Affinage

HDAC6

Protein deacetylase HDAC6 · UniProt Q9UBN7

Length
1215 aa
Mass
131.4 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HDAC6 is a cytoplasmic class IIb lysine deacetylase that functions as a multifunctional signaling hub linking cytoskeletal dynamics, proteostasis, immune sensing, and metabolic regulation through deacetylation of a broad array of non-histone substrates. Its two catalytic domains deacetylate α-tubulin (controlling microtubule dynamics, cilia length, and cell migration), Hsp90 (governing chaperone activity and glucocorticoid receptor maturation), cortactin (driving actin-dependent migration, angiogenesis, and autophagosome–lysosome fusion), RIG-I (enabling antiviral interferon responses to RNA viruses), ERK1 (stimulating MAPK signaling), titin (modulating sarcomere stiffness), and TET2 (initiating active DNA demethylation in response to valine deprivation sensed through its primate-specific SE14 domain) (PMID:15916966, PMID:21847094, PMID:26746851, PMID:29259132, PMID:35575093, PMID:39567688). Its C-terminal ZnF-UBP domain binds ubiquitin to drive aggresome formation, stress granule assembly, and dynein-dependent transport of NLRP3/pyrin inflammasome components to the MTOC for caspase-1 activation (PMID:35476995, PMID:32943500). HDAC6 activity is positively regulated by GRK2 phosphorylation and FTase–microtubule association, and HDAC6 also directly interacts with the leptin receptor in hypothalamic neurons to suppress leptin signaling, positioning it as a metabolic regulator (PMID:22193721, PMID:38569472).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 2005 High

    Identifying HDAC6 as the Hsp90 deacetylase established a paradigm in which a cytoplasmic deacetylase controls chaperone function and downstream client protein (GR) maturation, answering how Hsp90 acetylation is regulated.

    Evidence In vitro deacetylase assay, Co-IP, and HDAC6 genetic inactivation with GR functional readouts in mammalian cells

    PMID:15916966

    Open questions at the time
    • Structural basis of HDAC6–Hsp90 interaction not resolved
    • Whether both HDAC6 catalytic domains contribute to Hsp90 deacetylation was not mapped
  2. 2009 High

    Discovery that FTase and the inhibitor MIIP regulate HDAC6 activity revealed upstream control mechanisms: FTase–microtubule association is required for HDAC6's tubulin deacetylase activity, while MIIP binds both catalytic domains to inhibit activity and reduce HDAC6 stability.

    Evidence Co-IP, in vitro microtubule binding, FTase knockdown, MIIP yeast two-hybrid/GST pulldown with HDAC6 activity and migration assays

    PMID:19228685 PMID:20008322

    Open questions at the time
    • Whether FTase regulation extends to non-tubulin HDAC6 substrates was not tested
    • Structural basis of MIIP–HDAC6 inhibition unknown
  3. 2011 High

    Identification of cortactin as an HDAC6 substrate driving angiogenesis and cell migration—independent of tubulin deacetylation and ubiquitin binding—demonstrated substrate-specific functional outputs, while GRK2 phosphorylation of HDAC6 revealed a kinase-mediated activation mechanism governing motility.

    Evidence Reciprocal Co-IP, catalytic mutants, in vivo sprouting/zebrafish angiogenesis assays, GRK2 in vitro kinase assay with migration readouts

    PMID:21847094 PMID:22193721

    Open questions at the time
    • Specific HDAC6 phosphorylation site(s) by GRK2 not mapped
    • Whether cortactin deacetylation and GRK2 activation converge in the same signaling context was not addressed
  4. 2012 High

    Cell-type-specific deletion of HDAC6 in serotonin neurons demonstrated that the Hsp90–GR axis operates in the brain to regulate stress-related behavior, translating the biochemical mechanism into a neural circuit-level phenotype.

    Evidence Pet1-Cre conditional knockout in serotonin neurons with behavioral, electrophysiological, and biochemical readouts

    PMID:22457490

    Open questions at the time
    • Whether other HDAC6 substrates beyond Hsp90/GR contribute to the behavioral phenotype was not dissected
    • Translational relevance to human anxiety disorders not established
  5. 2013 High

    HDAC6 was shown to control primary cilium stability: overexpression induces deciliation and activates MAPK/Hedgehog signaling, while inhibition restores cilia, establishing HDAC6 as a regulator of cilium-dependent tumor suppression in cholangiocarcinoma.

    Evidence shRNA and pharmacological HDAC6 inhibition with cilium restoration and in vivo xenograft tumor growth reduction

    PMID:23370327

    Open questions at the time
    • Whether HDAC6 deacetylates specific ciliary substrates beyond tubulin was not resolved
    • Mechanism linking HDAC6-mediated deciliation to Hedgehog pathway activation not fully delineated
  6. 2014 Medium

    Dido3 targeting of HDAC6 to the centrosome was shown to govern primary cilium length via local tubulin deacetylation, and separately HDAC6 was found to deacetylate tau within the microtubule-binding domain, linking HDAC6 to neurodegenerative protein homeostasis.

    Evidence siRNA knockdown with quantitative cilium-length measurements; HDAC6-selective inhibitor and shRNA in oligodendrocytes with tau phosphorylation/turnover readouts

    PMID:24464872 PMID:24667272

    Open questions at the time
    • Direct Dido3–HDAC6 binding interface not structurally characterized
    • Functional consequence of tau deacetylation by HDAC6 in neurons in vivo not established
  7. 2016 High

    HDAC6 was identified as the deacetylase for RIG-I at K909, enabling viral RNA sensing and antiviral interferon production; HDAC6 KO mice showed dramatic susceptibility to RNA viruses, establishing HDAC6 as a critical innate immune regulator.

    Evidence Co-IP, K909 site-specific mutagenesis, HDAC6 KO mice with RNA virus infection models

    PMID:26746851

    Open questions at the time
    • Whether HDAC6 regulates other innate immune sensors beyond RIG-I was not tested
    • Signal that triggers HDAC6–RIG-I interaction upon infection not identified
  8. 2017 High

    Discovery that HDAC6 deacetylates ERK1 at K72 to stimulate kinase activity revealed a positive feed-forward loop between HDAC6 and MAPK signaling, and separately HDAC6 was found to deacetylate p53 at K381/382.

    Evidence Mass spectrometry, in vitro kinase assay with acetylation-mimicking mutants for ERK1; Co-IP with site-specific acetylation mapping for p53

    PMID:28153791 PMID:29259132

    Open questions at the time
    • In vivo significance of ERK1 deacetylation by HDAC6 not tested in animal models
    • Conditions controlling HDAC6 nuclear entry to deacetylate p53 not fully defined
  9. 2018 High

    HDAC6 was shown to promote autophagosome–lysosome fusion via ATP13A2-dependent lysosomal recruitment and cortactin deacetylation, establishing HDAC6 as a regulator of the late autophagy pathway.

    Evidence In vitro fusion reconstitution, deacetylase-inactive mutant rescue, Drosophila and mouse models; HDAC6 KO phenocopying pharmacological inhibition of autophagosome–lysosome fusion

    PMID:30318510 PMID:30538141

    Open questions at the time
    • Whether HDAC6 regulates autophagosome–lysosome fusion in all cell types or only specific contexts is unclear
    • Whether cortactin is the sole relevant substrate for fusion is not determined
  10. 2020 High

    HDAC6 was established as a dynein adapter that transports ubiquitinated NLRP3 and pyrin inflammasome components to the MTOC for assembly and caspase-1 activation, revealing a non-enzymatic scaffolding role in innate immunity distinct from its deacetylase function.

    Evidence Co-IP, live-cell imaging, shRNA/KO mice, reconstitution assays with IL-1β/caspase-1 readouts

    PMID:32943500

    Open questions at the time
    • Whether HDAC6 deacetylase activity also contributes to inflammasome regulation in addition to its adapter role was not fully resolved
    • Structural basis of HDAC6–dynein–NLRP3 ternary complex not determined
  11. 2020 Medium

    HDAC6 was found to deacetylate cortactin in pyramidal neurons to regulate dendrite morphogenesis and Golgi polarization, and separately to ubiquitinate Chk1 via E3 ligase activity, revealing a non-canonical enzymatic function.

    Evidence In utero electroporation with cortactin acetylation-mimetic mutants for neuronal function; in vitro ubiquitination assay with domain mapping and epistasis for Chk1

    PMID:32711564 PMID:33020410

    Open questions at the time
    • E3 ligase activity of HDAC6 has not been independently confirmed by other laboratories
    • Whether Chk1 ubiquitination by HDAC6 is relevant outside radiation-response contexts is unknown
  12. 2022 High

    Structural and functional characterization of the ZnF-UBP domain showed it binds ubiquitin to support aggresome formation, stress granule assembly, and viral uncoating; separately, this domain was found to directly bind tau's polyproline region to reduce self-aggregation, and HDAC6 was shown to deacetylate titin to modulate sarcomere stiffness in cardiomyocytes.

    Evidence Crystal structure of ZnF-UBP/DARPin complex with viral infection assays; GST pulldown/ThT aggregation assay for tau; recombinant HDAC6 on isolated myofibrils with HDAC6 KO mice and mechanical measurements

    PMID:33237772 PMID:35476995 PMID:35575093

    Open questions at the time
    • Whether ZnF-UBP-mediated tau disaggregation occurs in vivo remains untested
    • Specific titin acetylation sites targeted by HDAC6 not fully mapped
  13. 2024 High

    Three paradigm-shifting discoveries expanded HDAC6 function: it senses valine through its SE14 domain to regulate nuclear retention and TET2 deacetylation-driven DNA demethylation; it catalyzes α-tubulin lactylation as a lactyltransferase; and it interacts with the leptin receptor in hypothalamic neurons to suppress leptin signaling.

    Evidence Direct valine–SE14 binding assay, HDAC6–TET2 Co-IP with TDG epistasis and xenograft models; MS-identified lactylation site with in vitro enzymatic assay and neurite outgrowth; HDAC6–LepR Co-IP with AgRP-neuron-specific conditional KO and diet-induced obesity models

    PMID:38569472 PMID:39333081 PMID:39567688

    Open questions at the time
    • Lactyltransferase activity awaits independent confirmation and structural characterization
    • Whether valine sensing by HDAC6 operates in non-tumor contexts is unexplored
    • LepR interaction mechanism and whether HDAC6 deacetylates LepR directly are not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include how HDAC6 substrate selectivity is spatiotemporally regulated across its numerous cytoplasmic and nuclear substrates, whether its E3 ligase and lactyltransferase activities are independent catalytic functions or coupled to deacetylation, and how its metabolite-sensing (valine) and non-enzymatic adapter (inflammasome transport) roles integrate with its canonical deacetylase function.
  • No unified structural model of full-length HDAC6 with substrates
  • Relative contributions of deacetylase vs. ubiquitin-binding vs. adapter functions in disease contexts are poorly parsed
  • Systematic identification of tissue-specific HDAC6 substrate repertoires is lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0008092 cytoskeletal protein binding 3 GO:0016740 transferase activity 1 GO:0016874 ligase activity 1 GO:0098772 molecular function regulator activity 1 GO:0140299 molecular sensor activity 1
Localization
GO:0005829 cytosol 5 GO:0005856 cytoskeleton 3 GO:0005634 nucleus 2 GO:0005815 microtubule organizing center 2 GO:0005764 lysosome 1
Pathway
R-HSA-392499 Metabolism of proteins 8 R-HSA-162582 Signal Transduction 2 R-HSA-168256 Immune System 2 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-9612973 Autophagy 2 R-HSA-8953854 Metabolism of RNA 1
Partners
ACTR2DDX58GRK2HSP90AA1LEPRMAPTNLRP3TET2

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 HDAC6 functions as a deacetylase for Hsp90; inactivation of HDAC6 leads to Hsp90 hyperacetylation, dissociation of the cochaperone p23, loss of chaperone activity, and defective glucocorticoid receptor (GR) maturation (impaired ligand binding, nuclear translocation, and transcriptional activation). In vitro deacetylase assay, Co-IP, genetic knockout/inactivation with GR functional readouts Molecular cell High 15916966
2011 HDAC6 interacts with and deacetylates cortactin in endothelial cells, and this deacetylation is required for HDAC6-driven cell migration, sprouting, and angiogenesis; ubiquitin-binding and α-tubulin deacetylase activities are dispensable for this angiogenic function. Co-IP, shRNA knockdown, HDAC6 catalytic mutants, in vitro sprouting assay, in vivo matrigel plug assay, zebrafish vessel formation The EMBO journal High 21847094
2011 GRK2 directly associates with and phosphorylates HDAC6, stimulating its α-tubulin deacetylase activity; GRK2 and HDAC6 colocalize in lamellipodia of migrating cells, promoting local tubulin deacetylation and enhanced motility; phosphorylation of GRK2 at S670 specifically potentiates its ability to regulate HDAC6. Direct binding assay, in vitro kinase assay, Co-IP, immunofluorescence colocalization, migration assays with kinase-dead mutants The EMBO journal High 22193721
2012 HDAC6 controls Hsp90 acetylation in the brain serotonin neurons, modulating Hsp90-GR protein–protein interactions, hormone/stress-induced GR translocation, and downstream GR signaling; serotonin-neuron-selective HDAC6 deletion dramatically reduced anxiety and blocked social avoidance in stress models. Pet1-Cre conditional knockout, pharmacological inhibition, Co-IP, electrophysiology, behavioral testing The Journal of neuroscience High 22457490
2016 HDAC6 deacetylates RIG-I at lysine 909 in the C-terminal domain in response to viral RNA, promoting RIG-I viral RNA sensing and antiviral interferon production; HDAC6 transiently binds RIG-I, and HDAC6 depletion impairs antiviral responses to RNA (but not DNA) viruses; HDAC6 KO mice are highly susceptible to RNA virus infection. Co-IP, site-specific mutagenesis (K909), HDAC6 KO mice, antiviral assays, luciferase reporter The EMBO journal High 26746851
2020 HDAC6 acts as an indispensable dynein adapter mediating microtubule-dependent transport of ubiquitinated NLRP3 and pyrin inflammasome components to the microtubule-organizing center (MTOC), where assembly and caspase-1 activation occur; HDAC6 is required for NLRP3/pyrin inflammasome activation in vitro and in vivo. Co-IP, shRNA/KO in mice, live-cell imaging, reconstitution assays, IL-1β/caspase-1 activation assays Science High 32943500
2018 ATP13A2 facilitates recruitment of HDAC6 to lysosomes; HDAC6 deacetylates cortactin at lysosomes, promoting lysosomal localization of cortactin and autophagosome–lysosome fusion; deacetylase-inactive HDAC6 failed to rescue autophagosome–lysosome fusion in ATP13A2-deficient cells. Co-IP, in vitro reconstitution of fusion, deacetylase-inactive mutant, Drosophila and mouse models, immunofluorescence The Journal of cell biology High 30538141
2009 IIp45 (MIIP) directly binds HDAC6 via its two catalytic domains (identified by yeast two-hybrid and confirmed by GST pulldown and Co-IP), inhibits HDAC6 deacetylase activity, increases acetylated α-tubulin, reduces HDAC6 protein stability, and thereby inhibits cell migration. Yeast two-hybrid, GST pulldown, Co-IP, HDAC activity assay, cell migration assay, siRNA knockdown The Journal of biological chemistry High 20008322
2009 Protein farnesyltransferase (FTase) forms a complex with HDAC6 and microtubules in vivo and in vitro; FTase binds microtubules via its α-subunit in a C-terminus-of-tubulin-dependent manner, and this association is required for HDAC6 deacetylase activity; removal of FTase by FTI treatment or stable FTα knockdown abrogates HDAC6 activity. Co-IP, in vitro microtubule binding assay, FTase knockdown, HDAC6 activity assay The Journal of biological chemistry Medium 19228685
2014 Dido3-dependent targeting of HDAC6 to the centrosome is a key determinant of primary cilium size in growth-arrested cells; Dido3 availability at the centrosome governs ciliary HDAC6 levels and controls tubulin acetylation to determine cilium length. Live-cell imaging, immunofluorescence, siRNA knockdown, quantitative cilium-length measurements Nature communications Medium 24667272
2013 HDAC6 overexpression induces deciliation of normal cholangiocytes and promotes proliferation and anchorage-independent growth; shRNA or pharmacological inhibition of HDAC6 restores primary cilia in cholangiocarcinoma cells and reduces tumor growth; cilia loss activates MAPK and Hedgehog signaling. shRNA knockdown, tubastatin-A pharmacological inhibition, IFT88-shRNA rescue, in vivo xenograft model Cancer research High 23370327
2017 HDAC6 deacetylates p53 at lysines 381/382 via its deacetylase domain; HDAC6 binds the C-terminal region of p53; HDAC6-selective inhibitor blocks HDAC6 nuclear localization, resulting in elevated p53 acetylation and altered apoptotic outcomes. Co-IP, site-specific acetylation mapping, nuclear localization assay, siRNA knockdown Cancer letters Medium 28153791
2017 HDAC6 deacetylates ERK1 at lysine 72, adjacent to the ATP-binding lysine 71; deacetylation by HDAC6 stimulates ERK1 kinase activity toward ELK1; acetylation-mimicking ERK1-K72Q mutant shows reduced phosphorylation, reduced ATP binding, and decreased kinase activity in vitro and in cells, establishing a positive feed-forward loop between HDAC6 and ERK1. Co-IP, mass spectrometry, in vitro kinase assay, acetylation-mimicking/deacetylation-mimicking mutants, luciferase reporter The Journal of biological chemistry High 29259132
2016 HDAC6 is required for TGF-β1-induced EMT via HDAC6-dependent deacetylation of HSP90, which mediates downstream Notch-1 signaling; inhibition of HDAC6 (by tubacin or siRNA) or HSP90 attenuates TGF-β1-induced Notch-1 target gene expression (HEY-1, HES-1) and EMT markers in lung cancer cells. siRNA knockdown, tubacin pharmacological inhibition, Western blot for Notch-1 pathway components, HSP90 inhibitor epistasis Scientific reports Medium 27499032
2013 Hypoxia enhances HDAC6 tubulin deacetylase activity through EGFR pathway activation; activated HDAC6 triggers Smad3 phosphorylation and nuclear accumulation, promoting invadopodia formation; HDAC6 inhibition or knockdown blocks both hypoxia-induced Smad3 activation and invadopodia formation. HDAC6 activity assay, siRNA knockdown, pharmacological inhibition, immunofluorescence, invadopodia formation assay PloS one Medium 23405166
2014 HDAC6 interacts with tau and deacetylates it within the 4R microtubule-binding domain; HDAC6 inhibition leads to tau acetylation, reduced tau microtubule binding, increased tau phosphorylation at pathological sites, and reduced tau turnover rate in oligodendrocytes. HDAC6-selective inhibitor (tubastatin A), shRNA knockdown, isoform-expressing cell lines, Western blot with site-specific antibodies Glia Medium 24464872
2016 HDAC6 deacetylates HMGN2 at lysine K2, promoting Stat5a-mediated transcription and breast cancer cell growth; HDAC6 inhibition in vitro and in vivo increases HMGN2 acetylation and reduces Stat5a signaling. Co-IP, site-specific mutagenesis of HMGN2-K2, HDAC6 inhibition in vitro and in vivo, luciferase reporter, xenograft Molecular cancer research Medium 27358110
2018 HDAC6 inhibition abrogates autophagosome–lysosome fusion, consistent with a role in regulating the autophagy pathway by controlling this fusion step; genetic HDAC6 KO phenocopied drug-induced inhibition of autophagosome–lysosome fusion. HDAC6 KO, pharmacological inhibition with C1A, LC3/p62 substrate analysis British journal of cancer Medium 30318510
2020 HDAC6 accumulates preferentially at neuromuscular junctions (NMJs); pharmacological inhibition of HDAC6 protects against microtubule disorganization and reduces acetylcholine receptor (AChR) cluster size; the endogenous HDAC6 inhibitor paxillin interacts with HDAC6, colocalizes with AChR aggregates, and regulates AChR cluster formation. Immunofluorescence, pharmacological inhibition, Co-IP of paxillin–HDAC6 interaction, AChR clustering assay The Journal of cell biology Medium 32697819
2022 HDAC6 colocalized with Z-disks in cardiomyocytes and deacetylates sarcomeric proteins including titin; HDAC6 deletion or inhibition increases myofibril stiffness through a titin PEVK-element-dependent mechanism; ex vivo treatment of mouse, rat, and human myofibrils with recombinant HDAC6 decreases myofibril stiffness; HDAC6-deficient mice display exacerbated diastolic dysfunction under hypertension or aging. Recombinant HDAC6 treatment of isolated myofibrils, HDAC6 KO mice, mechanical stiffness measurements, proteomics, domain-deletion analysis The Journal of clinical investigation High 35575093
2020 HDAC6 deacetylates cortactin in pyramidal neurons; HDAC6 knockdown causes defective dendrite morphogenesis and abnormal Golgi polarization rescued by wild-type or deacetyl-mimetic cortactin; HDAC6 and SIRT2 cooperate to deacetylate cortactin for neuronal migration and dendrite development in the cerebral cortex in vivo. shRNA knockdown, cortactin acetylation/deacetylation mimetic mutants, in utero electroporation, immunofluorescence Molecular brain Medium 32711564
2022 HDAC6 deacetylates AKAP12 at K526/K531; deacetylation of K531 specifically increases AKAP12 ubiquitination, leading to proteasomal degradation of AKAP12 and promotion of colon cancer metastasis; HDAC6 and AKAP12 protein levels inversely correlate in human colon cancer specimens. Proteomics-based substrate identification, Co-IP, site-specific mutagenesis, proteasome inhibitor assay, cell migration assay Cancer letters Medium 36122629
2021 HDAC6 deacetylates PRMT5 at acetyllysine residues; PRMT5 acetylation enhances its methyltransferase activity and downstream symmetric dimethylation of substrates, revealing crosstalk between acetylation and methylation regulated by HDAC6. Proteomics-based substrate trapping mutant, Co-IP validation, in vitro deacetylation assay, methyltransferase activity assay ACS chemical biology Medium 34314149
2018 HDAC6 inhibition in vascular smooth muscle cells (VSMCs) increases acetylation and total protein levels of MRTF-A; HDAC6 co-immunoprecipitates with MRTF-A; HDAC6 inhibition preserves SRF-dependent contractile gene expression and mitigates neointimal lesion formation in injured rat carotid arteries. Co-IP of HDAC6–MRTF-A, tubastatin A pharmacological inhibition, luciferase reporter, in vivo carotid artery injury model, siRNA knockdown JACC. Basic to translational science Medium 30623138
2014 SMAR1 interacts with Ku70 and coordinates with HDAC6 to maintain Ku70 in a deacetylated state; SMAR1 knockdown causes enhanced Ku70 acetylation, impaired Ku70 chromatin recruitment, and altered Bax-mediated apoptosis after ionizing radiation. Co-IP, siRNA knockdown, chromatin fractionation, irradiation assay Cell death & disease Medium 25299772
2020 HDAC6 has ubiquitin E3 ligase activity and directly ubiquitinates Chk1 (interacting via the DAC1 domain); HDAC6 knockdown results in constitutively active Chk1, persistent G2 arrest after irradiation, and radiosensitivity in NSCLC cells; Chk1 depletion reverses the radiosensitive phenotype of HDAC6-knockdown cells. Co-IP, in vivo and in vitro ubiquitination assay, domain-mapping with DAC1 mutant, siRNA epistasis, colony formation assay Cells Medium 33020410
2024 HDAC6 acts as a lactyltransferase, using lactate to catalyze lactylation of α-tubulin at lysine 40 in soluble tubulin dimers; lactylated α-tubulin enhances microtubule dynamics and facilitates neurite outgrowth and branching; this lactyltransferase activity depends on HDAC6's deacetylase activity and is regulated by intracellular lactate concentration. Mass spectrometry identification of lactylation site, in vitro enzymatic assay, HDAC6 KO/inhibition, neurite outgrowth assay Nature communications Medium 39333081
2024 Human HDAC6 senses intracellular valine levels through direct valine binding via its primate-specific SE14 repeat domain; valine deprivation promotes HDAC6 nuclear retention; nuclear HDAC6 binds and deacetylates TET2, initiating active DNA demethylation and DNA damage through thymine DNA glycosylase-driven excision. Direct binding assay (valine–SE14 domain), nuclear fractionation, Co-IP of HDAC6–TET2, site-specific deacetylation mapping, TDG-epistasis, xenograft tumor model Nature High 39567688
2024 HDAC6 interacts with the leptin receptor (LepR) and reduces LepR signaling; pharmacological HDAC6 inhibition disrupts this interaction and augments leptin signaling; genetic depletion of HDAC6 in AgRP neurons eliminates the anti-obesity effect of HDAC6 inhibitors. Co-IP of HDAC6–LepR, Cre-mediated conditional KO in AgRP neurons, pharmacological inhibition, diet-induced obesity mouse model, food intake and body weight measurements Cell metabolism High 38569472
2022 The HDAC6 ZnF-UBP domain binds ubiquitin to facilitate aggresome formation, stress granule assembly, and influenza A virus (IAV) capsid uncoating; a designed ankyrin repeat protein (DARPin) blocking the ZnF ubiquitin-binding pocket impairs IAV and Zika virus infection as well as aggresome and stress granule formation; crystallographic analysis confirmed the ZnF-ubiquitin binding site. Crystal structure of ZnF-UBP/DARPin complex, in vitro ubiquitin binding assay, conditional DARPin expression in cells, viral infection assays Cell reports High 35476995
2020 HDAC6 ZnF-UBP domain directly interacts with the polyproline/repeat region of Tau, reducing Tau self-aggregation, disaggregating preformed Tau aggregates, and leading to Tau degradation in a concentration-dependent manner. Direct binding assay (GST pulldown/Co-IP), ThT aggregation assay, disaggregation assay Biochemistry Medium 33237772
2024 HDAC6 directly interacts with NGF and deacetylates it, promoting NGF ubiquitination and proteasomal degradation; reduced NGF protein levels maintain primordial follicle dormancy; overexpression of HDAC6 delays primordial follicle activation and prolongs reproductive lifespan in mice. Co-IP of HDAC6–NGF, deacetylation and ubiquitination assays, Hdac6-overexpressing transgenic mice, human ovarian cortical biopsies, RNA sequencing Theranostics Medium 38646645

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Molecular cell 953 15916966
2010 The role of HDAC6 in cancer. Journal of biomedicine & biotechnology 342 21076528
2020 HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation. Science (New York, N.Y.) 319 32943500
2001 Hd6, a rice quantitative trait locus involved in photoperiod sensitivity, encodes the alpha subunit of protein kinase CK2. Proceedings of the National Academy of Sciences of the United States of America 270 11416158
2013 HDAC6 inhibition restores ciliary expression and decreases tumor growth. Cancer research 182 23370327
2006 Crystal structures of human alpha-defensins HNP4, HD5, and HD6. Protein science : a publication of the Protein Society 174 17088326
2011 Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin. The EMBO journal 165 21847094
2000 Identification of heading date quantitative trait locus Hd6 and characterization of its epistatic interactions with Hd2 in rice using advanced backcross progeny. Genetics 125 10655238
2012 Development and therapeutic impact of HDAC6-selective inhibitors. Biochemical pharmacology 120 22728920
2012 HDAC6 regulates glucocorticoid receptor signaling in serotonin pathways with critical impact on stress resilience. The Journal of neuroscience : the official journal of the Society for Neuroscience 116 22457490
2017 Recent advances in the discovery of potent and selective HDAC6 inhibitors. European journal of medicinal chemistry 115 29133060
2014 Drugging the HDAC6-HSP90 interplay in malignant cells. Trends in pharmacological sciences 113 25234862
2016 HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG-I. The EMBO journal 111 26746851
2020 Targeting HDAC6 attenuates nicotine-induced macrophage pyroptosis via NF-κB/NLRP3 pathway. Atherosclerosis 101 33321327
2011 A novel GRK2/HDAC6 interaction modulates cell spreading and motility. The EMBO journal 100 22193721
2018 ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome-lysosome fusion. The Journal of cell biology 93 30538141
2016 HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma. Cancer letters 93 27267806
2020 HDAC6 in Diseases of Cognition and of Neurons. Cells 87 33374719
2019 Paneth cell α-defensins HD-5 and HD-6 display differential degradation into active antimicrobial fragments. Proceedings of the National Academy of Sciences of the United States of America 84 30808760
2013 Inclusion body formation, macroautophagy, and the role of HDAC6 in neurodegeneration. Acta neuropathologica 84 23912309
2013 The role of HDAC6 in Alzheimer's disease. Journal of Alzheimer's disease : JAD 83 22936009
2021 The Role of HDAC6 in Autophagy and NLRP3 Inflammasome. Frontiers in immunology 80 34777380
2017 HDAC6 deacetylates p53 at lysines 381/382 and differentially coordinates p53-induced apoptosis. Cancer letters 73 28153791
2019 High-selective HDAC6 inhibitor promotes HDAC6 degradation following autophagy modulation and enhanced antitumor immunity in glioblastoma. Biochemical pharmacology 71 30885763
2024 Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation. Nature communications 69 39333081
2016 The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease. Clinical science (London, England : 1979) 69 27154743
2014 HDAC6 inhibition results in tau acetylation and modulates tau phosphorylation and degradation in oligodendrocytes. Glia 69 24464872
2021 Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a. Journal of cachexia, sarcopenia and muscle 66 34725961
2018 The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease. International journal of molecular sciences 63 30096875
2016 Both HDAC5 and HDAC6 are required for the proliferation and metastasis of melanoma cells. Journal of translational medicine 57 26747087
2021 HDAC6 regulates primordial follicle activation through mTOR signaling pathway. Cell death & disease 50 34052832
2017 Targeting HSP90-HDAC6 Regulating Network Implicates Precision Treatment of Breast Cancer. International journal of biological sciences 49 28529458
2016 HDAC6 promotes cell proliferation and confers resistance to gefitinib in lung adenocarcinoma. Oncology reports 48 27221381
2013 HDAC6: physiological function and its selective inhibitors for cancer treatment. Drug discoveries & therapeutics 48 24423654
2009 IIp45 inhibits cell migration through inhibition of HDAC6. The Journal of biological chemistry 48 20008322
2022 HDAC6 modulates myofibril stiffness and diastolic function of the heart. The Journal of clinical investigation 47 35575093
2020 Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma. Cell death & disease 47 32488056
2020 HDAC6 regulates microtubule stability and clustering of AChRs at neuromuscular junctions. The Journal of cell biology 43 32697819
2018 Loss of HDAC6 alters gut microbiota and worsens obesity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 43 30102568
2014 Dido3-dependent HDAC6 targeting controls cilium size. Nature communications 43 24667272
2016 Requirement of HDAC6 for activation of Notch1 by TGF-β1. Scientific reports 40 27499032
2015 Ciliopathies: Does HDAC6 Represent a New Therapeutic Target? Trends in pharmacological sciences 40 26651415
2014 Limited efficacy of specific HDAC6 inhibition in urothelial cancer cells. Cancer biology & therapy 40 24618845
2023 New insights into the non-enzymatic function of HDAC6. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 39 37002569
2020 HDAC6 inhibitors: Translating genetic and molecular insights into a therapy for axonal CMT. Brain research 39 32006555
2018 The HDAC6 inhibitor C1A modulates autophagy substrates in diverse cancer cells and induces cell death. British journal of cancer 39 30318510
2018 HDAC6 inhibition disrupts maturational progression and meiotic apparatus assembly in mouse oocytes. Cell cycle (Georgetown, Tex.) 38 28598228
2018 Structure, Functions and Selective Inhibitors of HDAC6. Current topics in medicinal chemistry 38 30499393
2017 Histone deacetylase 6 (HDAC6) deacetylates extracellular signal-regulated kinase 1 (ERK1) and thereby stimulates ERK1 activity. The Journal of biological chemistry 36 29259132
2022 HDAC6-dependent deacetylation of AKAP12 dictates its ubiquitination and promotes colon cancer metastasis. Cancer letters 35 36122629
2018 Inhibition of HDAC6 activity in kidney diseases: a new perspective. Molecular medicine (Cambridge, Mass.) 35 30134806
2016 HDAC6 Deacetylates HMGN2 to Regulate Stat5a Activity and Breast Cancer Growth. Molecular cancer research : MCR 35 27358110
2013 HDAC6 deacetylase activity is required for hypoxia-induced invadopodia formation and cell invasion. PloS one 35 23405166
2018 HDAC6 at Crossroads of Infection and Innate Immunity. Trends in immunology 34 29937401
2023 Curriculum vitae of HDAC6 in solid tumors. International journal of biological macromolecules 33 36642357
2015 HDAC6 Promotes Cardiac Fibrosis Progression through Suppressing RASSF1A Expression. Cardiology 33 26401643
2018 MicroRNA-221 induces autophagy through suppressing HDAC6 expression and promoting apoptosis in pancreatic cancer. Oncology letters 32 30546469
2018 HDAC6 Regulates the MRTF-A/SRF Axis and Vascular Smooth Muscle Cell Plasticity. JACC. Basic to translational science 32 30623138
2009 The protein farnesyltransferase regulates HDAC6 activity in a microtubule-dependent manner. The Journal of biological chemistry 32 19228685
2018 A novel class of anthraquinone-based HDAC6 inhibitors. European journal of medicinal chemistry 31 30597327
2024 Human HDAC6 senses valine abundancy to regulate DNA damage. Nature 30 39567688
2022 Disrupting the HDAC6-ubiquitin interaction impairs infection by influenza and Zika virus and cellular stress pathways. Cell reports 30 35476995
2020 HDAC6 promotes growth, migration/invasion, and self-renewal of rhabdomyosarcoma. Oncogene 30 33199827
2017 Cellular defence or viral assist: the dilemma of HDAC6. The Journal of general virology 30 27959772
2020 Inhibition of HDAC6 Attenuates Diabetes-Induced Retinal Redox Imbalance and Microangiopathy. Antioxidants (Basel, Switzerland) 29 32660051
2020 Cortactin deacetylation by HDAC6 and SIRT2 regulates neuronal migration and dendrite morphogenesis during cerebral cortex development. Molecular brain 29 32711564
2020 HDAC6 ZnF UBP as the Modifier of Tau Structure and Function. Biochemistry 29 33237772
2017 HDAC6 regulates IL-17 expression in T lymphocytes: implications for HDAC6-targeted therapies. Theranostics 28 28382171
2019 Inhibition of HDAC6 alleviating lipopolysaccharide-induced p38MAPK phosphorylation and neuroinflammation in mice. Pharmaceutical biology 27 31124385
2017 HDAC6 inhibition suppresses chondrosarcoma by restoring the expression of primary cilia. Oncology reports 27 28586053
2014 HDAC6 regulates neuroblastoma cell migration and may play a role in the invasion process. Cancer biology & therapy 27 25482939
2016 AKT activation controls cell survival in response to HDAC6 inhibition. Cell death & disease 26 27362804
2020 Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors. ChemMedChem 25 32348628
2019 Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity. Blood advances 25 31015208
2022 Design, synthesis, and biological evalution of bifunctional inhibitors against Hsp90-HDAC6 interplay. European journal of medicinal chemistry 24 35834905
2016 Oncogenic K-ras confers SAHA resistance by up-regulating HDAC6 and c-myc expression. Oncotarget 24 26848526
2024 Small molecules targeting HDAC6 for cancer treatment: Current progress and novel strategies. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 39084081
2021 Role of HDAC6 and Its Selective Inhibitors in Gastrointestinal Cancer. Frontiers in cell and developmental biology 23 34938729
2020 Phospho-HDAC6 Gathers Into Protein Aggregates in Parkinson's Disease and Atypical Parkinsonisms. Frontiers in neuroscience 23 32655357
2014 SMAR1 coordinates HDAC6-induced deacetylation of Ku70 and dictates cell fate upon irradiation. Cell death & disease 23 25299772
2023 Selective inhibition of HDAC6 promotes bladder cancer radiosensitization and mitigates the radiation-induced CXCL1 signalling. British journal of cancer 22 36810912
2022 Dual Targeting Strategies on Histone Deacetylase 6 (HDAC6) and Heat Shock Protein 90 (Hsp90). Current medicinal chemistry 22 34477503
2022 Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells. Cancers 22 36497494
2020 HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1. Cells 22 33020410
2018 Involvement of HDAC6 in ischaemia and reperfusion-induced rat retinal injury. BMC ophthalmology 22 30453928
2024 The HDAC6 inhibitor AVS100 (SS208) induces a pro-inflammatory tumor microenvironment and potentiates immunotherapy. Science advances 21 39546602
2023 HDAC6 Degrades nsp8 of Porcine Deltacoronavirus through Deacetylation and Ubiquitination to Inhibit Viral Replication. Journal of virology 21 37133375
2019 The HDAC6-selective inhibitor is effective against non-Hodgkin lymphoma and synergizes with ibrutinib in follicular lymphoma. Molecular carcinogenesis 21 30693983
2021 Tektin4 loss promotes triple-negative breast cancer metastasis through HDAC6-mediated tubulin deacetylation and increases sensitivity to HDAC6 inhibitor. Oncogene 20 33654196
2020 The Role of HDAC6 in TDP-43-Induced Neurotoxicity and UPS Impairment. Frontiers in cell and developmental biology 20 33282865
2024 Targeting HDAC6 improves anti-CD47 immunotherapy. Journal of experimental & clinical cancer research : CR 19 38414061
2024 Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss. Cell metabolism 18 38569472
2020 Inhibition of HDAC6 by tubastatin A disrupts mouse oocyte meiosis via regulating histone modifications and mRNA expression. Journal of cellular physiology 18 32017059
2020 SET7 interacts with HDAC6 and suppresses the development of colon cancer through inactivation of HDAC6. American journal of translational research 18 32194908
2024 HDAC6-dependent deacetylation of NGF dictates its ubiquitination and maintains primordial follicle dormancy. Theranostics 17 38646645
2021 HDAC6 Substrate Discovery Using Proteomics-Based Substrate Trapping: HDAC6 Deacetylates PRMT5 to Influence Methyltransferase Activity. ACS chemical biology 17 34314149
2018 HDAC6 regulates dental mesenchymal stem cells and osteoclast differentiation. BMC oral health 17 30463548
2016 Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy. Pharmacology & therapeutics 17 27118337
2023 HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma. Scientific reports 16 37528157
2021 Discovery of a novel AR/HDAC6 dual inhibitor for prostate cancer treatment. Aging 16 33621955