{"gene":"HDAC6","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2002,"finding":"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.","method":"Cytoplasmic fractionation, co-immunoprecipitation, in vitro deacetylase assay with purified HDAC6 on assembled microtubules, overexpression and knockdown with alpha-tubulin acetylation readout, chemotaxis assay","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro deacetylase activity with purified protein, multiple orthogonal methods, widely replicated across labs","pmids":["12024216"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Co-immunoprecipitation, in vitro deacetylase assay, HDAC6 knockout/knockdown cells, glucocorticoid receptor functional assays (ligand binding, nuclear translocation, transcriptional activation)","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro deacetylase assay, multiple orthogonal functional readouts, genetic loss-of-function with defined substrate and downstream phenotype","pmids":["15916966"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Biophysical characterization (Zn ion content), biochemical binding assays, Co-IP, cellular ubiquitin chain accumulation assays, domain structure-function analysis","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — combination of biophysical, biochemical, and biological approaches in one study; characterization of ZnF-UBP domain with functional validation","pmids":["16810319"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, in vitro deacetylase assay, HDAC6 silencing/knockout (endothelial cells, zebrafish, mice), matrigel plug angiogenesis assay, domain mutant rescue experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, genetic loss-of-function in multiple organisms, domain-specific rescue experiments establishing catalytic requirement","pmids":["21847094"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, in vitro kinase assay, phosphorylation site mutagenesis (GRK2-K220R, GRK2-S670A), immunofluorescence co-localization, migration assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro kinase assay with site-directed mutagenesis, Co-IP, and functional migration readouts; single lab but multiple orthogonal methods","pmids":["22193721"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation, site-specific acetylation mapping (K909), HDAC6 knockdown/knockout cells and mice, antiviral response assays (IFN production), viral challenge experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP, defined acetylation site, genetic KO mice with specific antiviral phenotype, multiple orthogonal methods","pmids":["26746851"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation, in vitro reconstitution of autophagosome-lysosome fusion, deacetylase-inactive HDAC6 mutant rescue experiments, subcellular fractionation, Drosophila and mouse models","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro reconstitution, deacetylase-dead mutant, multiple model organisms, orthogonal biochemical and cell biology approaches","pmids":["30538141"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation, in vitro deacetylase assay, mass spectrometry acetylation site mapping, acetylation mimetic/deacetylation mimetic MLH1 mutants, 6-thioguanine resistance assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro deacetylase assay, MS-identified sites, mutagenesis with functional readout; single lab but multiple orthogonal methods","pmids":["30770470"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Genetic deletion (HDAC6 knockout mice), in vitro reconstitution, live-cell imaging at MTOC, caspase activation assays, IL-1β conversion assays","journal":"Science (New York, N.Y.)","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO in mice, in vitro reconstitution, live imaging, multiple inflammasome pathway readouts","pmids":["32943500"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, HDAC6 domain mapping (DAC1), HDAC6 knockdown with Chk1 rescue experiments, cell cycle analysis","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo ubiquitination assay with domain mapping, genetic KD with rescue, single lab","pmids":["33020410"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation, in vitro deacetylase assay, acetylation site mutagenesis (K385/387R), dimerization assays, viral neutralization assays, HDAC6 depletion/inhibition","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — in vitro deacetylase assay, site mutagenesis with functional rescue, Co-IP domain mapping; single lab with multiple orthogonal methods","pmids":["32796032"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Fluorescence microscopy (live imaging and fixed), immunofluorescence, HDAC6/Dido3 overexpression and knockdown, measurement of cilium length","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization experiments with functional consequence (cilium size), overexpression/KD, single lab but multiple orthogonal imaging approaches","pmids":["24667272"],"is_preprint":false},{"year":2013,"finding":"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.","method":"shRNA knockdown, pharmacological inhibition (tubastatin-A), overexpression, IFT88-shRNA rescue experiment, tumor xenograft model","journal":"Cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic and pharmacological loss-of-function with mechanistic rescue experiment linking HDAC6 specifically to cilia disassembly; single lab","pmids":["23370327"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Selective HDAC6 inhibitor (tubastatin A), shRNA knockdown, tau isoform-expressing cell lines, pulse-chase protein turnover assay, immunoblotting","journal":"Glia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological and genetic inhibition with defined acetylation site and turnover assay, single lab","pmids":["24464872"],"is_preprint":false},{"year":2014,"finding":"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.","method":"Co-immunoprecipitation, chromatin fractionation, knockdown experiments, immunofluorescence, cell death/apoptosis assays post-irradiation","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP demonstrating ternary complex, knockdown with defined acetylation and functional phenotype; single lab","pmids":["25299772"],"is_preprint":false},{"year":2020,"finding":"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.","method":"In vitro binding assays, Tau aggregation assays (thioflavin T, electron microscopy), recombinant ZnF UBP domain, NMR/biophysical conformational analysis","journal":"Biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro reconstitution of binding and disaggregation, multiple biophysical readouts; single lab","pmids":["33237772"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Substrate trapping (HDAC6 mutant), proteomics/MS, in vitro deacetylase assay, methyltransferase activity assay with acetylation-state PRMT5 variants","journal":"ACS chemical biology","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — unbiased substrate trapping proteomics plus in vitro validation of deacetylase activity and functional methyltransferase consequence; single lab","pmids":["34314149"],"is_preprint":false},{"year":2022,"finding":"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.","method":"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","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — recombinant protein treatment of human myofibrils, genetic KO, domain mapping, multiple species, orthogonal methods establishing titin as functional substrate","pmids":["35575093"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation, proteomic analysis, in vitro deacetylase assay, site-specific mutagenesis (K526/K531), ubiquitination assay, HDAC6 knockdown with rescue experiments, migration assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site-directed mutagenesis, ubiquitination and degradation assays; single lab with multiple orthogonal methods","pmids":["36122629"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Crystal structure of HDAC6 ZnF-DARPin complex, in vitro ubiquitin-binding assay, conditional DARPin expression in cells, viral infection assays, stress granule/aggresome quantification","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure of the complex, in vitro binding assay, functional validation in cells; single lab with structural and functional orthogonal methods","pmids":["35476995"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay establishing novel lactyltransferase activity, MS site identification, functional validation in neurons; single lab but multiple orthogonal methods","pmids":["39333081"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Nature","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — direct binding assay, structural domain identified (SE14), in vitro deacetylase assay on TET2, subcellular fractionation with functional consequence, multiple orthogonal methods","pmids":["39567688"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Cell metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, conditional KO, pharmacological dissection of central vs. peripheral mechanism; single lab with multiple orthogonal approaches","pmids":["38569472"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Immunofluorescence/confocal microscopy (NMJ localization), pharmacological inhibition, Co-immunoprecipitation of paxillin-HDAC6, AChR clustering assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization at NMJ, Co-IP of binding partner, pharmacological functional readout; single lab with multiple methods","pmids":["32697819"],"is_preprint":false},{"year":2023,"finding":"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.","method":"Co-immunoprecipitation, in vitro deacetylase assay, ubiquitination assay, site-directed mutagenesis (K46, K58), reverse genetics recombinant virus, viral replication assays","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro assays, mutagenesis with reverse genetics validation; single lab with multiple orthogonal methods","pmids":["37133375"],"is_preprint":false},{"year":2024,"finding":"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.","method":"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","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, in vitro enzymatic assay, transgenic mouse and human ovarian explant with mechanistic readout; single lab","pmids":["38646645"],"is_preprint":false},{"year":2021,"finding":"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.","method":"Co-immunoprecipitation (HDAC6-FoxO3a), chromatin immunoprecipitation (FoxO3a on myostatin promoter), confocal microscopy (FoxO3a nuclear localization), AMPK knockdown, luciferase reporter assay","journal":"Journal of cachexia, sarcopenia and muscle","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP of HDAC6-FoxO3a interaction, ChIP confirming promoter binding, confocal localization; single lab with multiple methods","pmids":["34725961"],"is_preprint":false},{"year":2024,"finding":"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.","method":"HDAC6 inhibitor (ITF3756), siRNA, CRISPR/Cas9 knockout, ATAC-seq, H3K27Ac ChIP-seq, transcriptomics, proteomics, P300 ubiquitination assay","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple inactivation strategies, genome-wide chromatin and transcriptomic readouts, P300 ubiquitination assay; single lab","pmids":["39155390"],"is_preprint":false}],"current_model":"HDAC6 is a cytoplasmic class IIb deacetylase with two catalytic domains and a C-terminal ZnF-UBP ubiquitin-binding domain; it deacetylates multiple non-histone substrates including alpha-tubulin (regulating microtubule dynamics and cell motility), Hsp90 (controlling chaperone activity and client protein maturation), cortactin (regulating actin dynamics and angiogenesis), RIG-I (activating antiviral RNA sensing), MLH1 (disrupting mismatch repair complex assembly), TRIM21 (promoting antiviral intracellular neutralization), titin (modulating sarcomere stiffness and cardiac diastolic function), and TET2 (initiating DNA demethylation in response to valine deprivation); additionally, HDAC6 acts as a valine sensor via its primate-specific SE14 domain controlling nucleo-cytoplasmic shuttling, functions as an E3 ubiquitin ligase for substrates such as Chk1, serves as a dynein adapter for transport of ubiquitinated cargoes and inflammasome components to the MTOC, and engages p97/VCP through its ZnF-UBP to regulate polyubiquitin chain turnover and aggresome formation."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":2002,"claim":"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","pmids":["12024216"],"confidence":"High","gaps":["Did not resolve how tubulin deacetylation mechanistically alters microtubule stability versus transport","Regulation of HDAC6 catalytic activity unaddressed"]},{"year":2005,"claim":"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","pmids":["15916966"],"confidence":"High","gaps":["Specific Hsp90 acetyl-lysine sites not fully mapped","Breadth of affected Hsp90 clients beyond GR not defined"]},{"year":2006,"claim":"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","pmids":["16810319"],"confidence":"High","gaps":["Precise chain-length selectivity in cells not fully resolved","How ubiquitin binding is integrated with deacetylase activity unclear"]},{"year":2011,"claim":"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","pmids":["21847094"],"confidence":"High","gaps":["Cortactin acetyl-site identity in this context not specified","Crosstalk with tubulin pool not resolved"]},{"year":2011,"claim":"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","pmids":["22193721"],"confidence":"High","gaps":["HDAC6 phosphorylation sites targeted by GRK2 not mapped","Whether other kinases regulate HDAC6 unaddressed"]},{"year":2014,"claim":"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","pmids":["24667272"],"confidence":"Medium","gaps":["Molecular nature of Dido3-HDAC6 interaction not biochemically defined","Single-lab imaging-based study"]},{"year":2013,"claim":"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","pmids":["23370327"],"confidence":"Medium","gaps":["Direct deacetylation event driving disassembly not isolated","Generalizability beyond cholangiocarcinoma untested here"]},{"year":2014,"claim":"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","pmids":["24464872"],"confidence":"Medium","gaps":["Direct versus indirect tau deacetylation not separated in cells","Single cell-type context"]},{"year":2014,"claim":"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","pmids":["25299772"],"confidence":"Medium","gaps":["Reciprocal validation of direct HDAC6-Ku70 deacetylation limited","Single-lab study"]},{"year":2016,"claim":"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","pmids":["26746851"],"confidence":"High","gaps":["Specificity for RNA but not DNA virus sensing mechanism incompletely defined","Kinetics of transient HDAC6-RIG-I binding unresolved"]},{"year":2018,"claim":"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","pmids":["30538141"],"confidence":"High","gaps":["How cortactin deacetylation mechanically aids fusion not fully defined","Other lysosomal HDAC6 substrates unexplored"]},{"year":2019,"claim":"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","pmids":["30770470"],"confidence":"High","gaps":["Physiological signals controlling MLH1 deacetylation unknown","Single-lab functional context"]},{"year":2020,"claim":"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","pmids":["32943500"],"confidence":"High","gaps":["Cargo-recognition determinants for inflammasome components not fully defined","Relationship to ubiquitin-binding versus motor-adapter roles unresolved"]},{"year":2020,"claim":"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","pmids":["33020410"],"confidence":"Medium","gaps":["Whether DAC1 ligase activity generalizes beyond Chk1 untested","Single-lab, requires independent confirmation of intrinsic E3 activity"]},{"year":2020,"claim":"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","pmids":["32796032"],"confidence":"High","gaps":["In vivo relevance to viral clearance not addressed","Single-lab study"]},{"year":2020,"claim":"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","pmids":["35476995"],"confidence":"High","gaps":["Endogenous regulators that gate the ZnF pocket in vivo unknown","Therapeutic translatability of DARPin untested"]},{"year":2020,"claim":"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","pmids":["32697819"],"confidence":"Medium","gaps":["Direct substrate at NMJ not defined","Single-lab, correlative localization"]},{"year":2020,"claim":"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","pmids":["33237772"],"confidence":"Medium","gaps":["In vivo disaggregase relevance not established","Single-lab in vitro reconstitution"]},{"year":2021,"claim":"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","pmids":["34314149"],"confidence":"Medium","gaps":["PRMT5 acetyl-sites and stoichiometry incompletely defined","Single-lab study"]},{"year":2021,"claim":"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","pmids":["34725961"],"confidence":"Medium","gaps":["Whether HDAC6 deacetylates FoxO3a directly not shown","Single-lab, correlative"]},{"year":2022,"claim":"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","pmids":["35575093"],"confidence":"High","gaps":["Titin acetyl-site regulation in vivo not fully mapped","Upstream signals controlling cardiac HDAC6 activity unknown"]},{"year":2022,"claim":"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","pmids":["36122629"],"confidence":"Medium","gaps":["Direct ligase for AKAP12 not identified","Single-lab study"]},{"year":2023,"claim":"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","pmids":["37133375"],"confidence":"Medium","gaps":["Generalizability to other coronaviruses untested","Single-lab study"]},{"year":2024,"claim":"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","pmids":["39333081"],"confidence":"High","gaps":["Structural basis for lactyl- versus deacetyl-transfer not resolved","Independent confirmation of intrinsic lactyltransferase activity pending"]},{"year":2024,"claim":"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","pmids":["39567688"],"confidence":"High","gaps":["How SE14 valine occupancy mechanistically gates localization unresolved","Physiological contexts of valine sensing in humans not fully mapped"]},{"year":2024,"claim":"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","pmids":["38569472"],"confidence":"Medium","gaps":["Whether LepR is a deacetylation substrate not established","Mechanism of interaction-dependent inhibition unclear"]},{"year":2024,"claim":"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","pmids":["38646645"],"confidence":"Medium","gaps":["NGF acetyl-sites not mapped","Direct ligase coupling not defined"]},{"year":2024,"claim":"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","pmids":["39155390"],"confidence":"Medium","gaps":["Mechanism by which HDAC6 controls P300 ubiquitination not defined","Direct versus indirect chromatin effects not fully separated"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[0,1,3,5,7,10,17,21]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[20]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[9]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[2,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8]},{"term_id":"GO:0140299","term_label":"molecular sensor activity","supporting_discovery_ids":[21]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,17]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[8,11]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[6]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[21]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[5,8,10]},{"term_id":"R-HSA-392499","term_label":"Metabolism of proteins","supporting_discovery_ids":[1,2]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,8]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[7]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[27]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[9]}],"complexes":[],"partners":["HSP90","CTTN","RIGI","TRIM21","MLH1","VCP","GRK2","TET2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UBN7","full_name":"Protein deacetylase HDAC6","aliases":["E3 ubiquitin-protein ligase HDAC6","Tubulin-lysine deacetylase HDAC6"],"length_aa":1215,"mass_kda":131.4,"function":"Deacetylates a wide range of non-histone substrates (PubMed:12024216, PubMed:18606987, PubMed:20308065, PubMed:24882211, PubMed:26246421, PubMed:30538141, PubMed:31857589, PubMed:30770470, PubMed:38534334, PubMed:39567688). Plays a central role in microtubule-dependent cell motility by mediating deacetylation of tubulin (PubMed:12024216, PubMed:20308065, PubMed:26246421). Required for cilia disassembly via deacetylation of alpha-tubulin (PubMed:17604723, PubMed:26246421). Alpha-tubulin deacetylation results in destabilization of dynamic microtubules (By similarity). Promotes deacetylation of CTTN, leading to actin polymerization, promotion of autophagosome-lysosome fusion and completion of autophagy (PubMed:30538141). Deacetylates SQSTM1 (PubMed:31857589). Deacetylates peroxiredoxins PRDX1 and PRDX2, decreasing their reducing activity (PubMed:18606987). Deacetylates antiviral protein RIGI in the presence of viral mRNAs which is required for viral RNA detection by RIGI (By similarity). Sequentially deacetylates and polyubiquitinates DNA mismatch repair protein MSH2 which leads to MSH2 degradation, reducing cellular sensitivity to DNA-damaging agents and decreasing cellular DNA mismatch repair activities (PubMed:24882211). Deacetylates DNA mismatch repair protein MLH1 which prevents recruitment of the MutL alpha complex (formed by the MLH1-PMS2 heterodimer) to the MutS alpha complex (formed by the MSH2-MSH6 heterodimer), leading to tolerance of DNA damage (PubMed:30770470). Deacetylates RHOT1/MIRO1 which blocks mitochondrial transport and mediates axon growth inhibition (By similarity). Deacetylates transcription factor SP1 which leads to increased expression of ENG, positively regulating angiogenesis (PubMed:38534334). Deacetylates KHDRBS1/SAM68 which regulates alternative splicing by inhibiting the inclusion of CD44 alternate exons (PubMed:26080397). Deacetylates PRDM16 (By similarity). Acts as a valine sensor by binding to valine through the primate-specific SE14 repeat region (PubMed:39567688). In valine deprivation conditions, translocates from the cytoplasm to the nucleus where it deacetylates TET2 which promotes TET2-dependent DNA demethylation, leading to DNA damage (PubMed:39567688). Promotes odontoblast differentiation following IPO7-mediated nuclear import and subsequent repression of RUNX2 expression (By similarity). In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome (PubMed:17846173). Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and targets them to the aggresome, facilitating their clearance by autophagy (PubMed:17846173). Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer (PubMed:24413532) (Microbial infection) Deacetylates the SARS-CoV-2 N protein which promotes association of the viral N protein with human G3BP1, leading to disruption of cellular stress granule formation and facilitating viral replication","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Nucleus; Perikaryon; Cell projection, dendrite; Cell projection, axon; Cell projection, cilium; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q9UBN7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HDAC6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"UBB","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/HDAC6","total_profiled":1310},"omim":[{"mim_id":"618686","title":"TEKTIN 5; TEKT5","url":"https://www.omim.org/entry/618686"},{"mim_id":"614312","title":"ZINC FINGER MYND-CONTAINING PROTEIN 15; ZMYND15","url":"https://www.omim.org/entry/614312"},{"mim_id":"612722","title":"ELONGATOR ACETYLTRANSFERASE COMPLEX, SUBUNIT 3; ELP3","url":"https://www.omim.org/entry/612722"},{"mim_id":"608634","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 3; HMND3","url":"https://www.omim.org/entry/608634"},{"mim_id":"608544","title":"HISTONE DEACETYLASE 10; HDAC10","url":"https://www.omim.org/entry/608544"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Centrosome","reliability":"Supported"},{"location":"Basal body","reliability":"Supported"},{"location":"Cytosol","reliability":"Supported"},{"location":"Nucleoplasm","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HDAC6"},"hgnc":{"alias_symbol":["KIAA0901","JM21","HD6","FLJ16239","PPP1R90","KDAC6"],"prev_symbol":[]},"alphafold":{"accession":"Q9UBN7","domains":[{"cath_id":"3.40.800.20","chopping":"106-437","consensus_level":"high","plddt":96.908,"start":106,"end":437},{"cath_id":"3.40.800.20","chopping":"480-492_500-804_812-833","consensus_level":"medium","plddt":96.5651,"start":480,"end":833},{"cath_id":"3.30.40.10","chopping":"1115-1206","consensus_level":"high","plddt":93.7774,"start":1115,"end":1206}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBN7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBN7-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UBN7-F1-predicted_aligned_error_v6.png","plddt_mean":76.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HDAC6","jax_strain_url":"https://www.jax.org/strain/search?query=HDAC6"},"sequence":{"accession":"Q9UBN7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UBN7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UBN7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UBN7"}},"corpus_meta":[{"pmid":"12024216","id":"PMC_12024216","title":"HDAC6 is a microtubule-associated deacetylase.","date":"2002","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/12024216","citation_count":2012,"is_preprint":false},{"pmid":"15916966","id":"PMC_15916966","title":"HDAC6 regulates Hsp90 acetylation and chaperone-dependent activation of glucocorticoid receptor.","date":"2005","source":"Molecular cell","url":"https://pubmed.ncbi.nlm.nih.gov/15916966","citation_count":955,"is_preprint":false},{"pmid":"18472263","id":"PMC_18472263","title":"HDAC6: a key regulator of cytoskeleton, cell migration and cell-cell interactions.","date":"2008","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18472263","citation_count":428,"is_preprint":false},{"pmid":"21076528","id":"PMC_21076528","title":"The role of HDAC6 in cancer.","date":"2010","source":"Journal of biomedicine & biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/21076528","citation_count":346,"is_preprint":false},{"pmid":"32943500","id":"PMC_32943500","title":"HDAC6 mediates an aggresome-like mechanism for NLRP3 and pyrin inflammasome activation.","date":"2020","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/32943500","citation_count":324,"is_preprint":false},{"pmid":"17694087","id":"PMC_17694087","title":"HDAC6, at the crossroads between cytoskeleton and cell signaling by acetylation and ubiquitination.","date":"2007","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/17694087","citation_count":317,"is_preprint":false},{"pmid":"23356410","id":"PMC_23356410","title":"HDAC6 as a target for neurodegenerative diseases: what makes it different from the other HDACs?","date":"2013","source":"Molecular neurodegeneration","url":"https://pubmed.ncbi.nlm.nih.gov/23356410","citation_count":274,"is_preprint":false},{"pmid":"11416158","id":"PMC_11416158","title":"Hd6, a rice quantitative trait locus involved in photoperiod sensitivity, encodes the alpha subunit of protein kinase CK2.","date":"2001","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/11416158","citation_count":271,"is_preprint":false},{"pmid":"16810319","id":"PMC_16810319","title":"HDAC6-p97/VCP controlled polyubiquitin chain turnover.","date":"2006","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/16810319","citation_count":228,"is_preprint":false},{"pmid":"23370327","id":"PMC_23370327","title":"HDAC6 inhibition restores ciliary expression and decreases tumor growth.","date":"2013","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/23370327","citation_count":184,"is_preprint":false},{"pmid":"21847094","id":"PMC_21847094","title":"Class IIb HDAC6 regulates endothelial cell migration and angiogenesis by deacetylation of cortactin.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/21847094","citation_count":166,"is_preprint":false},{"pmid":"18196966","id":"PMC_18196966","title":"HDAC6 a new cellular stress surveillance factor.","date":"2007","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/18196966","citation_count":119,"is_preprint":false},{"pmid":"25234862","id":"PMC_25234862","title":"Drugging the HDAC6-HSP90 interplay in malignant cells.","date":"2014","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/25234862","citation_count":116,"is_preprint":false},{"pmid":"29133060","id":"PMC_29133060","title":"Recent advances in the discovery of potent and selective HDAC6 inhibitors.","date":"2017","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29133060","citation_count":116,"is_preprint":false},{"pmid":"26746851","id":"PMC_26746851","title":"HDAC6 regulates cellular viral RNA sensing by deacetylation of RIG-I.","date":"2016","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/26746851","citation_count":111,"is_preprint":false},{"pmid":"33321327","id":"PMC_33321327","title":"Targeting HDAC6 attenuates nicotine-induced macrophage pyroptosis via NF-κB/NLRP3 pathway.","date":"2020","source":"Atherosclerosis","url":"https://pubmed.ncbi.nlm.nih.gov/33321327","citation_count":102,"is_preprint":false},{"pmid":"22193721","id":"PMC_22193721","title":"A novel GRK2/HDAC6 interaction modulates cell spreading and motility.","date":"2011","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22193721","citation_count":101,"is_preprint":false},{"pmid":"27267806","id":"PMC_27267806","title":"HDAC6 promotes cell proliferation and confers resistance to temozolomide in glioblastoma.","date":"2016","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/27267806","citation_count":94,"is_preprint":false},{"pmid":"7565675","id":"PMC_7565675","title":"The DNA-binding properties of two heat shock factors, HSF1 and HSF3, are induced in the avian erythroblast cell line HD6.","date":"1995","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/7565675","citation_count":94,"is_preprint":false},{"pmid":"30538141","id":"PMC_30538141","title":"ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome-lysosome fusion.","date":"2018","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30538141","citation_count":94,"is_preprint":false},{"pmid":"33374719","id":"PMC_33374719","title":"HDAC6 in Diseases of Cognition and of Neurons.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33374719","citation_count":89,"is_preprint":false},{"pmid":"34777380","id":"PMC_34777380","title":"The Role of HDAC6 in Autophagy and NLRP3 Inflammasome.","date":"2021","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34777380","citation_count":86,"is_preprint":false},{"pmid":"22936009","id":"PMC_22936009","title":"The role of HDAC6 in Alzheimer's disease.","date":"2013","source":"Journal of Alzheimer's disease : JAD","url":"https://pubmed.ncbi.nlm.nih.gov/22936009","citation_count":85,"is_preprint":false},{"pmid":"23912309","id":"PMC_23912309","title":"Inclusion body formation, macroautophagy, and the role of HDAC6 in neurodegeneration.","date":"2013","source":"Acta neuropathologica","url":"https://pubmed.ncbi.nlm.nih.gov/23912309","citation_count":84,"is_preprint":false},{"pmid":"39333081","id":"PMC_39333081","title":"Metabolic regulation of cytoskeleton functions by HDAC6-catalyzed α-tubulin lactylation.","date":"2024","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/39333081","citation_count":82,"is_preprint":false},{"pmid":"30885763","id":"PMC_30885763","title":"High-selective HDAC6 inhibitor promotes HDAC6 degradation following autophagy modulation and enhanced antitumor immunity in glioblastoma.","date":"2019","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/30885763","citation_count":72,"is_preprint":false},{"pmid":"36036883","id":"PMC_36036883","title":"HDAC6: A unique HDAC family member as a cancer target.","date":"2022","source":"Cellular oncology (Dordrecht, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/36036883","citation_count":71,"is_preprint":false},{"pmid":"24464872","id":"PMC_24464872","title":"HDAC6 inhibition results in tau acetylation and modulates tau phosphorylation and degradation in oligodendrocytes.","date":"2014","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/24464872","citation_count":70,"is_preprint":false},{"pmid":"27154743","id":"PMC_27154743","title":"The therapeutic hope for HDAC6 inhibitors in malignancy and chronic disease.","date":"2016","source":"Clinical science (London, England : 1979)","url":"https://pubmed.ncbi.nlm.nih.gov/27154743","citation_count":69,"is_preprint":false},{"pmid":"34725961","id":"PMC_34725961","title":"Metformin induces muscle atrophy by transcriptional regulation of myostatin via HDAC6 and FoxO3a.","date":"2021","source":"Journal of cachexia, sarcopenia and muscle","url":"https://pubmed.ncbi.nlm.nih.gov/34725961","citation_count":68,"is_preprint":false},{"pmid":"30096875","id":"PMC_30096875","title":"The Therapeutic Strategy of HDAC6 Inhibitors in Lymphoproliferative Disease.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30096875","citation_count":63,"is_preprint":false},{"pmid":"24932665","id":"PMC_24932665","title":"Interplay between HDAC6 and its interacting partners: essential roles in the aggresome-autophagy pathway and neurodegenerative diseases.","date":"2014","source":"DNA and cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/24932665","citation_count":61,"is_preprint":false},{"pmid":"26747087","id":"PMC_26747087","title":"Both HDAC5 and HDAC6 are required for the proliferation and metastasis of melanoma cells.","date":"2016","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/26747087","citation_count":58,"is_preprint":false},{"pmid":"34052832","id":"PMC_34052832","title":"HDAC6 regulates primordial follicle activation through mTOR signaling pathway.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/34052832","citation_count":52,"is_preprint":false},{"pmid":"27221381","id":"PMC_27221381","title":"HDAC6 promotes cell proliferation and confers resistance to gefitinib in lung adenocarcinoma.","date":"2016","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/27221381","citation_count":49,"is_preprint":false},{"pmid":"32488056","id":"PMC_32488056","title":"Characterization of a new small-molecule inhibitor of HDAC6 in glioblastoma.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32488056","citation_count":49,"is_preprint":false},{"pmid":"20538901","id":"PMC_20538901","title":"Sepsis and glucocorticoids upregulate p300 and downregulate HDAC6 expression and activity in skeletal muscle.","date":"2010","source":"American journal of physiology. Regulatory, integrative and comparative physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20538901","citation_count":49,"is_preprint":false},{"pmid":"35575093","id":"PMC_35575093","title":"HDAC6 modulates myofibril stiffness and diastolic function of the heart.","date":"2022","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/35575093","citation_count":48,"is_preprint":false},{"pmid":"24423654","id":"PMC_24423654","title":"HDAC6: physiological function and its selective inhibitors for cancer treatment.","date":"2013","source":"Drug discoveries & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/24423654","citation_count":48,"is_preprint":false},{"pmid":"32697819","id":"PMC_32697819","title":"HDAC6 regulates microtubule stability and clustering of AChRs at neuromuscular junctions.","date":"2020","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/32697819","citation_count":44,"is_preprint":false},{"pmid":"30102568","id":"PMC_30102568","title":"Loss of HDAC6 alters gut microbiota and worsens obesity.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/30102568","citation_count":44,"is_preprint":false},{"pmid":"24667272","id":"PMC_24667272","title":"Dido3-dependent HDAC6 targeting controls cilium size.","date":"2014","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/24667272","citation_count":43,"is_preprint":false},{"pmid":"37002569","id":"PMC_37002569","title":"New insights into the non-enzymatic function of HDAC6.","date":"2023","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/37002569","citation_count":40,"is_preprint":false},{"pmid":"26651415","id":"PMC_26651415","title":"Ciliopathies: Does HDAC6 Represent a New Therapeutic Target?","date":"2015","source":"Trends in pharmacological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/26651415","citation_count":40,"is_preprint":false},{"pmid":"32006555","id":"PMC_32006555","title":"HDAC6 inhibitors: Translating genetic and molecular insights into a therapy for axonal CMT.","date":"2020","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/32006555","citation_count":40,"is_preprint":false},{"pmid":"30499393","id":"PMC_30499393","title":"Structure, Functions and Selective Inhibitors of HDAC6.","date":"2018","source":"Current topics in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30499393","citation_count":39,"is_preprint":false},{"pmid":"30444165","id":"PMC_30444165","title":"HDAC6 differentially regulates autophagy in stem-like versus differentiated cancer cells.","date":"2018","source":"Autophagy","url":"https://pubmed.ncbi.nlm.nih.gov/30444165","citation_count":39,"is_preprint":false},{"pmid":"28598228","id":"PMC_28598228","title":"HDAC6 inhibition disrupts maturational progression and meiotic apparatus assembly in mouse oocytes.","date":"2018","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/28598228","citation_count":38,"is_preprint":false},{"pmid":"30134806","id":"PMC_30134806","title":"Inhibition of HDAC6 activity in kidney diseases: a new perspective.","date":"2018","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/30134806","citation_count":36,"is_preprint":false},{"pmid":"39567688","id":"PMC_39567688","title":"Human HDAC6 senses valine abundancy to regulate DNA damage.","date":"2024","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/39567688","citation_count":35,"is_preprint":false},{"pmid":"29937401","id":"PMC_29937401","title":"HDAC6 at Crossroads of Infection and Innate Immunity.","date":"2018","source":"Trends in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/29937401","citation_count":35,"is_preprint":false},{"pmid":"30770470","id":"PMC_30770470","title":"HDAC6 regulates DNA damage response via deacetylating MLH1.","date":"2019","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30770470","citation_count":35,"is_preprint":false},{"pmid":"36122629","id":"PMC_36122629","title":"HDAC6-dependent deacetylation of AKAP12 dictates its ubiquitination and promotes colon cancer metastasis.","date":"2022","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/36122629","citation_count":35,"is_preprint":false},{"pmid":"36642357","id":"PMC_36642357","title":"Curriculum vitae of HDAC6 in solid tumors.","date":"2023","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/36642357","citation_count":34,"is_preprint":false},{"pmid":"38527593","id":"PMC_38527593","title":"Hippocampal HDAC6 promotes POCD by regulating NLRP3-induced microglia pyroptosis via HSP90/HSP70 in aged mice.","date":"2024","source":"Biochimica et biophysica acta. Molecular basis of disease","url":"https://pubmed.ncbi.nlm.nih.gov/38527593","citation_count":32,"is_preprint":false},{"pmid":"35476995","id":"PMC_35476995","title":"Disrupting the HDAC6-ubiquitin interaction impairs infection by influenza and Zika virus and cellular stress pathways.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35476995","citation_count":32,"is_preprint":false},{"pmid":"27959772","id":"PMC_27959772","title":"Cellular defence or viral assist: the dilemma of HDAC6.","date":"2017","source":"The Journal of general virology","url":"https://pubmed.ncbi.nlm.nih.gov/27959772","citation_count":31,"is_preprint":false},{"pmid":"33199827","id":"PMC_33199827","title":"HDAC6 promotes growth, migration/invasion, and self-renewal of rhabdomyosarcoma.","date":"2020","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/33199827","citation_count":31,"is_preprint":false},{"pmid":"32796032","id":"PMC_32796032","title":"HDAC6 regulates antibody-dependent intracellular neutralization of viruses via deacetylation of TRIM21.","date":"2020","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/32796032","citation_count":31,"is_preprint":false},{"pmid":"30597327","id":"PMC_30597327","title":"A novel class of anthraquinone-based HDAC6 inhibitors.","date":"2018","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30597327","citation_count":31,"is_preprint":false},{"pmid":"30360671","id":"PMC_30360671","title":"HDAC6 as a potential therapeutic target for peripheral nerve disorders.","date":"2018","source":"Expert opinion on therapeutic targets","url":"https://pubmed.ncbi.nlm.nih.gov/30360671","citation_count":30,"is_preprint":false},{"pmid":"28382171","id":"PMC_28382171","title":"HDAC6 regulates IL-17 expression in T lymphocytes: implications for HDAC6-targeted therapies.","date":"2017","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/28382171","citation_count":30,"is_preprint":false},{"pmid":"33237772","id":"PMC_33237772","title":"HDAC6 ZnF UBP as the Modifier of Tau Structure and Function.","date":"2020","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/33237772","citation_count":29,"is_preprint":false},{"pmid":"31124385","id":"PMC_31124385","title":"Inhibition of HDAC6 alleviating lipopolysaccharide-induced p38MAPK phosphorylation and neuroinflammation in mice.","date":"2019","source":"Pharmaceutical biology","url":"https://pubmed.ncbi.nlm.nih.gov/31124385","citation_count":28,"is_preprint":false},{"pmid":"25482939","id":"PMC_25482939","title":"HDAC6 regulates neuroblastoma cell migration and may play a role in the invasion process.","date":"2014","source":"Cancer biology & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/25482939","citation_count":27,"is_preprint":false},{"pmid":"32348628","id":"PMC_32348628","title":"Design and Synthesis of Dihydroxamic Acids as HDAC6/8/10 Inhibitors.","date":"2020","source":"ChemMedChem","url":"https://pubmed.ncbi.nlm.nih.gov/32348628","citation_count":26,"is_preprint":false},{"pmid":"27362804","id":"PMC_27362804","title":"AKT activation controls cell survival in response to HDAC6 inhibition.","date":"2016","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/27362804","citation_count":26,"is_preprint":false},{"pmid":"31015208","id":"PMC_31015208","title":"Rational cotargeting of HDAC6 and BET proteins yields synergistic antimyeloma activity.","date":"2019","source":"Blood advances","url":"https://pubmed.ncbi.nlm.nih.gov/31015208","citation_count":25,"is_preprint":false},{"pmid":"35834905","id":"PMC_35834905","title":"Design, synthesis, and biological evalution of bifunctional inhibitors against Hsp90-HDAC6 interplay.","date":"2022","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35834905","citation_count":25,"is_preprint":false},{"pmid":"23644884","id":"PMC_23644884","title":"HDAC6 and ovarian cancer.","date":"2013","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/23644884","citation_count":24,"is_preprint":false},{"pmid":"34477503","id":"PMC_34477503","title":"Dual Targeting Strategies on Histone Deacetylase 6 (HDAC6) and Heat Shock Protein 90 (Hsp90).","date":"2022","source":"Current medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/34477503","citation_count":24,"is_preprint":false},{"pmid":"34938729","id":"PMC_34938729","title":"Role of HDAC6 and Its Selective Inhibitors in Gastrointestinal Cancer.","date":"2021","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/34938729","citation_count":24,"is_preprint":false},{"pmid":"39084081","id":"PMC_39084081","title":"Small molecules targeting HDAC6 for cancer treatment: Current progress and novel strategies.","date":"2024","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/39084081","citation_count":24,"is_preprint":false},{"pmid":"32655357","id":"PMC_32655357","title":"Phospho-HDAC6 Gathers Into Protein Aggregates in Parkinson's Disease and Atypical Parkinsonisms.","date":"2020","source":"Frontiers in neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/32655357","citation_count":24,"is_preprint":false},{"pmid":"36810912","id":"PMC_36810912","title":"Selective inhibition of HDAC6 promotes bladder cancer radiosensitization and mitigates the radiation-induced CXCL1 signalling.","date":"2023","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36810912","citation_count":24,"is_preprint":false},{"pmid":"26848526","id":"PMC_26848526","title":"Oncogenic K-ras confers SAHA resistance by up-regulating HDAC6 and c-myc expression.","date":"2016","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/26848526","citation_count":24,"is_preprint":false},{"pmid":"25299772","id":"PMC_25299772","title":"SMAR1 coordinates HDAC6-induced deacetylation of Ku70 and dictates cell fate upon irradiation.","date":"2014","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/25299772","citation_count":23,"is_preprint":false},{"pmid":"33020410","id":"PMC_33020410","title":"HDAC6 Regulates Radiosensitivity of Non-Small Cell Lung Cancer by Promoting Degradation of Chk1.","date":"2020","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33020410","citation_count":23,"is_preprint":false},{"pmid":"39546602","id":"PMC_39546602","title":"The HDAC6 inhibitor AVS100 (SS208) induces a pro-inflammatory tumor microenvironment and potentiates immunotherapy.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/39546602","citation_count":22,"is_preprint":false},{"pmid":"37133375","id":"PMC_37133375","title":"HDAC6 Degrades nsp8 of Porcine Deltacoronavirus through Deacetylation and Ubiquitination to Inhibit Viral Replication.","date":"2023","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/37133375","citation_count":22,"is_preprint":false},{"pmid":"36497494","id":"PMC_36497494","title":"Dual LSD1 and HDAC6 Inhibition Induces Doxorubicin Sensitivity in Acute Myeloid Leukemia Cells.","date":"2022","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36497494","citation_count":22,"is_preprint":false},{"pmid":"32013157","id":"PMC_32013157","title":"HDAC6-an Emerging Target Against Chronic Myeloid Leukemia?","date":"2020","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/32013157","citation_count":21,"is_preprint":false},{"pmid":"36076996","id":"PMC_36076996","title":"Targeting HDAC6 to Overcome Autophagy-Promoted Anti-Cancer Drug Resistance.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36076996","citation_count":21,"is_preprint":false},{"pmid":"33282865","id":"PMC_33282865","title":"The Role of HDAC6 in TDP-43-Induced Neurotoxicity and UPS Impairment.","date":"2020","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/33282865","citation_count":21,"is_preprint":false},{"pmid":"34944907","id":"PMC_34944907","title":"HDAC6 Inhibition Extinguishes Autophagy in Cancer: Recent Insights.","date":"2021","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/34944907","citation_count":20,"is_preprint":false},{"pmid":"38569472","id":"PMC_38569472","title":"Central inhibition of HDAC6 re-sensitizes leptin signaling during obesity to induce profound weight loss.","date":"2024","source":"Cell metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/38569472","citation_count":19,"is_preprint":false},{"pmid":"38414061","id":"PMC_38414061","title":"Targeting HDAC6 improves anti-CD47 immunotherapy.","date":"2024","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/38414061","citation_count":19,"is_preprint":false},{"pmid":"32194908","id":"PMC_32194908","title":"SET7 interacts with HDAC6 and suppresses the development of colon cancer through inactivation of HDAC6.","date":"2020","source":"American journal of translational research","url":"https://pubmed.ncbi.nlm.nih.gov/32194908","citation_count":19,"is_preprint":false},{"pmid":"38646645","id":"PMC_38646645","title":"HDAC6-dependent deacetylation of NGF dictates its ubiquitination and maintains primordial follicle dormancy.","date":"2024","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/38646645","citation_count":17,"is_preprint":false},{"pmid":"37528157","id":"PMC_37528157","title":"HDAC1 and HDAC6 are essential for driving growth in IDH1 mutant glioma.","date":"2023","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/37528157","citation_count":17,"is_preprint":false},{"pmid":"27118337","id":"PMC_27118337","title":"Diverse roles of HDAC6 in viral infection: Implications for antiviral therapy.","date":"2016","source":"Pharmacology & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/27118337","citation_count":17,"is_preprint":false},{"pmid":"30463548","id":"PMC_30463548","title":"HDAC6 regulates dental mesenchymal stem cells and osteoclast differentiation.","date":"2018","source":"BMC oral health","url":"https://pubmed.ncbi.nlm.nih.gov/30463548","citation_count":17,"is_preprint":false},{"pmid":"34314149","id":"PMC_34314149","title":"HDAC6 Substrate Discovery Using Proteomics-Based Substrate Trapping: HDAC6 Deacetylates PRMT5 to Influence Methyltransferase Activity.","date":"2021","source":"ACS chemical biology","url":"https://pubmed.ncbi.nlm.nih.gov/34314149","citation_count":17,"is_preprint":false},{"pmid":"32221047","id":"PMC_32221047","title":"HDAC6 promotes sepsis development by impairing PHB1-mediated mitochondrial respiratory chain function.","date":"2020","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/32221047","citation_count":17,"is_preprint":false},{"pmid":"35167193","id":"PMC_35167193","title":"ARID1A-deficient cells require HDAC6 for progression of endometrial carcinoma.","date":"2022","source":"Molecular oncology","url":"https://pubmed.ncbi.nlm.nih.gov/35167193","citation_count":16,"is_preprint":false},{"pmid":"33621955","id":"PMC_33621955","title":"Discovery of a novel AR/HDAC6 dual inhibitor for prostate cancer treatment.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33621955","citation_count":16,"is_preprint":false},{"pmid":"39155390","id":"PMC_39155390","title":"HDAC6 inhibition disrupts HDAC6-P300 interaction reshaping the cancer chromatin landscape.","date":"2024","source":"Clinical epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/39155390","citation_count":15,"is_preprint":false},{"pmid":"36595522","id":"PMC_36595522","title":"Novel dual LSD1/HDAC6 inhibitor for the treatment of cancer.","date":"2023","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/36595522","citation_count":15,"is_preprint":false},{"pmid":"38857566","id":"PMC_38857566","title":"Advances in dual-targeting inhibitors of HDAC6 for cancer treatment.","date":"2024","source":"European journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/38857566","citation_count":15,"is_preprint":false},{"pmid":"37586844","id":"PMC_37586844","title":"Radiotherapy-induced Immune Response Enhanced by Selective HDAC6 Inhibition.","date":"2023","source":"Molecular cancer therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/37586844","citation_count":15,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":46039,"output_tokens":7924,"usd":0.128489,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":17249,"output_tokens":7810,"usd":0.140747,"stage2_stop_reason":"end_turn"},"total_usd":0.269236,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Cytoplasmic fractionation, co-immunoprecipitation, in vitro deacetylase assay with purified HDAC6 on assembled microtubules, overexpression and knockdown with alpha-tubulin acetylation readout, chemotaxis assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro deacetylase activity with purified protein, multiple orthogonal methods, widely replicated across labs\",\n      \"pmids\": [\"12024216\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylase assay, HDAC6 knockout/knockdown cells, glucocorticoid receptor functional assays (ligand binding, nuclear translocation, transcriptional activation)\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro deacetylase assay, multiple orthogonal functional readouts, genetic loss-of-function with defined substrate and downstream phenotype\",\n      \"pmids\": [\"15916966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Biophysical characterization (Zn ion content), biochemical binding assays, Co-IP, cellular ubiquitin chain accumulation assays, domain structure-function analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — combination of biophysical, biochemical, and biological approaches in one study; characterization of ZnF-UBP domain with functional validation\",\n      \"pmids\": [\"16810319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylase assay, HDAC6 silencing/knockout (endothelial cells, zebrafish, mice), matrigel plug angiogenesis assay, domain mutant rescue experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, genetic loss-of-function in multiple organisms, domain-specific rescue experiments establishing catalytic requirement\",\n      \"pmids\": [\"21847094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro kinase assay, phosphorylation site mutagenesis (GRK2-K220R, GRK2-S670A), immunofluorescence co-localization, migration assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro kinase assay with site-directed mutagenesis, Co-IP, and functional migration readouts; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"22193721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, site-specific acetylation mapping (K909), HDAC6 knockdown/knockout cells and mice, antiviral response assays (IFN production), viral challenge experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP, defined acetylation site, genetic KO mice with specific antiviral phenotype, multiple orthogonal methods\",\n      \"pmids\": [\"26746851\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro reconstitution of autophagosome-lysosome fusion, deacetylase-inactive HDAC6 mutant rescue experiments, subcellular fractionation, Drosophila and mouse models\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro reconstitution, deacetylase-dead mutant, multiple model organisms, orthogonal biochemical and cell biology approaches\",\n      \"pmids\": [\"30538141\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylase assay, mass spectrometry acetylation site mapping, acetylation mimetic/deacetylation mimetic MLH1 mutants, 6-thioguanine resistance assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro deacetylase assay, MS-identified sites, mutagenesis with functional readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30770470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Genetic deletion (HDAC6 knockout mice), in vitro reconstitution, live-cell imaging at MTOC, caspase activation assays, IL-1β conversion assays\",\n      \"journal\": \"Science (New York, N.Y.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO in mice, in vitro reconstitution, live imaging, multiple inflammasome pathway readouts\",\n      \"pmids\": [\"32943500\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro and in vivo ubiquitination assay, HDAC6 domain mapping (DAC1), HDAC6 knockdown with Chk1 rescue experiments, cell cycle analysis\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo ubiquitination assay with domain mapping, genetic KD with rescue, single lab\",\n      \"pmids\": [\"33020410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylase assay, acetylation site mutagenesis (K385/387R), dimerization assays, viral neutralization assays, HDAC6 depletion/inhibition\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro deacetylase assay, site mutagenesis with functional rescue, Co-IP domain mapping; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32796032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Fluorescence microscopy (live imaging and fixed), immunofluorescence, HDAC6/Dido3 overexpression and knockdown, measurement of cilium length\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization experiments with functional consequence (cilium size), overexpression/KD, single lab but multiple orthogonal imaging approaches\",\n      \"pmids\": [\"24667272\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"shRNA knockdown, pharmacological inhibition (tubastatin-A), overexpression, IFT88-shRNA rescue experiment, tumor xenograft model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic and pharmacological loss-of-function with mechanistic rescue experiment linking HDAC6 specifically to cilia disassembly; single lab\",\n      \"pmids\": [\"23370327\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Selective HDAC6 inhibitor (tubastatin A), shRNA knockdown, tau isoform-expressing cell lines, pulse-chase protein turnover assay, immunoblotting\",\n      \"journal\": \"Glia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological and genetic inhibition with defined acetylation site and turnover assay, single lab\",\n      \"pmids\": [\"24464872\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, chromatin fractionation, knockdown experiments, immunofluorescence, cell death/apoptosis assays post-irradiation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP demonstrating ternary complex, knockdown with defined acetylation and functional phenotype; single lab\",\n      \"pmids\": [\"25299772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro binding assays, Tau aggregation assays (thioflavin T, electron microscopy), recombinant ZnF UBP domain, NMR/biophysical conformational analysis\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro reconstitution of binding and disaggregation, multiple biophysical readouts; single lab\",\n      \"pmids\": [\"33237772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Substrate trapping (HDAC6 mutant), proteomics/MS, in vitro deacetylase assay, methyltransferase activity assay with acetylation-state PRMT5 variants\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — unbiased substrate trapping proteomics plus in vitro validation of deacetylase activity and functional methyltransferase consequence; single lab\",\n      \"pmids\": [\"34314149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — recombinant protein treatment of human myofibrils, genetic KO, domain mapping, multiple species, orthogonal methods establishing titin as functional substrate\",\n      \"pmids\": [\"35575093\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, proteomic analysis, in vitro deacetylase assay, site-specific mutagenesis (K526/K531), ubiquitination assay, HDAC6 knockdown with rescue experiments, migration assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site-directed mutagenesis, ubiquitination and degradation assays; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"36122629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Crystal structure of HDAC6 ZnF-DARPin complex, in vitro ubiquitin-binding assay, conditional DARPin expression in cells, viral infection assays, stress granule/aggresome quantification\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure of the complex, in vitro binding assay, functional validation in cells; single lab with structural and functional orthogonal methods\",\n      \"pmids\": [\"35476995\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay establishing novel lactyltransferase activity, MS site identification, functional validation in neurons; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"39333081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — direct binding assay, structural domain identified (SE14), in vitro deacetylase assay on TET2, subcellular fractionation with functional consequence, multiple orthogonal methods\",\n      \"pmids\": [\"39567688\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Cell metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, conditional KO, pharmacological dissection of central vs. peripheral mechanism; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"38569472\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Immunofluorescence/confocal microscopy (NMJ localization), pharmacological inhibition, Co-immunoprecipitation of paxillin-HDAC6, AChR clustering assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization at NMJ, Co-IP of binding partner, pharmacological functional readout; single lab with multiple methods\",\n      \"pmids\": [\"32697819\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro deacetylase assay, ubiquitination assay, site-directed mutagenesis (K46, K58), reverse genetics recombinant virus, viral replication assays\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro assays, mutagenesis with reverse genetics validation; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37133375\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, in vitro enzymatic assay, transgenic mouse and human ovarian explant with mechanistic readout; single lab\",\n      \"pmids\": [\"38646645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (HDAC6-FoxO3a), chromatin immunoprecipitation (FoxO3a on myostatin promoter), confocal microscopy (FoxO3a nuclear localization), AMPK knockdown, luciferase reporter assay\",\n      \"journal\": \"Journal of cachexia, sarcopenia and muscle\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP of HDAC6-FoxO3a interaction, ChIP confirming promoter binding, confocal localization; single lab with multiple methods\",\n      \"pmids\": [\"34725961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"HDAC6 inhibitor (ITF3756), siRNA, CRISPR/Cas9 knockout, ATAC-seq, H3K27Ac ChIP-seq, transcriptomics, proteomics, P300 ubiquitination assay\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple inactivation strategies, genome-wide chromatin and transcriptomic readouts, P300 ubiquitination assay; single lab\",\n      \"pmids\": [\"39155390\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HDAC6 is a cytoplasmic class IIb deacetylase with two catalytic domains and a C-terminal ZnF-UBP ubiquitin-binding domain; it deacetylates multiple non-histone substrates including alpha-tubulin (regulating microtubule dynamics and cell motility), Hsp90 (controlling chaperone activity and client protein maturation), cortactin (regulating actin dynamics and angiogenesis), RIG-I (activating antiviral RNA sensing), MLH1 (disrupting mismatch repair complex assembly), TRIM21 (promoting antiviral intracellular neutralization), titin (modulating sarcomere stiffness and cardiac diastolic function), and TET2 (initiating DNA demethylation in response to valine deprivation); additionally, HDAC6 acts as a valine sensor via its primate-specific SE14 domain controlling nucleo-cytoplasmic shuttling, functions as an E3 ubiquitin ligase for substrates such as Chk1, serves as a dynein adapter for transport of ubiquitinated cargoes and inflammasome components to the MTOC, and engages p97/VCP through its ZnF-UBP to regulate polyubiquitin chain turnover and aggresome formation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #1]. 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 [#0], and this tubulin-deacetylase activity is potentiated by GRK2-mediated phosphorylation at sites of active migration [#4]. 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 [#1], and it remodels the actin cytoskeleton by deacetylating cortactin to drive endothelial migration, sprouting, and angiogenesis independently of tubulin deacetylation [#3]. 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 [#2]; 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 [#19]. Beyond classical deacetylation, HDAC6 carries out additional catalytic activities: it lactylates alpha-tubulin at lysine 40 to enhance microtubule dynamics and neurite outgrowth [#20], and acts as an E3 ubiquitin ligase through its DAC1 domain to ubiquitinate Chk1 [#9]. It serves as a dynein adapter directing ubiquitinated cargo and NLRP3/pyrin inflammasome components to the MTOC [#8], 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 [#21]. HDAC6 further deacetylates substrates linking it to innate antiviral sensing (RIG-I, TRIM21) [#5, #10], DNA mismatch repair (MLH1) [#7], and cardiac sarcomere stiffness via titin [#17].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2002,\n      \"claim\": \"Established HDAC6 as a bona fide cytoplasmic tubulin deacetylase, defining its first non-histone substrate and a role in cell motility.\",\n      \"evidence\": \"in vitro deacetylase assay on purified HDAC6 and assembled microtubules, fractionation, chemotaxis assay\",\n      \"pmids\": [\"12024216\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve how tubulin deacetylation mechanistically alters microtubule stability versus transport\", \"Regulation of HDAC6 catalytic activity unaddressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed HDAC6 governs chaperone activity by deacetylating Hsp90, extending its function from cytoskeleton to protein folding/maturation.\",\n      \"evidence\": \"in vitro deacetylase assay, HDAC6-deficient cells, glucocorticoid receptor functional readouts\",\n      \"pmids\": [\"15916966\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific Hsp90 acetyl-lysine sites not fully mapped\", \"Breadth of affected Hsp90 clients beyond GR not defined\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"biophysical/biochemical ubiquitin-binding assays, Co-IP, cellular ubiquitin-accumulation assays, domain analysis\",\n      \"pmids\": [\"16810319\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise chain-length selectivity in cells not fully resolved\", \"How ubiquitin binding is integrated with deacetylase activity unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified cortactin as a substrate and dissected domain-specific requirements, showing angiogenic function depends on catalysis but not ubiquitin binding or tubulin deacetylation.\",\n      \"evidence\": \"reciprocal Co-IP, in vitro deacetylase assay, multi-organism knockout, domain-mutant rescue, angiogenesis assays\",\n      \"pmids\": [\"21847094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cortactin acetyl-site identity in this context not specified\", \"Crosstalk with tubulin pool not resolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed upstream regulation of HDAC6, with GRK2 binding and phosphorylating HDAC6 to stimulate tubulin deacetylation locally in lamellipodia.\",\n      \"evidence\": \"in vitro kinase assay, phosphosite mutagenesis, co-localization imaging, migration assays\",\n      \"pmids\": [\"22193721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"HDAC6 phosphorylation sites targeted by GRK2 not mapped\", \"Whether other kinases regulate HDAC6 unaddressed\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected HDAC6 to ciliogenesis through Dido3-dependent centrosomal targeting controlling ciliary tubulin acetylation and cilium size.\",\n      \"evidence\": \"live and fixed imaging, HDAC6/Dido3 overexpression and knockdown, cilium length measurement\",\n      \"pmids\": [\"24667272\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular nature of Dido3-HDAC6 interaction not biochemically defined\", \"Single-lab imaging-based study\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established HDAC6 as a driver of ciliary disassembly with tumor-promoting consequences, using an IFT88 rescue to prove cilia-dependence.\",\n      \"evidence\": \"shRNA, tubastatin-A inhibition, overexpression, IFT88-shRNA rescue, xenograft\",\n      \"pmids\": [\"23370327\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct deacetylation event driving disassembly not isolated\", \"Generalizability beyond cholangiocarcinoma untested here\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Linked HDAC6 to tau proteostasis, showing inhibition increases tau acetylation in the microtubule-binding domain and slows turnover.\",\n      \"evidence\": \"tubastatin A and shRNA, tau isoform cell lines, pulse-chase turnover assay\",\n      \"pmids\": [\"24464872\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect tau deacetylation not separated in cells\", \"Single cell-type context\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Placed HDAC6 in a DNA-damage/apoptosis axis by maintaining Ku70 deacetylation with SMAR1, controlling Bax sequestration and radioresistance.\",\n      \"evidence\": \"Co-IP of ternary complex, chromatin fractionation, knockdown, post-irradiation apoptosis assays\",\n      \"pmids\": [\"25299772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reciprocal validation of direct HDAC6-Ku70 deacetylation limited\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrated HDAC6 activates innate antiviral RNA sensing by deacetylating RIG-I at K909, with knockout mice susceptible to RNA viruses.\",\n      \"evidence\": \"reciprocal Co-IP, acetyl-site mapping, KO cells and mice, IFN and viral challenge assays\",\n      \"pmids\": [\"26746851\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specificity for RNA but not DNA virus sensing mechanism incompletely defined\", \"Kinetics of transient HDAC6-RIG-I binding unresolved\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Showed HDAC6 promotes autophagosome-lysosome fusion via lysosomal recruitment by ATP13A2 and cortactin deacetylation.\",\n      \"evidence\": \"Co-IP, in vitro fusion reconstitution, deacetylase-dead rescue, fractionation, fly/mouse models\",\n      \"pmids\": [\"30538141\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cortactin deacetylation mechanically aids fusion not fully defined\", \"Other lysosomal HDAC6 substrates unexplored\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified MLH1 as a substrate whose deacetylation blocks MutSα-MutLα assembly, linking HDAC6 to mismatch-repair regulation and damage tolerance.\",\n      \"evidence\": \"Co-IP, in vitro deacetylase assay, MS site mapping, acetyl-mimetic mutants, 6-thioguanine resistance\",\n      \"pmids\": [\"30770470\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signals controlling MLH1 deacetylation unknown\", \"Single-lab functional context\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established HDAC6 as a dynein adapter essential for MTOC delivery and aggresome-like assembly of NLRP3 and pyrin inflammasomes.\",\n      \"evidence\": \"KO mice, in vitro reconstitution, MTOC live imaging, caspase and IL-1β assays\",\n      \"pmids\": [\"32943500\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cargo-recognition determinants for inflammasome components not fully defined\", \"Relationship to ubiquitin-binding versus motor-adapter roles unresolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Reported a non-canonical E3 ligase activity, with HDAC6's DAC1 domain ubiquitinating Chk1 and modulating radiosensitivity.\",\n      \"evidence\": \"in vitro/in vivo ubiquitination, domain mapping, knockdown with Chk1 rescue, cell-cycle analysis\",\n      \"pmids\": [\"33020410\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether DAC1 ligase activity generalizes beyond Chk1 untested\", \"Single-lab, requires independent confirmation of intrinsic E3 activity\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended antiviral function to antibody-dependent intracellular neutralization by deacetylating TRIM21 at K385/K387 to promote its dimerization.\",\n      \"evidence\": \"Co-IP/PRYSPRY mapping, in vitro deacetylase assay, site mutagenesis, dimerization and neutralization assays\",\n      \"pmids\": [\"32796032\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance to viral clearance not addressed\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"ZnF-DARPin crystal structure, ubiquitin-binding assay, conditional DARPin expression, viral infection and granule quantification\",\n      \"pmids\": [\"35476995\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous regulators that gate the ZnF pocket in vivo unknown\", \"Therapeutic translatability of DARPin untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identified HDAC6 enrichment at neuromuscular junctions and a paxillin-HDAC6 axis regulating AChR clustering and microtubule organization.\",\n      \"evidence\": \"confocal NMJ localization, pharmacological inhibition, paxillin-HDAC6 Co-IP, AChR clustering assays\",\n      \"pmids\": [\"32697819\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct substrate at NMJ not defined\", \"Single-lab, correlative localization\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated the ZnF-UBP domain directly binds tau's polyproline/repeat region to reduce aggregation and disaggregate fibrils, implicating HDAC6 in tau clearance.\",\n      \"evidence\": \"recombinant ZnF-UBP binding, ThT/EM aggregation assays, biophysical conformational analysis\",\n      \"pmids\": [\"33237772\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vivo disaggregase relevance not established\", \"Single-lab in vitro reconstitution\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Revealed acetylation-methylation crosstalk by identifying PRMT5 as a substrate whose deacetylation lowers its methyltransferase output.\",\n      \"evidence\": \"substrate-trapping proteomics, in vitro deacetylase and methyltransferase assays\",\n      \"pmids\": [\"34314149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"PRMT5 acetyl-sites and stoichiometry incompletely defined\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked HDAC6 to muscle atrophy by interacting with FoxO3a to promote its nuclear localization and myostatin transcription downstream of metformin.\",\n      \"evidence\": \"Co-IP, ChIP on myostatin promoter, nuclear localization imaging, AMPK knockdown, luciferase reporter\",\n      \"pmids\": [\"34725961\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether HDAC6 deacetylates FoxO3a directly not shown\", \"Single-lab, correlative\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Defined titin as a sarcomeric substrate, with HDAC6 deacetylating the PEVK element to reduce myofibril stiffness and protect against diastolic dysfunction.\",\n      \"evidence\": \"KO mice, recombinant HDAC6 treatment of human/rodent myofibrils, mechanics, proteomics, Z-disk co-localization\",\n      \"pmids\": [\"35575093\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Titin acetyl-site regulation in vivo not fully mapped\", \"Upstream signals controlling cardiac HDAC6 activity unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected HDAC6 to colon cancer metastasis by deacetylating AKAP12 to promote its ubiquitin-dependent degradation and PKC reactivation.\",\n      \"evidence\": \"Co-IP, proteomics, in vitro deacetylase assay, site mutagenesis, ubiquitination and migration assays\",\n      \"pmids\": [\"36122629\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ligase for AKAP12 not identified\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Demonstrated antiviral targeting of coronavirus nsp8 via combined deacetylation (K46) and ubiquitination (K58) driving proteasomal degradation.\",\n      \"evidence\": \"Co-IP, deacetylase and ubiquitination assays, mutagenesis, reverse-genetics recombinant virus, replication assays\",\n      \"pmids\": [\"37133375\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generalizability to other coronaviruses untested\", \"Single-lab study\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Uncovered a novel lactyltransferase activity, with HDAC6 lactylating alpha-tubulin K40 to enhance microtubule dynamics and neurite outgrowth in a lactate-dependent manner.\",\n      \"evidence\": \"in vitro lactyltransferase assay with purified HDAC6, MS site ID, overexpression/KO, microtubule and neurite imaging\",\n      \"pmids\": [\"39333081\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for lactyl- versus deacetyl-transfer not resolved\", \"Independent confirmation of intrinsic lactyltransferase activity pending\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"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.\",\n      \"evidence\": \"valine-binding assay, fractionation, HDAC6-TET2 Co-IP, in vitro TET2 deacetylase assay, SE14 mutagenesis, demethylation/damage assays\",\n      \"pmids\": [\"39567688\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SE14 valine occupancy mechanistically gates localization unresolved\", \"Physiological contexts of valine sensing in humans not fully mapped\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Placed HDAC6 in central metabolic control by interacting with the leptin receptor to dampen leptin signaling, with anti-obesity effects mediated through AgRP neurons.\",\n      \"evidence\": \"Co-IP, inhibitor treatment of obese mice, AgRP-specific conditional KO, BBB-permeable inhibitor comparison\",\n      \"pmids\": [\"38569472\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether LepR is a deacetylation substrate not established\", \"Mechanism of interaction-dependent inhibition unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Linked HDAC6 to ovarian follicle dormancy by deacetylating NGF to accelerate its ubiquitin-dependent degradation.\",\n      \"evidence\": \"Co-IP, in vitro deacetylase and ubiquitination assays, transgenic mice, human ovarian explants, follicle activation assays\",\n      \"pmids\": [\"38646645\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"NGF acetyl-sites not mapped\", \"Direct ligase coupling not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed HDAC6 shapes the cancer chromatin landscape indirectly by stabilizing P300, with inactivation increasing H3 acetylation and opening chromatin.\",\n      \"evidence\": \"inhibitor/siRNA/CRISPR, ATAC-seq, H3K27Ac ChIP-seq, transcriptomics, P300 ubiquitination assay\",\n      \"pmids\": [\"39155390\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which HDAC6 controls P300 ubiquitination not defined\", \"Direct versus indirect chromatin effects not fully separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [0, 1, 3, 5, 7, 10, 17, 21]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [20]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [2, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0140299\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 17]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [8, 11]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [6]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [5, 8, 10]},\n      {\"term_id\": \"R-HSA-392499\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 8]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [7]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [27]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"HSP90\", \"CTTN\", \"RIGI\", \"TRIM21\", \"MLH1\", \"VCP\", \"GRK2\", \"TET2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}