Affinage

ATAT1

Alpha-tubulin N-acetyltransferase 1 · UniProt Q5SQI0

Length
421 aa
Mass
46.8 kDa
Annotated
2026-06-09
21 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/7 claims corpus-supported (86%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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.

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 2010 High

    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

    PMID:20829795

    Open questions at the time
    • Did not resolve the structural basis of luminal K40 access
    • Regulatory inputs controlling enzyme activity unknown at this stage
  2. 2012 High

    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

    PMID:22658602

    Open questions at the time
    • Molecular basis of the non-enzymatic function not defined
    • Mechanism linking K40 acetylation to 15-protofilament architecture unresolved
  3. 2012 Medium

    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

    PMID:22902175

    Open questions at the time
    • Direct catalysis of cortactin acetylation by ATAT1 not biochemically isolated
    • Single cell line; in vivo relevance untested
  4. 2013 High

    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

    PMID:24373971

    Open questions at the time
    • Binding partners mediating the structural role not identified
    • Mechanism connecting ATAT1 to mitochondrial number unresolved
  5. 2014 Medium

    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

    PMID:25494100

    Open questions at the time
    • Direct link between tubulin acetylation and Myh10 transcription not established
    • Single-lab correlative chain
  6. 2015 Medium

    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

    PMID:26700226

    Open questions at the time
    • No functional consequence established for any localization
    • Antibody-based localization not corroborated by tagged-protein imaging
  7. 2017 Medium

    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

    PMID:28687926

    Open questions at the time
    • Mechanism by which acetylated MTs accelerate GR transport not defined
    • In vivo relevance untested
  8. 2019 High

    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

    PMID:31897425

    Open questions at the time
    • Vesicle adaptor tethering ATAT1 not identified
    • How motility-coupled acetylation feeds back on motors unresolved
  9. 2019 High

    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

    PMID:30953095

    Open questions at the time
    • Signaling that triggers stress-induced ATAT1 activation not mapped
    • Mechanism coupling acetylation to migration unresolved
  10. 2020 High

    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

    PMID:33066011

    Open questions at the time
    • Phosphosite(s) on ATAT1 not all mapped
    • Cellular cues activating PAK1 toward ATAT1 not defined
  11. 2021 Medium

    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

    PMID:33986251

    Open questions at the time
    • Structural basis of p27-ATAT1 binding not resolved
    • Single-lab Co-IP for the interaction
  12. 2024 Medium

    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

    PMID:38835115

    Open questions at the time
    • How acetylation loss elevates CTSL not mechanistically defined
    • Single cell line
  13. 2024 Medium

    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

    PMID:37862210

    Open questions at the time
    • Molecular link between acetylation and phagocytic machinery unresolved
    • Whether effect is enzymatic or structural untested
  14. 2025 High

    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

    PMID:40689828

    Open questions at the time
    • Mechanism of stiffness-triggered ATAT1 nuclear export not defined
    • Direct GEF-H1 release step not biochemically reconstituted
  15. 2025 Medium

    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

    PMID:41468432

    Open questions at the time
    • Whether JPT2 directly binds ATAT1 not shown
    • Functional impact on acetylation output not quantified

Open questions

Synthesis pass · forward-looking unresolved questions
  • How ATAT1's enzymatic versus structural functions are partitioned across its diverse cellular roles, and what signals govern its dynamic subcellular relocalization, remain unresolved.
  • No unified structural model coupling regulation, localization, and luminal access
  • Direct binding partners mediating non-enzymatic functions largely unidentified

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 3 GO:0140096 catalytic activity, acting on a protein 2
Localization
GO:0005634 nucleus 2 GO:0005794 Golgi apparatus 2 GO:0005856 cytoskeleton 1 GO:0005929 cilium 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-168256 Immune System 2 R-HSA-1266738 Developmental Biology 1 R-HSA-5653656 Vesicle-mediated transport 1 R-HSA-9612973 Autophagy 1
Partners
CDKN1BCTTNJPT2PAK1

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 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. In vitro acetyltransferase assay, genetic disruption in Tetrahymena and C. elegans, zebrafish depletion, C. elegans genetic epistasis Nature High 20829795
2012 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. C. elegans genetics with catalytically inactive MEC-17 mutants, electron microscopy of microtubule protofilament number, behavioral assays Current biology : CB High 22658602
2012 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. Co-immunoprecipitation/binding assay, siRNA knockdown, 3D invasion assay, immunofluorescence colocalization European journal of cell biology Medium 22902175
2013 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. Forward genetic screen in C. elegans, live imaging of axonal transport, epistasis with coel-1 mutant, acetyltransferase domain mutants Cell reports High 24373971
2014 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. Knockdown of Mec-17, pharmacological stimulation of acetylation, Co-IP of Myh10-Myh9, serum-starvation-induced ciliogenesis assay PloS one Medium 25494100
2015 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. Immunohistochemistry with specific ATAT1 antibody in rat tissues (trachea, oviduct, kidney, retina, testis, brain) Medical molecular morphology Medium 26700226
2016 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. Immunohistochemistry and western blot in normal and adrenalectomized rats Cell and tissue research Low 27314403
2017 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. siRNA knockdown, overexpression, western blot, real-time PCR in AtT20 cells; CRH/dexamethasone treatments Cell and tissue research Medium 28687926
2018 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. Immunofluorescence and confocal laser scanning microscopy through synchronized cell cycle stages in KD fibroblasts Medical molecular morphology Low 29869029
2019 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. Live imaging of ATAT1-vesicle movement in neurons in vivo, cell-free motility assays, ATAT1 knockout mouse neurons Science advances High 31897425
2019 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. Atat1 knockout mouse analysis, birth-dating neuronal migration experiments, stress-induced acetylation assays in MEFs, behavioral testing, flow cytometry Cellular and molecular life sciences : CMLS High 30953095
2020 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. In vitro kinase assay showing PAK1 phosphorylates MEC-17, PAK1 inhibitor treatment, proplatelet formation assay, MT acetylation quantification International journal of molecular sciences High 33066011
2021 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. Co-immunoprecipitation (p27-ATAT1 binding), siRNA knockdown of ATAT1, autophagosome trafficking imaging, autophagy flux assays in MEFs Cell death & disease Medium 33986251
2024 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. ATAT1 KO in MDA-MB-231 cells, RHOA promoter analysis, chromatin immunoprecipitation (ChIP), C/EBPβ deletion mutant overexpression, CTSL inhibitor treatment, invasion assay BMB reports Medium 38835115
2024 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. ATAT1 siRNA knockdown in cell lines, ATAT1 KO mice with ICH model, co-culture phagocytosis assay with fluorescently labeled RBCs, immunohistochemistry Neural regeneration research Medium 37862210
2025 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. 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 The Journal of cell biology High 40689828
2025 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. Proximity-labeling (BioID) with mass spectrometry, cryo-EM localization of JPT2 in lumen, Paclitaxel treatment, JPT2 KD with MEC17 distribution analysis Proceedings of the National Academy of Sciences of the United States of America Medium 41468432

Source papers

Stage 0 corpus · 21 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 MEC-17 is an alpha-tubulin acetyltransferase. Nature 391 20829795
2012 Genetically separable functions of the MEC-17 tubulin acetyltransferase affect microtubule organization. Current biology : CB 131 22658602
2012 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. European journal of cell biology 90 22902175
2013 Loss of MEC-17 leads to microtubule instability and axonal degeneration. Cell reports 76 24373971
2019 ATAT1-enriched vesicles promote microtubule acetylation via axonal transport. Science advances 51 31897425
2021 p27 controls autophagic vesicle trafficking in glucose-deprived cells via the regulation of ATAT1-mediated microtubule acetylation. Cell death & disease 36 33986251
2014 A Mec17-Myosin II Effector Axis Coordinates Microtubule Acetylation and Actin Dynamics to Control Primary Cilium Biogenesis. PloS one 34 25494100
2021 HAGLR aggravates neuropathic pain and promotes inflammatory response and apoptosis of lipopolysaccharide-treated SH-SY5Y cells by sequestering miR-182-5p from ATAT1 and activating NLRP3 inflammasome. Neurochemistry international 20 33626373
2019 ATAT1 regulates forebrain development and stress-induced tubulin hyperacetylation. Cellular and molecular life sciences : CMLS 19 30953095
2015 Intracellular localization of α-tubulin acetyltransferase ATAT1 in rat ciliated cells. Medical molecular morphology 19 26700226
2024 The α-tubulin acetyltransferase ATAT1: structure, cellular functions, and its emerging role in human diseases. Cellular and molecular life sciences : CMLS 17 38652325
2018 Dynamic localization of α-tubulin acetyltransferase ATAT1 through the cell cycle in human fibroblastic KD cells. Medical molecular morphology 12 29869029
2020 PAK1 Regulates MEC-17 Acetyltransferase Activity and Microtubule Acetylation during Proplatelet Extension. International journal of molecular sciences 9 33066011
2017 ATAT1 is essential for regulation of homeostasis-retaining cellular responses in corticotrophs along hypothalamic-pituitary-adrenal axis. Cell and tissue research 9 28687926
2024 ATAT1 deficiency enhances microglia/macrophage-mediated erythrophagocytosis and hematoma absorption following intracerebral hemorrhage. Neural regeneration research 4 37862210
2021 Pharmacophore anchor models of ATAT1 to discover potential inhibitors and lead optimization. Computational biology and chemistry 4 34052673
2016 Adrenalectomy facilitates ATAT1 expression and α-tubulin acetylation in ACTH-producing corticotrophs. Cell and tissue research 4 27314403
2025 B cell mechanotransduction via ATAT1 coordinates actin and lysosomal dynamics at the immune synapse. The Journal of cell biology 3 40689828
2025 B cell mechanotransduction via ATAT1 coordinates actin and lysosomal dynamics at the immune synapse. The Journal of cell biology 1 40690562
2024 Genetic disruption of ATAT1 causes RhoA downregulation through abnormal truncation of C/EBPβ. BMB reports 1 38835115
2025 Systematic identification of microtubule lumen proteins reveals a taxane-sensitive luminal resident JPT2 regulating MEC17 accessibility. Proceedings of the National Academy of Sciences of the United States of America 0 41468432

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