Affinage

HDAC6

Protein deacetylase HDAC6 · UniProt Q9UBN7

Length
1215 aa
Mass
131.4 kDa
Annotated
2026-06-10
100 papers in source corpus 28 papers cited in narrative 28 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

HDAC6 is a cytoplasmic class IIb deacetylase that integrates protein-quality control, cytoskeletal dynamics, and stress signaling by deacetylating a broad set of non-histone substrates (PMID:12024216, PMID:15916966). Through its two catalytic domains it removes acetyl groups from alpha-tubulin in assembled microtubules, globally regulating tubulin acetylation, microtubule-based transport, and chemotactic cell motility (PMID:12024216), and this tubulin-deacetylase activity is potentiated by GRK2-mediated phosphorylation at sites of active migration (PMID:22193721). It controls chaperone function by deacetylating Hsp90, whose hyperacetylation upon HDAC6 loss dissociates the co-chaperone p23 and impairs maturation of clients such as the glucocorticoid receptor (PMID:15916966), and it remodels the actin cytoskeleton by deacetylating cortactin to drive endothelial migration, sprouting, and angiogenesis independently of tubulin deacetylation (PMID:21847094). HDAC6 couples ubiquitin-dependent proteostasis to the cytoskeleton via a C-terminal ZnF-UBP domain that binds ubiquitin monomers with high affinity, controls polyubiquitin chain turnover, and engages p97/VCP, which dissociates HDAC6-ubiquitin complexes (PMID:16810319); the same domain mediates aggresome and stress-granule formation and is exploited by influenza A and Zika viruses, as resolved by a co-crystal structure with a pocket-blocking DARPin (PMID:35476995). Beyond classical deacetylation, HDAC6 carries out additional catalytic activities: it lactylates alpha-tubulin at lysine 40 to enhance microtubule dynamics and neurite outgrowth (PMID:39333081), and acts as an E3 ubiquitin ligase through its DAC1 domain to ubiquitinate Chk1 (PMID:33020410). It serves as a dynein adapter directing ubiquitinated cargo and NLRP3/pyrin inflammasome components to the MTOC (PMID:32943500), and in humans functions as a valine sensor whose primate-specific SE14 repeat triggers nuclear retention and TET2 deacetylation to initiate DNA demethylation under valine deprivation (PMID:39567688). HDAC6 further deacetylates substrates linking it to innate antiviral sensing (RIG-I, TRIM21) (PMID:26746851, PMID:32796032), DNA mismatch repair (MLH1) (PMID:30770470), and cardiac sarcomere stiffness via titin (PMID:35575093).

Mechanistic history

Synthesis pass · year-by-year structured walk · 28 steps
  1. 2002 High

    Established HDAC6 as a bona fide cytoplasmic tubulin deacetylase, defining its first non-histone substrate and a role in cell motility.

    Evidence in vitro deacetylase assay on purified HDAC6 and assembled microtubules, fractionation, chemotaxis assay

    PMID:12024216

    Open questions at the time
    • Did not resolve how tubulin deacetylation mechanistically alters microtubule stability versus transport
    • Regulation of HDAC6 catalytic activity unaddressed
  2. 2005 High

    Showed HDAC6 governs chaperone activity by deacetylating Hsp90, extending its function from cytoskeleton to protein folding/maturation.

    Evidence in vitro deacetylase assay, HDAC6-deficient cells, glucocorticoid receptor functional readouts

    PMID:15916966

    Open questions at the time
    • Specific Hsp90 acetyl-lysine sites not fully mapped
    • Breadth of affected Hsp90 clients beyond GR not defined
  3. 2006 High

    Defined the ZnF-UBP domain as a high-affinity ubiquitin sensor coupling HDAC6 to polyubiquitin turnover and the p97/VCP machinery, linking it to proteostasis.

    Evidence biophysical/biochemical ubiquitin-binding assays, Co-IP, cellular ubiquitin-accumulation assays, domain analysis

    PMID:16810319

    Open questions at the time
    • Precise chain-length selectivity in cells not fully resolved
    • How ubiquitin binding is integrated with deacetylase activity unclear
  4. 2011 High

    Identified cortactin as a substrate and dissected domain-specific requirements, showing angiogenic function depends on catalysis but not ubiquitin binding or tubulin deacetylation.

    Evidence reciprocal Co-IP, in vitro deacetylase assay, multi-organism knockout, domain-mutant rescue, angiogenesis assays

    PMID:21847094

    Open questions at the time
    • Cortactin acetyl-site identity in this context not specified
    • Crosstalk with tubulin pool not resolved
  5. 2011 High

    Revealed upstream regulation of HDAC6, with GRK2 binding and phosphorylating HDAC6 to stimulate tubulin deacetylation locally in lamellipodia.

    Evidence in vitro kinase assay, phosphosite mutagenesis, co-localization imaging, migration assays

    PMID:22193721

    Open questions at the time
    • HDAC6 phosphorylation sites targeted by GRK2 not mapped
    • Whether other kinases regulate HDAC6 unaddressed
  6. 2014 Medium

    Connected HDAC6 to ciliogenesis through Dido3-dependent centrosomal targeting controlling ciliary tubulin acetylation and cilium size.

    Evidence live and fixed imaging, HDAC6/Dido3 overexpression and knockdown, cilium length measurement

    PMID:24667272

    Open questions at the time
    • Molecular nature of Dido3-HDAC6 interaction not biochemically defined
    • Single-lab imaging-based study
  7. 2013 Medium

    Established HDAC6 as a driver of ciliary disassembly with tumor-promoting consequences, using an IFT88 rescue to prove cilia-dependence.

    Evidence shRNA, tubastatin-A inhibition, overexpression, IFT88-shRNA rescue, xenograft

    PMID:23370327

    Open questions at the time
    • Direct deacetylation event driving disassembly not isolated
    • Generalizability beyond cholangiocarcinoma untested here
  8. 2014 Medium

    Linked HDAC6 to tau proteostasis, showing inhibition increases tau acetylation in the microtubule-binding domain and slows turnover.

    Evidence tubastatin A and shRNA, tau isoform cell lines, pulse-chase turnover assay

    PMID:24464872

    Open questions at the time
    • Direct versus indirect tau deacetylation not separated in cells
    • Single cell-type context
  9. 2014 Medium

    Placed HDAC6 in a DNA-damage/apoptosis axis by maintaining Ku70 deacetylation with SMAR1, controlling Bax sequestration and radioresistance.

    Evidence Co-IP of ternary complex, chromatin fractionation, knockdown, post-irradiation apoptosis assays

    PMID:25299772

    Open questions at the time
    • Reciprocal validation of direct HDAC6-Ku70 deacetylation limited
    • Single-lab study
  10. 2016 High

    Demonstrated HDAC6 activates innate antiviral RNA sensing by deacetylating RIG-I at K909, with knockout mice susceptible to RNA viruses.

    Evidence reciprocal Co-IP, acetyl-site mapping, KO cells and mice, IFN and viral challenge assays

    PMID:26746851

    Open questions at the time
    • Specificity for RNA but not DNA virus sensing mechanism incompletely defined
    • Kinetics of transient HDAC6-RIG-I binding unresolved
  11. 2018 High

    Showed HDAC6 promotes autophagosome-lysosome fusion via lysosomal recruitment by ATP13A2 and cortactin deacetylation.

    Evidence Co-IP, in vitro fusion reconstitution, deacetylase-dead rescue, fractionation, fly/mouse models

    PMID:30538141

    Open questions at the time
    • How cortactin deacetylation mechanically aids fusion not fully defined
    • Other lysosomal HDAC6 substrates unexplored
  12. 2019 High

    Identified MLH1 as a substrate whose deacetylation blocks MutSα-MutLα assembly, linking HDAC6 to mismatch-repair regulation and damage tolerance.

    Evidence Co-IP, in vitro deacetylase assay, MS site mapping, acetyl-mimetic mutants, 6-thioguanine resistance

    PMID:30770470

    Open questions at the time
    • Physiological signals controlling MLH1 deacetylation unknown
    • Single-lab functional context
  13. 2020 High

    Established HDAC6 as a dynein adapter essential for MTOC delivery and aggresome-like assembly of NLRP3 and pyrin inflammasomes.

    Evidence KO mice, in vitro reconstitution, MTOC live imaging, caspase and IL-1β assays

    PMID:32943500

    Open questions at the time
    • Cargo-recognition determinants for inflammasome components not fully defined
    • Relationship to ubiquitin-binding versus motor-adapter roles unresolved
  14. 2020 Medium

    Reported a non-canonical E3 ligase activity, with HDAC6's DAC1 domain ubiquitinating Chk1 and modulating radiosensitivity.

    Evidence in vitro/in vivo ubiquitination, domain mapping, knockdown with Chk1 rescue, cell-cycle analysis

    PMID:33020410

    Open questions at the time
    • Whether DAC1 ligase activity generalizes beyond Chk1 untested
    • Single-lab, requires independent confirmation of intrinsic E3 activity
  15. 2020 High

    Extended antiviral function to antibody-dependent intracellular neutralization by deacetylating TRIM21 at K385/K387 to promote its dimerization.

    Evidence Co-IP/PRYSPRY mapping, in vitro deacetylase assay, site mutagenesis, dimerization and neutralization assays

    PMID:32796032

    Open questions at the time
    • In vivo relevance to viral clearance not addressed
    • Single-lab study
  16. 2020 High

    Showed the ZnF-UBP ubiquitin pocket drives aggresome/stress-granule formation and is hijacked by influenza A and Zika viruses, validated structurally with a blocking DARPin.

    Evidence ZnF-DARPin crystal structure, ubiquitin-binding assay, conditional DARPin expression, viral infection and granule quantification

    PMID:35476995

    Open questions at the time
    • Endogenous regulators that gate the ZnF pocket in vivo unknown
    • Therapeutic translatability of DARPin untested
  17. 2020 Medium

    Identified HDAC6 enrichment at neuromuscular junctions and a paxillin-HDAC6 axis regulating AChR clustering and microtubule organization.

    Evidence confocal NMJ localization, pharmacological inhibition, paxillin-HDAC6 Co-IP, AChR clustering assays

    PMID:32697819

    Open questions at the time
    • Direct substrate at NMJ not defined
    • Single-lab, correlative localization
  18. 2020 Medium

    Demonstrated the ZnF-UBP domain directly binds tau's polyproline/repeat region to reduce aggregation and disaggregate fibrils, implicating HDAC6 in tau clearance.

    Evidence recombinant ZnF-UBP binding, ThT/EM aggregation assays, biophysical conformational analysis

    PMID:33237772

    Open questions at the time
    • In vivo disaggregase relevance not established
    • Single-lab in vitro reconstitution
  19. 2021 Medium

    Revealed acetylation-methylation crosstalk by identifying PRMT5 as a substrate whose deacetylation lowers its methyltransferase output.

    Evidence substrate-trapping proteomics, in vitro deacetylase and methyltransferase assays

    PMID:34314149

    Open questions at the time
    • PRMT5 acetyl-sites and stoichiometry incompletely defined
    • Single-lab study
  20. 2021 Medium

    Linked HDAC6 to muscle atrophy by interacting with FoxO3a to promote its nuclear localization and myostatin transcription downstream of metformin.

    Evidence Co-IP, ChIP on myostatin promoter, nuclear localization imaging, AMPK knockdown, luciferase reporter

    PMID:34725961

    Open questions at the time
    • Whether HDAC6 deacetylates FoxO3a directly not shown
    • Single-lab, correlative
  21. 2022 High

    Defined titin as a sarcomeric substrate, with HDAC6 deacetylating the PEVK element to reduce myofibril stiffness and protect against diastolic dysfunction.

    Evidence KO mice, recombinant HDAC6 treatment of human/rodent myofibrils, mechanics, proteomics, Z-disk co-localization

    PMID:35575093

    Open questions at the time
    • Titin acetyl-site regulation in vivo not fully mapped
    • Upstream signals controlling cardiac HDAC6 activity unknown
  22. 2022 Medium

    Connected HDAC6 to colon cancer metastasis by deacetylating AKAP12 to promote its ubiquitin-dependent degradation and PKC reactivation.

    Evidence Co-IP, proteomics, in vitro deacetylase assay, site mutagenesis, ubiquitination and migration assays

    PMID:36122629

    Open questions at the time
    • Direct ligase for AKAP12 not identified
    • Single-lab study
  23. 2023 Medium

    Demonstrated antiviral targeting of coronavirus nsp8 via combined deacetylation (K46) and ubiquitination (K58) driving proteasomal degradation.

    Evidence Co-IP, deacetylase and ubiquitination assays, mutagenesis, reverse-genetics recombinant virus, replication assays

    PMID:37133375

    Open questions at the time
    • Generalizability to other coronaviruses untested
    • Single-lab study
  24. 2024 High

    Uncovered a novel lactyltransferase activity, with HDAC6 lactylating alpha-tubulin K40 to enhance microtubule dynamics and neurite outgrowth in a lactate-dependent manner.

    Evidence in vitro lactyltransferase assay with purified HDAC6, MS site ID, overexpression/KO, microtubule and neurite imaging

    PMID:39333081

    Open questions at the time
    • Structural basis for lactyl- versus deacetyl-transfer not resolved
    • Independent confirmation of intrinsic lactyltransferase activity pending
  25. 2024 High

    Defined a primate-specific valine-sensing function: SE14-mediated valine binding controls nuclear shuttling and TET2 deacetylation to drive DNA demethylation and damage upon valine deprivation.

    Evidence valine-binding assay, fractionation, HDAC6-TET2 Co-IP, in vitro TET2 deacetylase assay, SE14 mutagenesis, demethylation/damage assays

    PMID:39567688

    Open questions at the time
    • How SE14 valine occupancy mechanistically gates localization unresolved
    • Physiological contexts of valine sensing in humans not fully mapped
  26. 2024 Medium

    Placed HDAC6 in central metabolic control by interacting with the leptin receptor to dampen leptin signaling, with anti-obesity effects mediated through AgRP neurons.

    Evidence Co-IP, inhibitor treatment of obese mice, AgRP-specific conditional KO, BBB-permeable inhibitor comparison

    PMID:38569472

    Open questions at the time
    • Whether LepR is a deacetylation substrate not established
    • Mechanism of interaction-dependent inhibition unclear
  27. 2024 Medium

    Linked HDAC6 to ovarian follicle dormancy by deacetylating NGF to accelerate its ubiquitin-dependent degradation.

    Evidence Co-IP, in vitro deacetylase and ubiquitination assays, transgenic mice, human ovarian explants, follicle activation assays

    PMID:38646645

    Open questions at the time
    • NGF acetyl-sites not mapped
    • Direct ligase coupling not defined
  28. 2024 Medium

    Showed HDAC6 shapes the cancer chromatin landscape indirectly by stabilizing P300, with inactivation increasing H3 acetylation and opening chromatin.

    Evidence inhibitor/siRNA/CRISPR, ATAC-seq, H3K27Ac ChIP-seq, transcriptomics, P300 ubiquitination assay

    PMID:39155390

    Open questions at the time
    • Mechanism by which HDAC6 controls P300 ubiquitination not defined
    • Direct versus indirect chromatin effects not fully separated

Open questions

Synthesis pass · forward-looking unresolved questions
  • How HDAC6's multiple enzymatic modes — deacetylation, intrinsic E3 ligase activity, and lactyltransferase activity — are coordinated and selectively engaged across its diverse substrates remains unresolved.
  • No unified structural model integrating DAC1/DAC2 catalysis, ZnF-UBP ubiquitin sensing, and SE14 metabolite sensing
  • Substrate-selection logic governing which activity acts on which target is undefined
  • Independent replication of E3 ligase and lactyltransferase activities limited to single labs

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0140313 molecular sequestering activity 2 GO:0008092 cytoskeletal protein binding 1 GO:0016740 transferase activity 1 GO:0016874 ligase activity 1 GO:0060090 molecular adaptor activity 1 GO:0140299 molecular sensor activity 1
Localization
GO:0005815 microtubule organizing center 2 GO:0005856 cytoskeleton 2 GO:0005634 nucleus 1 GO:0005764 lysosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-9612973 Autophagy 2 R-HSA-1640170 Cell Cycle 1 R-HSA-4839726 Chromatin organization 1 R-HSA-73894 DNA Repair 1
Partners
CTTNGRK2HSP90MLH1RIGITET2TRIM21VCP

Evidence

Reading pass · 28 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 HDAC6 is a tubulin deacetylase that localizes exclusively in the cytoplasm, associates with microtubules, and co-localizes with the microtubule motor complex containing p150(glued). In vitro, purified HDAC6 potently deacetylates alpha-tubulin in assembled microtubules. Overexpression of HDAC6 leads to global deacetylation of alpha-tubulin and promotes chemotactic cell movement. Cytoplasmic fractionation, co-immunoprecipitation, in vitro deacetylase assay with purified HDAC6 on assembled microtubules, overexpression and knockdown with alpha-tubulin acetylation readout, chemotaxis assay Nature High 12024216
2005 HDAC6 functions as an Hsp90 deacetylase. Inactivation of HDAC6 leads to Hsp90 hyperacetylation, dissociation of Hsp90 from its co-chaperone p23, and loss of chaperone activity. In HDAC6-deficient cells, Hsp90-dependent maturation of the glucocorticoid receptor (GR) is compromised, resulting in GR defective in ligand binding, nuclear translocation, and transcriptional activation. Co-immunoprecipitation, in vitro deacetylase assay, HDAC6 knockout/knockdown cells, glucocorticoid receptor functional assays (ligand binding, nuclear translocation, transcriptional activation) Molecular cell High 15916966
2006 HDAC6 contains a C-terminal zinc finger ubiquitin-binding domain (ZnF-UBP) with the highest known affinity for ubiquitin monomers, which mediates the ability of HDAC6 to negatively control cellular polyubiquitin chain turnover. The HDAC6-interacting chaperone p97/VCP dissociates HDAC6-ubiquitin complexes and counteracts HDAC6-promoted accumulation of polyubiquitinated proteins. Biophysical characterization (Zn ion content), biochemical binding assays, Co-IP, cellular ubiquitin chain accumulation assays, domain structure-function analysis The EMBO journal High 16810319
2011 HDAC6 interacts with and deacetylates the actin-remodeling protein cortactin in endothelial cells. This deacetylation is essential for endothelial cell migration, sprouting, and angiogenesis in vitro and in vivo. HDAC6 function in angiogenesis requires its catalytic activity but is independent of ubiquitin binding and deacetylation of alpha-tubulin. Co-immunoprecipitation, in vitro deacetylase assay, HDAC6 silencing/knockout (endothelial cells, zebrafish, mice), matrigel plug angiogenesis assay, domain mutant rescue experiments The EMBO journal High 21847094
2011 G protein-coupled receptor kinase 2 (GRK2) directly associates with and phosphorylates HDAC6 to stimulate its alpha-tubulin deacetylase activity. Phosphorylation of GRK2 at S670 potentiates its ability to regulate HDAC6. GRK2 and HDAC6 co-localize in lamellipodia of migrating cells, leading to local tubulin deacetylation and enhanced cell motility. Co-immunoprecipitation, in vitro kinase assay, phosphorylation site mutagenesis (GRK2-K220R, GRK2-S670A), immunofluorescence co-localization, migration assays The EMBO journal High 22193721
2016 HDAC6 deacetylates RIG-I at lysine 909 in the C-terminal region upon viral RNA exposure, promoting RIG-I sensing of viral RNAs. HDAC6 transiently binds RIG-I; depletion of HDAC6 impairs antiviral responses against RNA viruses but not DNA viruses. HDAC6 knockout mice are highly susceptible to RNA virus infections. Co-immunoprecipitation, site-specific acetylation mapping (K909), HDAC6 knockdown/knockout cells and mice, antiviral response assays (IFN production), viral challenge experiments The EMBO journal High 26746851
2018 ATP13A2 facilitates recruitment of HDAC6 to lysosomes, where HDAC6 deacetylates cortactin to promote autophagosome-lysosome fusion. Wild-type HDAC6, but not a deacetylase-inactive mutant, restored autophagosome-lysosome fusion and promoted lysosomal localization of cortactin in ATP13A2-deficient cells. Co-immunoprecipitation, in vitro reconstitution of autophagosome-lysosome fusion, deacetylase-inactive HDAC6 mutant rescue experiments, subcellular fractionation, Drosophila and mouse models The Journal of cell biology High 30538141
2019 HDAC6 interacts with and deacetylates MLH1 (MutL homolog 1) both in vitro and in vivo. Four novel acetylation sites in MLH1 were identified by MS. Deacetylation of MLH1 by HDAC6 blocks assembly of the MutSα-MutLα mismatch repair complex, leading to DNA damage tolerance. Co-immunoprecipitation, in vitro deacetylase assay, mass spectrometry acetylation site mapping, acetylation mimetic/deacetylation mimetic MLH1 mutants, 6-thioguanine resistance assay The Journal of biological chemistry High 30770470
2020 HDAC6 functions as a dynein adapter and is indispensable for microtubule transport and assembly of NLRP3 and pyrin inflammasomes at the microtubule-organizing center (MTOC). HDAC6 mediates an aggresome-like mechanism for inflammasome activation and provides an inherent mechanism for inflammasome downregulation by autophagy. Genetic deletion (HDAC6 knockout mice), in vitro reconstitution, live-cell imaging at MTOC, caspase activation assays, IL-1β conversion assays Science (New York, N.Y.) High 32943500
2020 HDAC6 ubiquitinates Chk1 in vitro and in vivo via its DAC1 domain, which contains E3 ubiquitin ligase activity. HDAC6 and Chk1 directly interact via the DAC1 domain. In HDAC6 knockdown NSCLC cells, Chk1 fails to resolve post-ionizing radiation, leading to preferential G2 arrest and radiosensitivity. Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, HDAC6 domain mapping (DAC1), HDAC6 knockdown with Chk1 rescue experiments, cell cycle analysis Cells Medium 33020410
2020 HDAC6 interacts with TRIM21 through its PRYSPRY motif and deacetylates TRIM21 at lysine 385 and lysine 387, promoting TRIM21 homodimerization. Inhibiting HDAC6 increases TRIM21 acetylation, blocks its dimerization and ubiquitination, and impairs antibody-dependent intracellular neutralization of viruses. Co-immunoprecipitation, in vitro deacetylase assay, acetylation site mutagenesis (K385/387R), dimerization assays, viral neutralization assays, HDAC6 depletion/inhibition The Journal of biological chemistry High 32796032
2014 Dido3-dependent targeting of HDAC6 to the centrosome/basal body is a key determinant of cilium size in growth-arrested cells. The amount of either Dido3 or HDAC6 negatively correlates with cilium size. Dido3 availability at the centrosome governs ciliary HDAC6 levels, and redistribution of the two proteins controls tubulin acetylation. Localization of both proteins depends on the actin network. Fluorescence microscopy (live imaging and fixed), immunofluorescence, HDAC6/Dido3 overexpression and knockdown, measurement of cilium length Nature communications Medium 24667272
2013 HDAC6 inhibition in cholangiocarcinoma cells (by shRNA or tubastatin-A) restores expression of primary cilia, decreases cell proliferation and anchorage-independent growth. HDAC6 overexpression in normal cholangiocytes induces deciliation and increased proliferation. The effects of tubastatin-A on tumor cells were abolished when cilia could not regenerate (IFT88-shRNA), establishing HDAC6 as a driver of ciliary disassembly. shRNA knockdown, pharmacological inhibition (tubastatin-A), overexpression, IFT88-shRNA rescue experiment, tumor xenograft model Cancer research Medium 23370327
2014 HDAC6 inhibition in oligodendrocytes leads to tau acetylation within the 4R microtubule-binding domain, reducing tau turnover rate such that acetylated tau is degraded more slowly. HDAC6 inhibition also causes morphological alterations, microtubule bundling, and increased pathological hyperphosphorylation of tau. Selective HDAC6 inhibitor (tubastatin A), shRNA knockdown, tau isoform-expressing cell lines, pulse-chase protein turnover assay, immunoblotting Glia Medium 24464872
2014 SMAR1 is a novel interacting partner of Ku70 and coordinates with HDAC6 to maintain Ku70 in a deacetylated state. SMAR1 knockdown results in enhanced Ku70 acetylation and impaired Ku70 recruitment to chromatin. HDAC6 deacetylates Ku70 to regulate its association with Bax, preventing Bax mitochondrial translocation and conferring radioresistance. Co-immunoprecipitation, chromatin fractionation, knockdown experiments, immunofluorescence, cell death/apoptosis assays post-irradiation Cell death & disease Medium 25299772
2020 HDAC6 ZnF UBP domain directly interacts with the polyproline/repeat region of Tau protein, reducing Tau self-aggregation propensity and disaggregating preformed aggregates in a concentration-dependent manner. This interaction also brings about conformational changes in Tau and results in its degradation. In vitro binding assays, Tau aggregation assays (thioflavin T, electron microscopy), recombinant ZnF UBP domain, NMR/biophysical conformational analysis Biochemistry Medium 33237772
2021 PRMT5 is a novel substrate of HDAC6. HDAC6 deacetylates PRMT5's acetyllysine residues; PRMT5 acetylation enhances its methyltransferase activity and symmetrical dimethylation of downstream substrates, revealing crosstalk between acetylation and methylation. Substrate was identified by HDAC6 substrate-trapping mutants and proteomics. Substrate trapping (HDAC6 mutant), proteomics/MS, in vitro deacetylase assay, methyltransferase activity assay with acetylation-state PRMT5 variants ACS chemical biology Medium 34314149
2022 HDAC6 regulates myofibril stiffness by deacetylating titin within its PEVK element (282-amino-acid region). HDAC6 co-localizes with Z-disks in sarcomeres. Ex vivo treatment of myofibrils with recombinant HDAC6 decreased myofibril stiffness; HDAC6 deficiency increased stiffness. HDAC6-deficient mice show exacerbated diastolic dysfunction under hypertension or aging. HDAC6 knockout mice, recombinant HDAC6 ex vivo treatment of mouse/rat/human myofibrils, myofibril mechanics, proteomics, HDAC6 overexpression in cardiomyocytes, immunofluorescence co-localization with Z-disks The Journal of clinical investigation High 35575093
2022 HDAC6 interacts with and deacetylates AKAP12 at K526/K531. Deacetylation of AKAP12 at K531 by HDAC6 increases its ubiquitination level and promotes proteasome-dependent degradation of AKAP12, facilitating colon cancer metastasis through reactivation of PKC isoforms. Co-immunoprecipitation, proteomic analysis, in vitro deacetylase assay, site-specific mutagenesis (K526/K531), ubiquitination assay, HDAC6 knockdown with rescue experiments, migration assays Cancer letters Medium 36122629
2022 HDAC6 ZnF ubiquitin-binding domain facilitates influenza A virus (IAV) infection by promoting aggresome/stress granule formation; IAV subverts this pathway during capsid uncoating. A DARPin blocking the ZnF pocket prevents ubiquitin interaction and impairs infection by IAV and Zika virus, and downregulates stress granules and aggresomes. Crystallographic analysis confirmed the DARPin blocks the ZnF Ub-binding pocket. Crystal structure of HDAC6 ZnF-DARPin complex, in vitro ubiquitin-binding assay, conditional DARPin expression in cells, viral infection assays, stress granule/aggresome quantification Cell reports High 35476995
2024 HDAC6 acts as a lactyltransferase, catalyzing alpha-tubulin lactylation at lysine 40 using lactate as substrate, a process dependent on its deacetylase activity. Intracellular lactate concentration triggers HDAC6 to lactylate alpha-tubulin. Lactylated alpha-tubulin (on soluble tubulin dimers) enhances microtubule dynamics and facilitates neurite outgrowth and branching in hippocampal neurons. In vitro lactyltransferase assay with purified HDAC6, site-specific identification of K40 lactylation by MS, HDAC6 overexpression/knockout, live-cell imaging of microtubule dynamics, neurite outgrowth assays Nature communications High 39333081
2024 Human HDAC6 serves as a valine sensor by directly binding valine through a primate-specific SE14 repeat domain. Valine deprivation causes HDAC6 retention in the nucleus, where it binds and deacetylates TET2, initiating active DNA demethylation via thymine DNA glycosylase-driven excision, promoting DNA damage. This nuclear shuttling is unique to human (not mouse) HDAC6. Valine-binding assay, nucleus/cytoplasm fractionation, HDAC6 localization (immunofluorescence), Co-IP of HDAC6-TET2, in vitro deacetylase assay on TET2, DNA demethylation and DNA damage assays, SE14 domain mutagenesis Nature High 39567688
2024 HDAC6 interacts with the leptin receptor (LepR) and reduces LepR activity. Pharmacological inhibition of HDAC6 disrupts this interaction and augments leptin signaling. Genetic depletion of Hdac6 specifically in AgRP-expressing neurons abolishes the anti-obesity effect of HDAC6 inhibitors, placing the mechanism centrally. Co-immunoprecipitation, HDAC6 inhibitor treatment of diet-induced obese mice, conditional Hdac6 knockout in AgRP neurons, BBB-permeable vs. impermeable inhibitor comparison, food intake and body weight measurements Cell metabolism Medium 38569472
2020 HDAC6 accumulates preferentially at neuromuscular junctions (NMJs). Pharmacological inhibition of HDAC6 protects against MT disorganization and reduces AChR cluster size. The endogenous HDAC6 inhibitor paxillin interacts with HDAC6 in skeletal muscle cells, co-localizes with AChR aggregates, and regulates AChR formation, revealing an MT/HDAC6/paxillin axis in NMJ maintenance. Immunofluorescence/confocal microscopy (NMJ localization), pharmacological inhibition, Co-immunoprecipitation of paxillin-HDAC6, AChR clustering assays The Journal of cell biology Medium 32697819
2023 HDAC6 targets porcine deltacoronavirus nonstructural protein nsp8 for proteasomal degradation via deacetylation at K46 and ubiquitination at K58. HDAC6 directly interacts with nsp8 during PDCoV infection. Recombinant PDCoV with K46 or K58 mutations was resistant to HDAC6 antiviral activity, showing higher replication compared to wild-type. Co-immunoprecipitation, in vitro deacetylase assay, ubiquitination assay, site-directed mutagenesis (K46, K58), reverse genetics recombinant virus, viral replication assays Journal of virology Medium 37133375
2024 HDAC6 directly interacts with NGF and deacetylates NGF, thereby accelerating NGF ubiquitination and proteasomal degradation. Reduced NGF protein levels resulting from HDAC6 activity maintain dormancy of primordial follicles. Co-immunoprecipitation (HDAC6-NGF), in vitro deacetylase assay, ubiquitination assay, HDAC6 overexpression transgenic mouse model, HDAC6 inhibition in human ovarian cortex and mouse models, follicle activation assays Theranostics Medium 38646645
2021 HDAC6 interacts with FoxO3a (a key transcription factor of myostatin) in muscle cells following metformin treatment. Metformin-induced HDAC6-FoxO3a interaction increases nuclear localization of FoxO3a, driving FoxO3a binding to the myostatin promoter and inducing myostatin transcription, leading to muscle atrophy. Co-immunoprecipitation (HDAC6-FoxO3a), chromatin immunoprecipitation (FoxO3a on myostatin promoter), confocal microscopy (FoxO3a nuclear localization), AMPK knockdown, luciferase reporter assay Journal of cachexia, sarcopenia and muscle Medium 34725961
2024 HDAC6 inactivation disrupts the HDAC6-P300 interaction, leading to altered P300 ubiquitination, P300 stabilization, and consequently increased histone H3K9/K14/K27 acetylation (chromatin opening). This reshapes the cancer chromatin landscape and downregulates genes critical for cancer cell survival. HDAC6 inhibitor (ITF3756), siRNA, CRISPR/Cas9 knockout, ATAC-seq, H3K27Ac ChIP-seq, transcriptomics, proteomics, P300 ubiquitination assay Clinical epigenetics Medium 39155390

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 HDAC6 is a microtubule-associated deacetylase. Nature 2012 12024216
2005 HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor. Molecular cell 955 15916966
2008 HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions. Trends in cell biology 428 18472263
2010 The role of HDAC6 in cancer. Journal of biomedicine & biotechnology 346 21076528
2020 HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation. Science (New York, N.Y.) 324 32943500
2007 HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination. Oncogene 317 17694087
2013 HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs? Molecular neurodegeneration 274 23356410
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 271 11416158
2006 HDAC6-p97/VCP controlled polyubiquitin chain turnover. The EMBO journal 228 16810319
2013 HDAC6 inhibition restores ciliary expression and decreases tumor growth. Cancer research 184 23370327
2011 Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin. The EMBO journal 166 21847094
2007 HDAC6 a new cellular stress surveillance factor. Cell cycle (Georgetown, Tex.) 119 18196966
2017 Recent advances in the discovery of potent and selective HDAC6 inhibitors. European journal of medicinal chemistry 116 29133060
2014 Drugging the HDAC6-HSP90 interplay in malignant cells. Trends in pharmacological sciences 116 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 102 33321327
2011 A novel GRK2/HDAC6 interaction modulates cell spreading and motility. The EMBO journal 101 22193721
2018 ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome-lysosome fusion. The Journal of cell biology 94 30538141
2016 HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma. Cancer letters 94 27267806
1995 The DNA-binding properties of two heat shock factors, HSF1 and HSF3, are induced in the avian erythroblast cell line HD6. Molecular and cellular biology 94 7565675
2020 HDAC6 in Diseases of Cognition and of Neurons. Cells 89 33374719
2021 The Role of HDAC6 in Autophagy and NLRP3 Inflammasome. Frontiers in immunology 86 34777380
2013 The role of HDAC6 in Alzheimer's disease. Journal of Alzheimer's disease : JAD 85 22936009
2013 Inclusion body formation, macroautophagy, and the role of HDAC6 in neurodegeneration. Acta neuropathologica 84 23912309
2024 Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation. Nature communications 82 39333081
2019 High-selective HDAC6 inhibitor promotes HDAC6 degradation following autophagy modulation and enhanced antitumor immunity in glioblastoma. Biochemical pharmacology 72 30885763
2022 HDAC6: A unique HDAC family member as a cancer target. Cellular oncology (Dordrecht, Netherlands) 71 36036883
2014 HDAC6 inhibition results in tau acetylation and modulates tau phosphorylation and degradation in oligodendrocytes. Glia 70 24464872
2016 The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease. Clinical science (London, England : 1979) 69 27154743
2021 Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a. Journal of cachexia, sarcopenia and muscle 68 34725961
2018 The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease. International journal of molecular sciences 63 30096875
2014 Interplay between HDAC6 and its interacting partners: essential roles in the aggresome-autophagy pathway and neurodegenerative diseases. DNA and cell biology 61 24932665
2016 Both HDAC5 and HDAC6 are required for the proliferation and metastasis of melanoma cells. Journal of translational medicine 58 26747087
2021 HDAC6 regulates primordial follicle activation through mTOR signaling pathway. Cell death & disease 52 34052832
2020 Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma. Cell death & disease 49 32488056
2016 HDAC6 promotes cell proliferation and confers resistance to gefitinib in lung adenocarcinoma. Oncology reports 49 27221381
2010 Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle. American journal of physiology. Regulatory, integrative and comparative physiology 49 20538901
2022 HDAC6 modulates myofibril stiffness and diastolic function of the heart. The Journal of clinical investigation 48 35575093
2013 HDAC6: physiological function and its selective inhibitors for cancer treatment. Drug discoveries & therapeutics 48 24423654
2020 HDAC6 regulates microtubule stability and clustering of AChRs at neuromuscular junctions. The Journal of cell biology 44 32697819
2018 Loss of HDAC6 alters gut microbiota and worsens obesity. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 44 30102568
2014 Dido3-dependent HDAC6 targeting controls cilium size. Nature communications 43 24667272
2023 New insights into the non-enzymatic function of HDAC6. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 40 37002569
2020 HDAC6 inhibitors: Translating genetic and molecular insights into a therapy for axonal CMT. Brain research 40 32006555
2015 Ciliopathies: Does HDAC6 Represent a New Therapeutic Target? Trends in pharmacological sciences 40 26651415
2018 HDAC6 differentially regulates autophagy in stem-like versus differentiated cancer cells. Autophagy 39 30444165
2018 Structure, Functions and Selective Inhibitors of HDAC6. Current topics in medicinal chemistry 39 30499393
2018 HDAC6 inhibition disrupts maturational progression and meiotic apparatus assembly in mouse oocytes. Cell cycle (Georgetown, Tex.) 38 28598228
2018 Inhibition of HDAC6 activity in kidney diseases: a new perspective. Molecular medicine (Cambridge, Mass.) 36 30134806
2024 Human HDAC6 senses valine abundancy to regulate DNA damage. Nature 35 39567688
2022 HDAC6-dependent deacetylation of AKAP12 dictates its ubiquitination and promotes colon cancer metastasis. Cancer letters 35 36122629
2019 HDAC6 regulates DNA damage response via deacetylating MLH1. The Journal of biological chemistry 35 30770470
2018 HDAC6 at Crossroads of Infection and Innate Immunity. Trends in immunology 35 29937401
2023 Curriculum vitae of HDAC6 in solid tumors. International journal of biological macromolecules 34 36642357
2024 Hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice. Biochimica et biophysica acta. Molecular basis of disease 32 38527593
2022 Disrupting the HDAC6-ubiquitin interaction impairs infection by influenza and Zika virus and cellular stress pathways. Cell reports 32 35476995
2020 HDAC6 regulates antibody-dependent intracellular neutralization of viruses via deacetylation of TRIM21. The Journal of biological chemistry 31 32796032
2020 HDAC6 promotes growth, migration/invasion, and self-renewal of rhabdomyosarcoma. Oncogene 31 33199827
2018 A novel class of anthraquinone-based HDAC6 inhibitors. European journal of medicinal chemistry 31 30597327
2017 Cellular defence or viral assist: the dilemma of HDAC6. The Journal of general virology 31 27959772
2018 HDAC6 as a potential therapeutic target for peripheral nerve disorders. Expert opinion on therapeutic targets 30 30360671
2017 HDAC6 regulates IL-17 expression in T lymphocytes: implications for HDAC6-targeted therapies. Theranostics 30 28382171
2020 HDAC6 ZnF UBP as the Modifier of Tau Structure and Function. Biochemistry 29 33237772
2019 Inhibition of HDAC6 alleviating lipopolysaccharide-induced p38MAPK phosphorylation and neuroinflammation in mice. Pharmaceutical biology 28 31124385
2014 HDAC6 regulates neuroblastoma cell migration and may play a role in the invasion process. Cancer biology & therapy 27 25482939
2020 Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors. ChemMedChem 26 32348628
2016 AKT activation controls cell survival in response to HDAC6 inhibition. Cell death & disease 26 27362804
2022 Design, synthesis, and biological evalution of bifunctional inhibitors against Hsp90-HDAC6 interplay. European journal of medicinal chemistry 25 35834905
2019 Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity. Blood advances 25 31015208
2024 Small molecules targeting HDAC6 for cancer treatment: Current progress and novel strategies. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 24 39084081
2023 Selective inhibition of HDAC6 promotes bladder cancer radiosensitization and mitigates the radiation-induced CXCL1 signalling. British journal of cancer 24 36810912
2022 Dual Targeting Strategies on Histone Deacetylase 6 (HDAC6) and Heat Shock Protein 90 (Hsp90). Current medicinal chemistry 24 34477503
2021 Role of HDAC6 and Its Selective Inhibitors in Gastrointestinal Cancer. Frontiers in cell and developmental biology 24 34938729
2020 Phospho-HDAC6 Gathers Into Protein Aggregates in Parkinson's Disease and Atypical Parkinsonisms. Frontiers in neuroscience 24 32655357
2016 Oncogenic K-ras confers SAHA resistance by up-regulating HDAC6 and c-myc expression. Oncotarget 24 26848526
2013 HDAC6 and ovarian cancer. International journal of molecular sciences 24 23644884
2020 HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1. Cells 23 33020410
2014 SMAR1 coordinates HDAC6-induced deacetylation of Ku70 and dictates cell fate upon irradiation. Cell death & disease 23 25299772
2024 The HDAC6 inhibitor AVS100 (SS208) induces a pro-inflammatory tumor microenvironment and potentiates immunotherapy. Science advances 22 39546602
2023 HDAC6 Degrades nsp8 of Porcine Deltacoronavirus through Deacetylation and Ubiquitination to Inhibit Viral Replication. Journal of virology 22 37133375
2022 Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells. Cancers 22 36497494
2022 Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance. International journal of molecular sciences 21 36076996
2020 HDAC6-an Emerging Target Against Chronic Myeloid Leukemia? Cancers 21 32013157
2020 The Role of HDAC6 in TDP-43-Induced Neurotoxicity and UPS Impairment. Frontiers in cell and developmental biology 21 33282865
2021 HDAC6 Inhibition Extinguishes Autophagy in Cancer: Recent Insights. Cancers 20 34944907
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 19 38569472
2020 SET7 interacts with HDAC6 and suppresses the development of colon cancer through inactivation of HDAC6. American journal of translational research 19 32194908
2024 HDAC6-dependent deacetylation of NGF dictates its ubiquitination and maintains primordial follicle dormancy. Theranostics 17 38646645
2023 HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma. Scientific reports 17 37528157
2021 HDAC6 Substrate Discovery Using Proteomics-Based Substrate Trapping: HDAC6 Deacetylates PRMT5 to Influence Methyltransferase Activity. ACS chemical biology 17 34314149
2020 HDAC6 promotes sepsis development by impairing PHB1-mediated mitochondrial respiratory chain function. Aging 17 32221047
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
2022 ARID1A-deficient cells require HDAC6 for progression of endometrial carcinoma. Molecular oncology 16 35167193
2021 Discovery of a novel AR/HDAC6 dual inhibitor for prostate cancer treatment. Aging 16 33621955
2024 Advances in dual-targeting inhibitors of HDAC6 for cancer treatment. European journal of medicinal chemistry 15 38857566
2024 HDAC6 inhibition disrupts HDAC6-P300 interaction reshaping the cancer chromatin landscape. Clinical epigenetics 15 39155390
2023 Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer. PloS one 15 36595522
2023 Radiotherapy-induced Immune Response Enhanced by Selective HDAC6 Inhibition. Molecular cancer therapeutics 15 37586844

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