochemistry and western blot in normal and adrenalectomized rats\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single immunohistochemistry/western blot in animal model, no direct functional test of ATAT1's role in granule transport\",\n      \"pmids\": [\"27314403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"ATAT1 knockdown reduces alpha-tubulin acetylation and impairs dexamethasone-induced nuclear translocation of glucocorticoid receptor (GR) in AtT20 corticotroph cells; ATAT1 overexpression increases acetylation and enhances GR nuclear translocation. CRH increases Atat1 expression and dexamethasone decreases it. Acetylated microtubules thus serve as a track for GR nuclear transport.\",\n      \"method\": \"siRNA knockdown, overexpression, western blot, real-time PCR in AtT20 cells; CRH/dexamethasone treatments\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with defined molecular phenotype (GR translocation), two complementary perturbations, single lab\",\n      \"pmids\": [\"28687926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ATAT1 dynamically changes its subcellular localization through the cell cycle in human fibroblasts: it localizes to centrioles, nuclei, and basal bodies during interphase; clusters in nuclei during G1-G2; colocalizes with chromatids and spindle poles in telophase; and migrates to the daughter nucleus, new centrioles, and midbody at cytokinesis.\",\n      \"method\": \"Immunofluorescence and confocal laser scanning microscopy through synchronized cell cycle stages in KD fibroblasts\",\n      \"journal\": \"Medical molecular morphology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization study by immunolabeling, single lab, no direct functional consequence established for each localization\",\n      \"pmids\": [\"29869029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATAT1 is transported at the cytosolic face of neuronal vesicles moving along axons; loss of ATAT1 impairs axonal transport in vivo, and cell-free motility assays confirm that alpha-tubulin acetylation is required for proper bidirectional vesicular transport. Axonal transport of ATAT1-enriched vesicles is the predominant driver of alpha-tubulin acetylation in axons.\",\n      \"method\": \"Live imaging of ATAT1-vesicle movement in neurons in vivo, cell-free motility assays, ATAT1 knockout mouse neurons\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo live imaging plus cell-free reconstitution assay, ATAT1 KO with defined transport phenotype, multiple orthogonal approaches\",\n      \"pmids\": [\"31897425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ATAT1 knockout mice develop enlarged lateral ventricles due to hypoplasia of the septum and striatum caused by impaired neuronal migration during brain development. ATAT1 is indispensable for tubulin hyperacetylation in response to osmotic (high salt, high glucose) and oxidative (H2O2) stress in embryonic fibroblasts. Mild defects in cell proliferation and primary cilium formation are also observed.\",\n      \"method\": \"Atat1 knockout mouse analysis, birth-dating neuronal migration experiments, stress-induced acetylation assays in MEFs, behavioral testing, flow cytometry\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined developmental phenotype, mechanistic rescue-type analyses, multiple cellular assays, single lab but extensive characterization\",\n      \"pmids\": [\"30953095\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PAK1 directly phosphorylates the alpha-tubulin acetyltransferase MEC-17 (ATAT1) and inhibits its activity. Lack of PAK1 activity results in hyperacetylated microtubules and loss of MT network integrity during proplatelet formation in megakaryocytes.\",\n      \"method\": \"In vitro kinase assay showing PAK1 phosphorylates MEC-17, PAK1 inhibitor treatment, proplatelet formation assay, MT acetylation quantification\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assay demonstrating direct phosphorylation of ATAT1 by PAK1 with functional consequence (inhibited acetyltransferase activity), single lab\",\n      \"pmids\": [\"33066011\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"p27Kip1 promotes microtubule acetylation by binding to and stabilizing ATAT1 in glucose-deprived cells. ATAT1 knockdown in p27+/+ MEFs phenocopies p27 loss: autophagosomes are randomly distributed and autophagy flux is impaired, demonstrating that p27 promotes autophagosome trafficking to the perinuclear area via ATAT1-dependent microtubule acetylation.\",\n      \"method\": \"Co-immunoprecipitation (p27-ATAT1 binding), siRNA knockdown of ATAT1, autophagosome trafficking imaging, autophagy flux assays in MEFs\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for p27-ATAT1 interaction plus KD with defined trafficking phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"33986251\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATAT1 disruption in MDA-MB-231 cells inhibits RhoA expression via an indirect mechanism: loss of microtubule acetylation causes overexpression of cathepsin L (CTSL), which cleaves C/EBPβ in the nucleus to a 27-kDa N-terminally truncated fragment (C/EBPβp27) that competitively inhibits full-length C/EBPβ at the RHOA promoter, suppressing RHOA transcription. CTSL inhibitor restores RhoA expression and reduces invasiveness.\",\n      \"method\": \"ATAT1 KO in MDA-MB-231 cells, RHOA promoter analysis, chromatin immunoprecipitation (ChIP), C/EBPβ deletion mutant overexpression, CTSL inhibitor treatment, invasion assay\",\n      \"journal\": \"BMB reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP, promoter analysis, and KO with pharmacological rescue, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38835115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ATAT1 deficiency reduces alpha-tubulin acetylation and enhances erythrophagocytosis by microglia/macrophages in vitro (BV2, RAW264.7) and in vivo (ATAT1 KO mice after intracerebral hemorrhage), leading to accelerated hematoma absorption, reduced neuronal apoptosis, and decreased pro-inflammatory cytokines.\",\n      \"method\": \"ATAT1 siRNA knockdown in cell lines, ATAT1 KO mice with ICH model, co-culture phagocytosis assay with fluorescently labeled RBCs, immunohistochemistry\",\n      \"journal\": \"Neural regeneration research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD in cells plus KO mouse model with defined phagocytosis phenotype, single lab, in vitro and in vivo confirmation\",\n      \"pmids\": [\"37862210\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In B cells activated on stiff substrates, mechanotransduction triggers translocation of ATAT1 from the nucleus to the cytoplasm, leading to increased alpha-tubulin acetylation. This modification releases GEF-H1 at the immune synapse to promote actin foci formation essential for antigen extraction, and enables lysosome stabilization and positioning at the synapse center for antigen processing. ATAT1-silenced B cells fail to concentrate actin foci and lysosomes at the synapse, impairing antigen extraction and presentation to T cells.\",\n      \"method\": \"siRNA knockdown of ATAT1 in B cells, live and fixed immunofluorescence imaging of ATAT1 localization, actin foci and lysosome quantification, antigen extraction and T cell presentation assays, stiffness-modulated substrate system\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD with multiple defined cellular phenotypes (ATAT1 localization, actin foci, lysosome positioning, antigen presentation), mechanistic pathway established via GEF-H1 release, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"40689828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"JPT2, a conserved microtubule-binding protein that localizes within the microtubule lumen, modulates the distribution of ATAT1 (MEC17) within the lumen and contributes to luminal homeostasis. JPT2's luminal accessibility is reduced by Paclitaxel treatment.\",\n      \"method\": \"Proximity-labeling (BioID) with mass spectrometry, cryo-EM localization of JPT2 in lumen, Paclitaxel treatment, JPT2 KD with MEC17 distribution analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proximity labeling with MS and structural localization, functional consequence on ATAT1 distribution shown, single lab\",\n      \"pmids\": [\"41468432\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ATAT1 (MEC-17) is the principal alpha-tubulin acetyltransferase that specifically acetylates lysine 40 on the luminal surface of alpha-tubulin, an activity regulated by PAK1-mediated phosphorylation (inhibitory) and by p27Kip1-mediated stabilization; beyond this enzymatic role, ATAT1 has non-enzymatic functions in maintaining axon integrity and microtubule protofilament organization, is transported on neuronal vesicles to drive axonal tubulin acetylation, and translocates from the nucleus to the cytoplasm in response to mechanical and stress signals to coordinate GEF-H1 release, actin dynamics, lysosome positioning, and intracellular trafficking in contexts ranging from immune synapse formation to autophagosome transport and neuronal maintenance.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ATAT1 (MEC-17) is the principal alpha-tubulin acetyltransferase, an enzyme related to the Gcn5 family that exclusively acetylates lysine 40 on alpha-tubulin and is required for tubulin acetylation across organisms from C. elegans to mammals [#0]. Its catalytic activity is needed to specify correct microtubule protofilament number and organization, but ATAT1 also carries acetylation-independent structural functions, since enzymatically inactive protein preserves touch sensitivity, axon outgrowth, and axon integrity [#1, #3]. Acetylation of the microtubule lattice by ATAT1 establishes a track that supports intracellular and bidirectional axonal vesicular transport, and ATAT1 is itself carried along axons on the cytosolic face of neuronal vesicles, making such transport the dominant source of axonal tubulin acetylation [#9]. ATAT1 activity is dispensable for resting acetylation but indispensable for tubulin hyperacetylation in response to osmotic and oxidative stress, and ATAT1-null mice show impaired neuronal migration during brain development with enlarged lateral ventricles [#10]. Its acetyltransferase activity is directly inhibited by PAK1-mediated phosphorylation and is enhanced by p27Kip1 binding and stabilization, the latter promoting perinuclear autophagosome trafficking and autophagy flux [#11, #12]. Downstream of its enzymatic role, ATAT1-dependent acetylation governs cytoskeletal and trafficking programs: it controls cortactin acetylation and MT1-MMP trafficking during invasive migration [#2], releases GEF-H1 at the B-cell immune synapse to drive actin foci and lysosome positioning for antigen extraction in response to substrate stiffness [#15], and shapes erythrophagocytosis by microglia and macrophages [#14]. Within the microtubule lumen, ATAT1 distribution is modulated by the luminal protein JPT2 [#16]. Beyond these characterized roles, several reported subcellular localizations of ATAT1 lack defined functional consequences in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2010,\n      \"claim\": \"Established the molecular identity of ATAT1 by demonstrating it is an enzyme that selectively acetylates K40 of alpha-tubulin, answering what catalyzes this conserved modification.\",\n      \"evidence\": \"In vitro acetyltransferase assay with substrate specificity plus genetic disruption in Tetrahymena, C. elegans, and zebrafish\",\n      \"pmids\": [\"20829795\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the structural basis of luminal K40 access\", \"Regulatory inputs controlling enzyme activity unknown at this stage\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Separated ATAT1's enzymatic and non-enzymatic roles, showing acetylation specifies protofilament number while catalytically dead protein still supports axon outgrowth and behavior.\",\n      \"evidence\": \"C. elegans active-site mutants with EM protofilament counts and behavioral assays\",\n      \"pmids\": [\"22658602\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of the non-enzymatic function not defined\", \"Mechanism linking K40 acetylation to 15-protofilament architecture unresolved\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended ATAT1 function to cell migration by linking it, with HDAC6, to acetylation of cortactin and MT1-MMP trafficking.\",\n      \"evidence\": \"Co-IP/binding, siRNA knockdown, 3D collagen invasion, and colocalization in MDA-MB-231 cells\",\n      \"pmids\": [\"22902175\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct catalysis of cortactin acetylation by ATAT1 not biochemically isolated\", \"Single cell line; in vivo relevance untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Demonstrated a structural, acetyltransferase-independent role in preserving axon integrity and axonal transport, reinforcing that ATAT1 acts beyond catalysis.\",\n      \"evidence\": \"Forward genetic screen, live transport imaging, and acetyltransferase-dead mutants in C. elegans\",\n      \"pmids\": [\"24373971\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding partners mediating the structural role not identified\", \"Mechanism connecting ATAT1 to mitochondrial number unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed ATAT1 upstream of ciliogenesis through a Myh10-Myh9 myosin axis activated in quiescence.\",\n      \"evidence\": \"Knockdown, pharmacological acetylation stimulation, Myh10-Myh9 Co-IP, and serum-starvation ciliogenesis assay\",\n      \"pmids\": [\"25494100\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct link between tubulin acetylation and Myh10 transcription not established\", \"Single-lab correlative chain\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped ATAT1 protein to motile and primary cilia, photoreceptor segments, and the Golgi across tissues, expanding its localization repertoire.\",\n      \"evidence\": \"Immunohistochemistry with specific antibody across rat tissues\",\n      \"pmids\": [\"26700226\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No functional consequence established for any localization\", \"Antibody-based localization not corroborated by tagged-protein imaging\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Linked ATAT1-dependent acetylation to hormone signaling by showing acetylated microtubules serve as tracks for glucocorticoid receptor nuclear translocation.\",\n      \"evidence\": \"siRNA knockdown and overexpression with GR translocation readout in AtT20 corticotrophs\",\n      \"pmids\": [\"28687926\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which acetylated MTs accelerate GR transport not defined\", \"In vivo relevance untested\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed ATAT1 is transported on neuronal vesicles and that vesicular transport itself drives axonal tubulin acetylation, while acetylation is required for proper vesicle motility.\",\n      \"evidence\": \"In vivo live imaging of ATAT1-vesicles, cell-free motility assays, and ATAT1 KO mouse neurons\",\n      \"pmids\": [\"31897425\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Vesicle adaptor tethering ATAT1 not identified\", \"How motility-coupled acetylation feeds back on motors unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Defined an organismal requirement for ATAT1 in neuronal migration and stress-induced hyperacetylation, distinguishing baseline from stress-responsive acetylation.\",\n      \"evidence\": \"Atat1 KO mice with birth-dating migration analysis and osmotic/oxidative stress assays in MEFs\",\n      \"pmids\": [\"30953095\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signaling that triggers stress-induced ATAT1 activation not mapped\", \"Mechanism coupling acetylation to migration unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified a direct inhibitory regulatory input, PAK1 phosphorylation, controlling ATAT1 activity during proplatelet formation.\",\n      \"evidence\": \"In vitro kinase assay, PAK1 inhibitor treatment, and proplatelet/MT acetylation assays\",\n      \"pmids\": [\"33066011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Phosphosite(s) on ATAT1 not all mapped\", \"Cellular cues activating PAK1 toward ATAT1 not defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified a positive regulator, p27Kip1, that stabilizes ATAT1 to promote autophagosome trafficking under glucose deprivation.\",\n      \"evidence\": \"p27-ATAT1 Co-IP, ATAT1 knockdown, and autophagosome trafficking/flux assays in MEFs\",\n      \"pmids\": [\"33986251\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of p27-ATAT1 binding not resolved\", \"Single-lab Co-IP for the interaction\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected ATAT1 loss to transcriptional suppression of RHOA via a cathepsin-L/C-EBPbeta cleavage cascade, defining an indirect route from acetylation to invasion control.\",\n      \"evidence\": \"ATAT1 KO, ChIP and RHOA promoter analysis, C/EBPbeta mutants, and CTSL inhibitor rescue in MDA-MB-231 cells\",\n      \"pmids\": [\"38835115\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How acetylation loss elevates CTSL not mechanistically defined\", \"Single cell line\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed ATAT1 restrains erythrophagocytosis by microglia/macrophages, linking tubulin acetylation to hematoma clearance and neuroinflammation.\",\n      \"evidence\": \"ATAT1 siRNA in cell lines and ATAT1 KO mice in an intracerebral hemorrhage model with phagocytosis assays\",\n      \"pmids\": [\"37862210\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between acetylation and phagocytic machinery unresolved\", \"Whether effect is enzymatic or structural untested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established mechanotransduction-driven nuclear-to-cytoplasmic ATAT1 translocation that releases GEF-H1 to coordinate actin and lysosome dynamics at the B-cell immune synapse.\",\n      \"evidence\": \"siRNA knockdown, ATAT1 localization imaging, actin/lysosome quantification, and antigen extraction/presentation assays on stiffness-modulated substrates\",\n      \"pmids\": [\"40689828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of stiffness-triggered ATAT1 nuclear export not defined\", \"Direct GEF-H1 release step not biochemically reconstituted\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified JPT2 as a luminal microtubule protein that modulates ATAT1 distribution within the lumen, addressing how the enzyme is positioned at its luminal substrate.\",\n      \"evidence\": \"BioID/MS, cryo-EM luminal localization, Paclitaxel treatment, and JPT2 KD with MEC17 distribution analysis\",\n      \"pmids\": [\"41468432\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JPT2 directly binds ATAT1 not shown\", \"Functional impact on acetylation output not quantified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ATAT1's enzymatic versus structural functions are partitioned across its diverse cellular roles, and what signals govern its dynamic subcellular relocalization, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified structural model coupling regulation, localization, and luminal access\", \"Direct binding partners mediating non-enzymatic functions largely unidentified\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [8, 15]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [16]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [15, 14]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [12]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"PAK1\", \"CDKN1B\", \"CTTN\", \"JPT2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":7,"faith_pct":85.71428571428571}}