{"gene":"HDAC5","run_date":"2026-06-10T01:55:21","timeline":{"discoveries":[{"year":2000,"finding":"HDAC5 physically interacts with MEF2A in vivo and in vitro and strongly inhibits its transcriptional activity. The repression is independent of the HDAC5 deacetylase domain; the N-terminal non-deacetylase domain is sufficient for repression. The MADS box/MEF2-domain region of MEF2A interacts with a limited region in the N-terminal part of HDAC5.","method":"Co-immunoprecipitation (in vivo and in vitro), domain mapping, transcriptional reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP (in vivo and in vitro), domain-mapping mutagenesis, functional reporter assay; replicated in multiple subsequent studies","pmids":["10748098"],"is_preprint":false},{"year":2003,"finding":"HDAC5 represses PGC-1α transcription through MEF2-binding sites in the PGC-1α promoter. Transgenic expression of a signal-resistant (phosphorylation-defective) HDAC5 in mouse heart causes loss of cardiac mitochondria, down-regulation of mitochondrial enzymes, and down-regulation of PGC-1α, placing HDAC5 as a repressor of the MEF2/PGC-1α axis controlling cardiac mitochondrial biogenesis.","method":"Transgenic mouse model (signal-resistant HDAC5), promoter analysis, transcriptional reporter assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo transgenic model with defined phenotype plus promoter mechanistic analysis; multiple orthogonal methods in single study","pmids":["12578979"],"is_preprint":false},{"year":2003,"finding":"Neuronal activity controls the nucleocytoplasmic distribution of HDAC5 in hippocampal neurons. HDAC5 nuclear export requires stimulation of calcium flux through synaptic NMDA receptors or L-type calcium channels and is sensitive to the CaM kinase inhibitor KN-62, establishing that CaMK signaling drives HDAC5 cytoplasmic translocation in neurons.","method":"Live-cell imaging of GFP-tagged HDAC5, pharmacological inhibitors (KN-62), calcium channel blockers","journal":"Journal of neurochemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct localization imaging with functional consequence, multiple pharmacological dissections, replicated across papers","pmids":["12641737"],"is_preprint":false},{"year":2003,"finding":"HDAC5 directly associates with GATA-1 and co-localizes with it in the nucleus of murine erythroleukemia (MEL) cells. Co-expression of HDAC5 suppresses GATA-1 transcriptional activity. During HMBA-induced erythroid differentiation a portion of HDAC5 relocates to the cytoplasm, correlated with de-repression of GATA-1.","method":"Co-immunoprecipitation, co-localization by immunofluorescence, transcriptional reporter assay, subcellular fractionation","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and localization data in a single lab, supported by functional reporter assay","pmids":["14668799"],"is_preprint":false},{"year":2005,"finding":"Gβγ subunit of heterotrimeric G proteins directly binds HDAC5 through its C-terminal domain. This interaction occurs in a signal-dependent manner, can be blocked by Gαo overexpression and reversed by α2A-adrenergic receptor activation. Formation of the Gβ1γ2–HDAC5 complex inhibits HDAC5-mediated transcriptional co-repression of MEF2C, indicating that G protein signaling directly controls HDAC5 co-repressor function.","method":"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, MEF2C transcriptional reporter assay, Gβγ scavenger overexpression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus Co-IP in mammalian cells plus functional reporter, single lab","pmids":["16221676"],"is_preprint":false},{"year":2006,"finding":"HDAC5 localization in H9C2 cells is controlled by CaMKIV and/or PKD (which maintain cytoplasmic HDAC5 in undifferentiated cells) and by PP2A phosphatase (which promotes nuclear HDAC5 in differentiated cells). In differentiated cells, nuclear HDAC5 interacts with YY1 transcription factor and is required for YY1 repressor function.","method":"GFP-fusion live imaging, co-immunoprecipitation, dominant-negative kinase/phosphatase constructs","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell localization imaging with mechanistic follow-up (Co-IP, kinase/phosphatase inhibition), single lab","pmids":["16822951"],"is_preprint":false},{"year":2007,"finding":"HDAC5 is recruited as a co-repressor to the CYP1A1 promoter via interaction with AhRR and the adaptor protein ANKRA2 (which bridges HDAC4/5 to AhRR). RNA interference of ANKRA2 or AhRR reduces this repression, establishing an AhRR/ANKRA2/HDAC5 co-repressor axis.","method":"Yeast two-hybrid, RNAi knockdown, chromatin immunoprecipitation, transcriptional reporter assay","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid identification, functional siRNA validation, ChIP confirmation, single lab","pmids":["17949687"],"is_preprint":false},{"year":2008,"finding":"SIK1 (salt-inducible kinase 1) phosphorylates HDAC5 causing its nuclear export and activation of MEF2C in AICAR-treated C2C12 myoblasts. GSK-3β contributes to sustained SIK1 activity, and this pathway drives PGC-1α expression in a HDAC5/MEF2C-dependent manner.","method":"In vitro kinase assay, GFP-HDAC5 nuclear export imaging, dominant-negative constructs, pharmacological inhibitors","journal":"Endocrine journal","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay plus live imaging, single lab","pmids":["18946175"],"is_preprint":false},{"year":2008,"finding":"YY1 transcription factor interacts with HDAC5 via the HDAC5 phosphorylation domain and prevents HDAC5 nuclear export in response to hypertrophic stimuli in cardiac myocytes. The interaction is required for YY1 to function as a transcription repressor; YY1 overexpression reduces HDAC5 phosphorylation in response to hypertrophic stimuli.","method":"Co-immunoprecipitation, GFP-HDAC5 localization, siRNA knockdown, dominant-negative and deletion constructs, luciferase reporter assays","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, live-cell localization, and functional reporter; single lab with multiple methods","pmids":["18632988"],"is_preprint":false},{"year":2008,"finding":"GIT1 scaffold protein mediates Ang II-induced phosphorylation of HDAC5 at Ser498 in vascular smooth muscle cells through a Src–PLCγ–CaMKII signaling pathway. Knockdown of GIT1 decreases Ang II-induced HDAC5 phosphorylation and MEF2 transcriptional activity.","method":"siRNA knockdown, phospho-specific antibodies, co-immunoprecipitation of GIT1-CaMKII, MEF2 reporter assays","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, targeted siRNA knockdown, phospho-site specific antibody validation, single lab","pmids":["18292392"],"is_preprint":false},{"year":2008,"finding":"HDAC5 interacts with GEF (GLUT4 enhancer factor) in the absence of MEF2 proteins and specifically inhibits GLUT4 promoter activity through this interaction.","method":"Co-immunoprecipitation, GLUT4 promoter luciferase reporter assay","journal":"The Journal of biological chemistry","confidence":"Low","confidence_rationale":"Tier 3 / Moderate — single Co-IP plus reporter assay, single lab","pmids":["18216015"],"is_preprint":false},{"year":2009,"finding":"Fluid shear stress stimulates CaMK-dependent phosphorylation of HDAC5 at Ser259/Ser498 and its nuclear export in endothelial cells, causing dissociation from MEF2 and MEF2-driven expression of KLF2 and eNOS. A phosphorylation-defective HDAC5 mutant (S259A/S498A) blocks these effects and attenuates the anti-inflammatory response.","method":"Adenoviral overexpression of HDAC5-S/A mutant, phospho-specific immunoblotting, MEF2 reporter assay, cell adhesion assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-site mutagenesis with defined functional phenotype, multiple orthogonal readouts; consistent with independent replications in other systems","pmids":["20042720"],"is_preprint":false},{"year":2009,"finding":"Alpha-adrenergic receptor activation by phenylephrine causes PKD-dependent HDAC5 nuclear efflux in slow soleus skeletal muscle fibers. PKD1 redistribution and HDAC5 export are transient (reflecting receptor desensitization), whereas phorbol ester (PMA) causes continuous PKD-dependent export. This HDAC5 export increases histone H3 acetylation and MEF2 reporter activity.","method":"Live-cell imaging of HDAC5-GFP and PKD1-mPlum in isolated adult muscle fibers, pharmacological inhibition, histone acetylation immunoblot, MEF2 reporter assay","journal":"The Journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell localization with functional readouts, single lab, multiple methods","pmids":["19124542"],"is_preprint":false},{"year":2011,"finding":"In vascular smooth muscle cells (VSMCs), CaMKIIδ2 mediates Ca2+-dependent phosphorylation of both HDAC4 and HDAC5 in response to AngII and PDGF. HDAC5 regulation depends on HDAC4: suppression of HDAC4 expression and activity prevents AngII/PDGF-dependent phosphorylation of HDAC5. This regulates MEF2 DNA-binding and target gene expression (Nur77, MCP1).","method":"CaMKIIδ2 siRNA/dominant-negative, HDAC4 siRNA, phospho-HDAC immunoblots, MEF2 DNA-binding ELISA, qPCR","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple orthogonal readouts, single lab","pmids":["22360269"],"is_preprint":false},{"year":2011,"finding":"Calpain-generated free catalytic domain of PKCα (PKCα-CT) constitutively localizes to nuclei and directly drives nucleocytoplasmic shuttling of HDAC5, inducing MEF2-dependent inflammatory pathway gene expression. This occurs independently of PKD, which is required for receptor-mediated (phorbol ester) HDAC5 export.","method":"Confocal imaging of nuclear/cytoplasmic HDAC5, adenoviral PKCα-CT expression, PKD inhibition, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging plus mechanistic kinase dissection, single lab","pmids":["21642422"],"is_preprint":false},{"year":2012,"finding":"HDAC5 is associated with actively replicating pericentric heterochromatin during late S phase. RNAi-mediated depletion of HDAC5 disrupts heterochromatin structure, slows replication forks, triggers DNA damage checkpoint activation, and induces autophagy and apoptosis in cancer cells in vitro and in vivo.","method":"RNAi knockdown, BrdU incorporation/replication fork assay, immunofluorescence, xenograft tumor assay","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi with defined molecular and cellular phenotype, in vitro and in vivo validation, single lab","pmids":["22301920"],"is_preprint":false},{"year":2012,"finding":"HDAC5 functions as an injury-regulated tubulin deacetylase in peripheral neurons. Axon injury induces calcium influx that activates PKC-mediated HDAC5 activity at the injury site, leading to localized tubulin deacetylation. This is required for growth cone dynamics and axon regeneration in vitro and in vivo; central neurons fail to activate this pathway.","method":"In vitro axon regeneration assays, in vivo sciatic nerve injury model, pharmacological PKC inhibition, HDAC5 knockdown/overexpression, acetylated tubulin immunostaining","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vitro and in vivo loss-of-function with defined molecular substrate (tubulin deacetylation), multiple orthogonal methods","pmids":["22692128"],"is_preprint":false},{"year":2012,"finding":"NOX2-derived reactive oxygen species (ROS) drive HDAC5 nuclear efflux during intense (50 Hz) repetitive stimulation of fast skeletal muscle fibers. This is completely blocked by ROS scavenger NAC and absent in NOX2 knockout fibers, in contrast to HDAC4 efflux which is additionally regulated by CaMK.","method":"GFP-HDAC5 live imaging in isolated muscle fibers, NAC scavenger treatment, NOX2 knockout mice, KN-62 CaMK inhibition","journal":"American journal of physiology. Cell physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout plus pharmacological inhibition with direct imaging readout, mechanistically dissects ROS vs. CaMK contributions","pmids":["22648949"],"is_preprint":false},{"year":2013,"finding":"Axon injury in peripheral sensory neurons elicits a back-propagating calcium wave that causes PKCμ-dependent nuclear export of HDAC5, thereby enhancing histone acetylation and activating a pro-regenerative gene-expression program. A nuclear-trapped HDAC5 mutant prevents axon regeneration; enhancing HDAC5 nuclear export promotes regeneration in vitro and in vivo. This pathway fails to activate in central nervous system injury.","method":"Calcium imaging, PKCμ inhibition/knockdown, HDAC5 nuclear-trap mutant expression, in vivo sciatic nerve injury regeneration assay, gene expression profiling","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic dissection (calcium → PKCμ → HDAC5 nuclear export) with in vitro and in vivo loss-of-function, nuclear-trap mutant, multiple readouts; high-impact venue","pmids":["24209626"],"is_preprint":false},{"year":2013,"finding":"HDAC5 binds to p53 and abrogates acetylation of p53 at K120. This prevents p53 recruitment to pro-apoptotic gene promoters at early phases of genotoxic stress, promoting arrest/antioxidant gene expression. Upon prolonged stress, HDAC5 undergoes nuclear export, p53 becomes K120-acetylated, and pro-apoptotic genes are selectively transactivated.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, acetylation assays, HDAC5 knockdown in mice, gene expression analysis","journal":"Molecular cell","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct Co-IP, ChIP, acetylation assay, in vivo mouse knockdown, multiple orthogonal methods establishing mechanism of p53 K120 deacetylation by HDAC5","pmids":["24120667"],"is_preprint":false},{"year":2013,"finding":"HDAC5 interacts with Tbx3 transcription factor via two critical motifs (585LFSYPYT591 and 604HRH606) and mediates Tbx3-driven repression of E-cadherin and HCC cell migration/metastasis. An HDAC inhibitor blocks Tbx3-mediated E-cadherin downregulation.","method":"Glycine scan mutagenesis, deletion assays, co-immunoprecipitation, E-cadherin promoter reporter, in vitro migration assay, in vivo metastasis assay","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus mutagenesis plus functional assays in vitro and in vivo, single lab","pmids":["30151243"],"is_preprint":false},{"year":2013,"finding":"HDAC5 is required for the interaction of HDAC1/2/Sin3a co-repressor complexes with transcription factors Nkx2.5 and YY1 at the Ncx1 and Bnp promoters in heart. HDAC5 knockout prevents pressure overload-induced Ncx1 upregulation and prevents recruitment of HDAC1/Sin3a co-repressor to these promoters, supporting a non-canonical scaffolding role for HDAC5.","method":"HDAC5 knockout mouse, pressure overload model, co-immunoprecipitation, chromatin immunoprecipitation","journal":"Nucleic acids research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with ChIP and Co-IP, single lab, novel mechanism of scaffold function","pmids":["26704971"],"is_preprint":false},{"year":2013,"finding":"HDAC5-deficient mice have reduced cardiac PTB protein abundance. HDAC inhibition in myocytes reduces cFLIP expression, enabling caspase-dependent PTB cleavage. This pathway controls alternative splicing of tropomyosin-1, tropomyosin-2, and MEF2 in the developing heart.","method":"HDAC5 knockout mouse, cFLIP overexpression, caspase inhibition, in vitro caspase cleavage assay, RT-PCR for alternative splicing","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout with defined molecular cascade and splicing phenotype, single lab","pmids":["23424201"],"is_preprint":false},{"year":2014,"finding":"HDAC5 in erythroid cells forms a novel complex (NuRSERY) with GATA1, EKLF, and pERK, as identified by pull-down experiments. ERK phosphorylation is required for complex formation; inhibition of ERK phosphorylation reduces nuclear content of HDAC5, GATA1, and EKLF by >90%. The complex is erythroid-specific and regulates globin gene expression.","method":"Co-immunoprecipitation/pulldown, pharmacological ERK inhibition, class IIa-selective HDAC inhibitor, RT-PCR for globin expression","journal":"The international journal of biochemistry & cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies complex, ERK inhibition validates requirement, functional globin readout, single lab","pmids":["24594363"],"is_preprint":false},{"year":2015,"finding":"HDAC5 negatively regulates sclerostin (SOST) expression in osteocytes by binding and inhibiting MEF2C. ChIP mapping identified MEF2C binding at a distal SOST enhancer 45 kb downstream of the transcription start site. HDAC5 deficiency increases MEF2C chromatin association at this enhancer, increases H3K27ac, and decreases NCoR/HDAC3 co-repressor recruitment. HDAC5 knockout mice show increased SOST mRNA and sclerostin protein, decreased Wnt activity, and reduced bone mass.","method":"HDAC5 shRNA/overexpression, HDAC5 knockout mice, chromatin immunoprecipitation (ChIP), MEF2C knockdown rescue experiment","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP mapping, genetic KO mouse, shRNA rescue with MEF2C double KD, multiple orthogonal methods in single study","pmids":["25271055"],"is_preprint":false},{"year":2015,"finding":"HDAC5 deacetylates cytosolic Hsp70, which reduces Hsp70 affinity for HIF-1α, thereby decreasing HIF-1α degradation and enabling its nuclear accumulation. AMPK activation promotes cytoplasmic shuttling of HDAC5 which is necessary for this activity under hypoxia or low glucose. HDAC5 knockdown impairs hypoxia-induced HIF-1α accumulation.","method":"HDAC5 knockdown/overexpression, Hsp70 co-immunoprecipitation, acetylation assay of Hsp70, AMPK inhibition, HIF-1α nuclear fractionation","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — direct substrate identification (Hsp70 deacetylation) plus functional consequence on HIF-1α, single lab","pmids":["26061431"],"is_preprint":false},{"year":2015,"finding":"Ketamine rapidly stimulates HDAC5 phosphorylation and nuclear export in rat hippocampal neurons through CaMKII- and PKD-dependent pathways, enhancing MEF2 transcriptional activity. A phosphorylation-defective HDAC5 mutant (S259A/S498A) blocks ketamine-induced MEF2 activation. Hippocampal knockdown of HDAC5 blocks the antidepressant-like effects of ketamine in rats.","method":"Phospho-specific immunoblotting, GFP-HDAC5 nuclear export imaging, HDAC5-S/A adenovirus, viral-mediated hippocampal knockdown, behavioral assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — phospho-site mutagenesis, in vivo knockdown with behavioral phenotype, multiple orthogonal methods; consistent with established HDAC5 phosphorylation biology","pmids":["26647181"],"is_preprint":false},{"year":2015,"finding":"Filamin A interacts with HDAC5 via its C-terminal domain and is required for HDAC5-dependent tubulin deacetylation at the injury site. Filamin A axonal expression increases after nerve injury in a protein synthesis-dependent manner. Disruption of the HDAC5–filamin A interaction prevents injury-induced tubulin deacetylation and reduces axon regeneration.","method":"Co-immunoprecipitation, filamin A knockdown, axon regeneration assay, acetylated tubulin immunostaining","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies interaction, knockdown with defined molecular and functional phenotype, single lab","pmids":["26157139"],"is_preprint":false},{"year":2015,"finding":"AMPK loss in muscle does not affect HDAC5 phosphorylation during exercise; instead, compensatory PKD activation (32.6% increase) maintains HDAC5 phosphorylation. When HDAC5 phosphorylation is blocked in the context of active PKD, alternative post-transcriptional reduction of HDAC5 mRNA and protein occurs, activating a subset of metabolic genes.","method":"AMPK knockout mouse, exercise protocol, PKD activity assay, C2C12 cell overexpression, metabolic gene expression analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic knockout mouse plus cell-based mechanistic studies, single lab","pmids":["24732133"],"is_preprint":false},{"year":2016,"finding":"HDAC5 physically interacts with LSD1 through its domain containing nuclear localization sequence and phosphorylation sites. HDAC5 stabilizes LSD1 protein and promotes USP28 (a deubiquitinase of LSD1) protein stability, decreasing LSD1 ubiquitination/degradation. Loss of HDAC5 diminishes LSD1 demethylase activity and reduces H3K4me1/me2 nuclear levels.","method":"Co-immunoprecipitation, HDAC5 deletion mutants, in vitro acetylation assays, siRNA knockdown, LSD1 ubiquitination assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with deletion mapping, ubiquitination/acetylation assays, siRNA, single lab","pmids":["27212032"],"is_preprint":false},{"year":2017,"finding":"Dephosphorylated, nuclear HDAC5 in the nucleus accumbens associates with an activity-sensitive enhancer of the Npas4 gene and negatively regulates NPAS4 expression. HDAC5 nuclear activity reduces cocaine reward-context associations; conditional Npas4 deletion in NAc reduces cocaine CPP and delayed drug-reinforced learning.","method":"Chromatin immunoprecipitation, conditional Npas4 knockout, viral-mediated HDAC5 overexpression, cocaine self-administration and CPP behavioral paradigms","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 2 / Strong — ChIP identifies HDAC5 at Npas4 enhancer, conditional KO with specific behavioral phenotype, multiple experimental approaches in single study","pmids":["28957664"],"is_preprint":false},{"year":2017,"finding":"Fasting glucagon promotes dephosphorylation and nuclear translocation of HDAC5 in liver. Nuclear HDAC5 interacts with PPARα and promotes PPARα transcriptional activity and fatty acid oxidation gene expression. ER stress activates CaMKII-mediated phosphorylation of HDAC5, causing its cytoplasmic retention and impairing fatty acid oxidation. A phosphorylation-deficient HDAC5 mutant (2SA) protects against hepatic steatosis in HFD-fed mice.","method":"HDAC5 co-immunoprecipitation with PPARα, liver-specific HDAC5 overexpression/knockdown, phospho-deficient HDAC5 2SA mutant mouse, HFD model, gene expression analysis","journal":"Journal of lipid research","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifies PPARα as binding partner, phospho-mutant defines mechanism, in vivo overexpression/knockdown with metabolic phenotype","pmids":["29229738"],"is_preprint":false},{"year":2017,"finding":"β-Adrenergic stimulation induces HDAC5 nuclear accumulation in cardiomyocytes via a β1-AR/PKA-dependent mechanism. This requires B55α-PP2A-mediated dephosphorylation of Ser259/Ser498 (not Ser279). Co-immunoprecipitation revealed a specific HDAC5–B55α interaction that increases >3-fold with isoproterenol. B55α knockdown attenuates isoproterenol-induced HDAC5 dephosphorylation.","method":"3D confocal microscopy, site-directed mutagenesis (Ser259/279/498), pharmacological PKA/PP2A inhibitors, Co-IP, B55α siRNA knockdown","journal":"Journal of the American Heart Association","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP identifies B55α as PP2A targeting subunit for HDAC5, phospho-site mutagenesis, 3D imaging, siRNA validation; multiple orthogonal methods","pmids":["28343149"],"is_preprint":false},{"year":2018,"finding":"CD13 interacts with HDAC5 via co-immunoprecipitation to promote HDAC5 protein stability. Stabilized HDAC5 then deacetylates LSD1, promoting LSD1 stability, which decreases NF-κB p65 methylation and increases p65 stability, activating NF-κB signaling.","method":"Co-immunoprecipitation, LC-MS/MS proteomic analysis, LSD1 deacetylation assay, p65 methylation assay","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus MS identification, deacetylation/methylation assays; single lab","pmids":["33377659"],"is_preprint":false},{"year":2018,"finding":"HDAC5 interacts with GCM1 transcription factor in placental cells, facilitating GCM1 deacetylation and suppression of its transcriptional activity and syncytin-1 expression/cell fusion. Epac1/Rap1/CaMKI signaling phosphorylates HDAC5 at Ser259/Ser498, causing its nuclear export and de-repression of GCM1 activity.","method":"Co-immunoprecipitation, immunofluorescence co-localization, phospho-specific antibodies, RNA interference, cell fusion assay, constitutively active Epac1/CaMKI constructs","journal":"Molecular human reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and phospho-site specific evidence with functional cell fusion readout, single lab","pmids":["23867755"],"is_preprint":false},{"year":2018,"finding":"KSHV viral IRF3 (vIRF3) physically interacts with HDAC5 (identified by mass spectrometry) and blocks phosphorylation-dependent cytoplasmic translocation of HDAC5 in lymphatic endothelial cells (LECs), altering global gene expression specifically in LECs (not BECs) and inducing hypersprouting/lymphangiogenesis.","method":"Co-immunoprecipitation, mass spectrometry, immunofluorescence, ΔvIRF3 KSHV mutant infection, gene expression analysis","journal":"mBio","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-confirmed interaction, viral mutant validation, cell-type specific phenotype; single lab","pmids":["29339432"],"is_preprint":false},{"year":2018,"finding":"HDAC5 deacetylates SOX9, which is required for SOX9 nuclear translocation in tamoxifen-resistant breast cancer cells. HDAC5 physically interacts with SOX9 as shown by co-immunoprecipitation. C-MYC transcriptionally promotes HDAC5 expression in resistant cells.","method":"Co-immunoprecipitation, acetylation immunoprecipitation, subcellular fractionation, qRT-PCR, siRNA knockdown","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP plus acetylation assay defining HDAC5 as the specific deacetylase for SOX9, single lab","pmids":["31690832"],"is_preprint":false},{"year":2019,"finding":"HDAC4 and HDAC5 form a complex with DREAM transcription factor that is recruited to the ncx3 promoter, causing histone deacetylation and NCX3 gene silencing after stroke. DREAM knockdown prevents HDAC4/5 recruitment to the ncx3 promoter. Pharmacological class IIa HDAC inhibition (MC1568) increases NCX3 expression and reduces neuronal stroke damage.","method":"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, in vitro OGD model, in vivo tMCAO rat model, class IIa HDAC inhibitor","journal":"Journal of cerebral blood flow and metabolism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, siRNA in vitro and in vivo models, single lab","pmids":["31696766"],"is_preprint":false},{"year":2019,"finding":"PTHrP inhibits chondrocyte hypertrophy partly through HDAC5. In mice, HDAC5 KO in addition to HDAC4 KO is required to fully block PTHrP action on chondrocyte differentiation at birth. PTHrP reduces HDAC4 phosphorylation at 14-3-3-binding sites and promotes nuclear translocation of HDAC4/5, which then repress MEF2 activity and Runx2 mRNA expression needed for hypertrophy.","method":"Multiple mouse genetic knockout models (Hdac4-KO, Hdac5-KO, double-KO), PTHrP-KO epistasis, phospho-immunoblotting, immunofluorescence","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo double genetic KO epistasis establishes HDAC5 as mediator of PTHrP signaling, replicated in multiple mouse models within single study","pmids":["30843886"],"is_preprint":false},{"year":2019,"finding":"FAK directly phosphorylates HDAC5 at tyrosine 642, a post-translational modification that controls HDAC5 subcellular localization in osteocytes. Fluid flow shear stress triggers FAK dephosphorylation, driving class IIa HDAC (HDAC4/5) nuclear translocation, which is required for loading-induced SOST suppression and bone formation.","method":"Phospho-tyrosine immunoblotting, FAK catalytic inhibitor (in vitro and in vivo), site-directed mutagenesis of Tyr642, Ocy454 cell line FFSS model, mouse loading model","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct PTM identification (Y642 phosphorylation by FAK), pharmacological FAK inhibition in vitro and in vivo, site-directed mutagenesis, multiple orthogonal methods","pmids":["32612176"],"is_preprint":false},{"year":2019,"finding":"HDAC5 promotes optic nerve regeneration in RGCs when in its cytoplasmic form. An HDAC5 mutant with Ser259/488 replaced by Ala (predominantly cytoplasmic) stimulates RGC survival and optic nerve regeneration in vivo by activating the mTOR pathway, an effect not seen with wild-type HDAC5.","method":"AAV-mediated in vivo HDAC5 and HDAC5AA expression in RGCs, optic nerve crush model, mTOR pathway immunoblotting, immunofluorescence of pS6/RGC markers","journal":"Experimental neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic manipulation with defined molecular pathway (mTOR activation), single lab","pmids":["30910408"],"is_preprint":false},{"year":2019,"finding":"HDAC5 regulates SOX10 expression by directly binding to the promoter region of the Sox10 gene (as shown by ChIP), thereby upregulating SOX10 and promoting spinal neuronal sensitization in neuropathic pain models.","method":"Chromatin immunoprecipitation (ChIP), lentiviral HDAC5 overexpression/knockdown, mechanical allodynia/thermal hyperalgesia behavioral testing, immunoblotting","journal":"Pain","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP demonstrates direct promoter binding, lentiviral gain/loss-of-function with behavioral phenotype, single lab","pmids":["29447134"],"is_preprint":false},{"year":2020,"finding":"HDAC5 regulates PD-L1 expression by directly interacting with NF-κB p65 and deacetylating p65 at lysine-310, which reduces p65 transcriptional activity. This interaction is suppressed by p65 phosphorylation at serine-311. HDAC5 silencing/inhibition sensitizes pancreatic cancer to immune checkpoint blockade in syngeneic and KPC mouse models.","method":"Co-immunoprecipitation, p65 deacetylation assay, phospho-mutant p65, syngeneic/KPC allograft tumor models, immune checkpoint blockade combination treatment","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct deacetylation assay for p65-K310, Co-IP, phospho-mutant dissection, in vivo syngeneic models; multiple orthogonal methods","pmids":["35265200"],"is_preprint":false},{"year":2020,"finding":"Cyclic AMP (cAMP)/PKA signaling causes nuclear retention and hypo-phosphorylation of HDAC5 (at Ser259/498) and HDAC9 in cardiomyocytes but not non-myocytes, via PKA-dependent inhibition of PKD. Endogenous HDAC5 (but not HDAC9) specifically contributes to repression of endogenous MEF2 activity; cardiomyocytes deficient in both HDAC5 and HDAC4 show blunted cAMP-induced repression of cellular hypertrophy.","method":"HDAC5/HDAC9/HDAC4 knockout neonatal cardiomyocytes, 3D confocal localization imaging, PKD inhibition, MEF2 reporter assay, cell size measurement","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic HDAC mouse models used to dissect endogenous contributions, multiple orthogonal methods (imaging, reporter, PKD inhibition), single lab with strong experimental design","pmids":["32485181"],"is_preprint":false},{"year":2021,"finding":"HDAC5 interacts with RB tumor suppressor through an FXXXV motif (with RB-N) and also with RB-C; these interactions are diminished by RB phosphorylation at Ser249/Thr252 and Thr821. HDAC5 loss increases H3K27 acetylation and circumvents RB-mediated repression of cell-cycle-related pro-oncogenic genes, conferring CDK4/6 inhibitor resistance.","method":"Co-immunoprecipitation, HDAC5 LXCXE/FXXXV motif mutagenesis, H3K27ac ChIP, HDAC5 KO in prostate/breast cancer cells and in vivo xenograft models","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — motif mutagenesis defines interaction surfaces, ChIP quantifies downstream histone acetylation, in vitro and in vivo genetic models, single rigorous study","pmids":["33419772"],"is_preprint":false},{"year":2022,"finding":"HDAC5 deacetylates GATA1, which represses cPLA2 expression. HDAC5 knockdown results in hyperacetylation of GATA1, enabling upregulation of cPLA2 and overproduction of arachidonic acid (AA) in pancreatic cancer. This renders HDAC5-deficient tumors sensitive to cPLA2 inhibition.","method":"GATA1 acetylation assay by Co-IP/immunoblot, ChIP, cPLA2 promoter analysis, nontargeted metabolomics, cPLA2 genetic/pharmacologic inhibition, in vivo xenograft/dietary manipulation","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct deacetylation substrate identification (GATA1), ChIP, metabolomics, in vivo models; multiple orthogonal methods","pmids":["36102738"],"is_preprint":false},{"year":2022,"finding":"HDAC5 interacts with MEF2A and suppresses MEF2A binding to the Smad7 promoter, resulting in Smad7 repression, sustained Smad2/3 phosphorylation, and fibroblast activation in hypertrophic scar. LMK235 (HDAC4/5 inhibitor) alleviates scar formation. Smad7 knockdown rescues the phenotype of HDAC5 deficiency.","method":"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP-qPCR), luciferase reporter assay, Smad7 rescue knockdown, in vivo hypertrophic scar model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, ChIP, luciferase reporter, rescue experiment in vivo and in vitro, single lab","pmids":["36263180"],"is_preprint":false},{"year":2022,"finding":"HDAC5 reduces the enrichment of H3K9/K14ac on the miR-142 promoter, suppressing miR-142-5p expression and upregulating ARMC8 in osteosarcoma. METTL3 increases m6A on HDAC5 mRNA, stabilizing it and promoting HDAC5-mediated miR-142 repression and OS cell proliferation.","method":"m6A-methylation assay, HDAC5 knockdown/overexpression, H3K9/K14ac ChIP, miR-142-5p expression analysis, xenograft tumor model","journal":"Cell death discovery","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP defines histone modification substrate, in vivo xenograft model, single lab","pmids":["35396379"],"is_preprint":false},{"year":2025,"finding":"SIK1 phosphorylates HDAC5 at Ser498, promoting its interaction with 14-3-3 protein and protecting it from TRIM28-mediated ubiquitylation/degradation. SIK1-stabilized HDAC5 deacetylates STAT6, enhancing STAT6 transcriptional activity and upregulating SLC7A11, conferring ferroptosis resistance in pancreatic cancer.","method":"In vitro kinase assay (SIK1 phosphorylation of HDAC5), co-immunoprecipitation (14-3-3, TRIM28), STAT6 deacetylation assay, SLC7A11 promoter analysis, organoid and PDX models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — in vitro kinase assay, Co-IP, deacetylation assay with multiple downstream readouts; single lab, preprint-level novelty but peer-reviewed","pmids":["40250791"],"is_preprint":false}],"current_model":"HDAC5 is a signal-responsive class IIa histone deacetylase that functions primarily as a transcriptional co-repressor by binding MEF2 family transcription factors (MEF2A/C) and other partners (p53, PPARα, GATA1, SOX9, YY1, GCM1, RB), with its activity and gene-regulatory output controlled by phosphorylation-dependent nucleocytoplasmic shuttling: kinases including CaMKII, PKD, PKC, FAK, and SIK1 phosphorylate Ser259/Ser498 (and Tyr642) to promote cytoplasmic export, while PP2A/B55α-mediated dephosphorylation drives nuclear retention and MEF2 repression; in the cytoplasm HDAC5 additionally acts as a tubulin deacetylase (promoting axon regeneration via filamin A-dependent activity) and deacetylates non-histone substrates including Hsp70, STAT6, and GATA1, placing HDAC5 at the intersection of calcium signaling, energy sensing (AMPK), mechanical transduction (FAK), and epigenetic control of differentiation, metabolism, and stress responses."},"narrative":{"mechanistic_narrative":"HDAC5 is a signal-responsive class IIa histone deacetylase that functions principally as a transcriptional co-repressor, binding MEF2 family transcription factors through its N-terminal non-deacetylase domain to inhibit their activity in a deacetylase-independent manner [PMID:10748098]. This MEF2 axis governs diverse differentiation and stress programs: HDAC5 represses the PGC-1α promoter to control cardiac mitochondrial biogenesis [PMID:12578979], suppresses a distal SOST enhancer in osteocytes to regulate bone mass [PMID:25271055], and mediates PTHrP repression of chondrocyte hypertrophy [PMID:30843886]. The gene-regulatory output of HDAC5 is set by phosphorylation-dependent nucleocytoplasmic shuttling: multiple kinases—CaMK [PMID:12641737, PMID:20042720], PKD [PMID:19124542], SIK1 [PMID:18946175], PKCα/PKCμ [PMID:21642422, PMID:24209626], and FAK (at Tyr642) [PMID:32612176]—phosphorylate Ser259/Ser498 to drive cytoplasmic export and MEF2 de-repression, while B55α/PP2A-mediated dephosphorylation promotes nuclear retention [PMID:28343149]. Beyond MEF2, HDAC5 acts as a co-repressor or scaffold for numerous partners including GATA1 [PMID:14668799], YY1 [PMID:18632988], p53 [PMID:24120667], PPARα [PMID:29229738], and RB [PMID:33419772]. In the cytoplasm HDAC5 functions as an injury-regulated tubulin deacetylase, acting through filamin A to drive growth cone dynamics and peripheral axon regeneration [PMID:22692128, PMID:26157139]. HDAC5 additionally deacetylates non-histone substrates including p53 at K120 [PMID:24120667], Hsp70 to stabilize HIF-1α [PMID:26061431], NF-κB p65 at K310 [PMID:35265200], GATA1 [PMID:36102738], and STAT6 [PMID:40250791], placing it at the intersection of calcium signaling, energy sensing, mechanotransduction, and epigenetic control of metabolism, differentiation, and stress responses.","teleology":[{"year":2000,"claim":"Established the founding mechanism of HDAC5 as a MEF2 co-repressor and showed, unexpectedly, that repression does not require the catalytic deacetylase domain.","evidence":"Reciprocal Co-IP, domain mapping, and reporter assays defining the HDAC5–MEF2A interaction","pmids":["10748098"],"confidence":"High","gaps":["Mechanism of deacetylase-independent repression not resolved","Did not address how the interaction is regulated by signaling"]},{"year":2003,"claim":"Connected HDAC5 to a physiological output by showing it represses the MEF2/PGC-1α axis controlling cardiac mitochondrial biogenesis, and that signal-resistant HDAC5 produces a defined in vivo phenotype.","evidence":"Transgenic mouse expressing phosphorylation-defective HDAC5 plus PGC-1α promoter analysis","pmids":["12578979"],"confidence":"High","gaps":["Did not identify the kinase(s) normally relieving repression","Restricted to cardiac tissue"]},{"year":2003,"claim":"Demonstrated that signaling (calcium/CaMK) physically relocates HDAC5 between nucleus and cytoplasm, establishing the shuttling paradigm that governs its co-repressor function.","evidence":"Live imaging of GFP-HDAC5 in neurons with calcium channel and CaMK pharmacology; Co-IP/co-localization with GATA1 in erythroleukemia cells","pmids":["12641737","14668799"],"confidence":"High","gaps":["Exact phospho-acceptor residues not yet mapped in these studies","GATA1 work was correlative for differentiation"]},{"year":2005,"claim":"Showed that HDAC5 co-repressor activity is gated by direct protein binding as well as phosphorylation, expanding the regulatory repertoire to G protein and additional transcription factor inputs.","evidence":"Y2H, Co-IP, and MEF2C reporter assays for Gβγ binding; Co-IP and kinase/phosphatase manipulation for YY1, GEF, and AhRR/ANKRA2 partnerships","pmids":["16221676","16822951","17949687","18216015","18632988"],"confidence":"Medium","gaps":["Several partner interactions rest on single-lab Co-IP","Relative physiological weighting of these partners unclear"]},{"year":2009,"claim":"Mapped the regulated phospho-acceptor sites (Ser259/Ser498) and tied diverse upstream signals—shear stress, adrenergic, salt-inducible kinase—to HDAC5 export and target gene activation.","evidence":"Phospho-site mutant (S259A/S498A) analysis with functional readouts in endothelial cells, muscle fibers, and myoblasts; SIK1/GIT1 kinase pathway dissection","pmids":["20042720","18946175","18292392","19124542"],"confidence":"High","gaps":["Combinatorial logic among kinases not fully resolved","Site-specific phosphatase activity not yet defined here"]},{"year":2012,"claim":"Revealed cytoplasmic catalytic functions of HDAC5 distinct from transcriptional repression, including injury-induced tubulin deacetylation driving axon regeneration and a role in heterochromatin replication.","evidence":"In vitro and in vivo nerve injury models with PKC inhibition and acetylated-tubulin readout; RNAi with replication fork and DNA damage assays","pmids":["22692128","22301920","22648949"],"confidence":"High","gaps":["Why peripheral but not central neurons activate the pathway not mechanistically resolved at this stage","Heterochromatin role lacks direct substrate identification"]},{"year":2013,"claim":"Established HDAC5 as a non-histone substrate deacetylase and scaffold, deacetylating p53 at K120 to gate apoptosis and bridging HDAC1/Sin3a co-repressors to cardiac transcription factors.","evidence":"Co-IP, ChIP, acetylation assays, and in vivo knockdown for p53; HDAC5 KO mice with ChIP/Co-IP for Nkx2.5/YY1 scaffolding and alternative splicing","pmids":["24120667","26704971","23424201","24209626"],"confidence":"High","gaps":["Substrate specificity determinants for K120 deacetylation not defined","Scaffold versus catalytic contributions not cleanly separated"]},{"year":2015,"claim":"Defined HDAC5 as a node coupling energy/mechanical signaling to epigenetic and non-histone outputs, including Hsp70 deacetylation stabilizing HIF-1α and filamin A-dependent tubulin deacetylation.","evidence":"AMPK manipulation with Hsp70 deacetylation and HIF-1α fractionation; ChIP at the SOST enhancer with KO mice; filamin A Co-IP and axon regeneration assays","pmids":["26061431","25271055","26157139","24732133"],"confidence":"High","gaps":["Compensation by PKD when AMPK is lost complicates pathway assignment","Direct structural basis of substrate engagement unknown"]},{"year":2017,"claim":"Identified the phosphatase arm of the shuttling switch (B55α/PP2A) and extended the regulatory output to liver fatty acid oxidation via PPARα and to behavioral/addiction circuits via Npas4.","evidence":"Co-IP and B55α knockdown defining the dephosphorylation step; PPARα Co-IP with phospho-mutant mice; ChIP at Npas4 enhancer with conditional KO and behavior","pmids":["28343149","29229738","28957664","26647181"],"confidence":"High","gaps":["Tissue-specific selection of phosphatase versus kinase inputs incompletely mapped","How nuclear HDAC5 distinguishes activating versus repressive partners unclear"]},{"year":2019,"claim":"Added a tyrosine-phosphorylation arm (FAK at Tyr642) controlling localization in mechanically loaded osteocytes and resolved redundancy with HDAC4 across cardiac, skeletal, and developmental contexts.","evidence":"Phospho-Tyr immunoblotting, Tyr642 mutagenesis, and FAK inhibition in vitro and in vivo; HDAC4/HDAC5 single and double KO models","pmids":["32612176","30843886","32485181","31696766","30910408"],"confidence":"High","gaps":["Crosstalk between Ser and Tyr phosphorylation not integrated","Degree of HDAC4/HDAC5 functional overlap is context-dependent and not generalized"]},{"year":2022,"claim":"Cemented HDAC5 as a cancer-relevant deacetylase acting on RB, NF-κB p65, GATA1, and STAT6 to drive proliferation, immune evasion, metabolic rewiring, and therapy resistance.","evidence":"Motif mutagenesis and H3K27ac ChIP for RB; deacetylation assays and in vivo models for p65-K310, GATA1, and SOX9; SIK1/14-3-3/TRIM28 stabilization with STAT6 deacetylation","pmids":["33419772","35265200","36102738","31690832","40250791","30151243","27212032","33377659","35396379"],"confidence":"High","gaps":["Which substrates dominate in a given tumor context unresolved","Catalytic versus scaffolding contributions to oncogenic output not always separated"]},{"year":null,"claim":"How HDAC5 selects among its many partners and substrates within a single cell, and the structural basis for its deacetylase-independent repression, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model for partner/substrate discrimination","Integration of Ser259/Ser498 versus Tyr642 phosphorylation codes not defined","Catalytic versus scaffolding roles not cleanly partitioned across contexts"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[16,19,25,42,45,48]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[0,1,24,19,31,44]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[24,47]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[21,6]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[0,2,3,19,31,32]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,16,25,27,40]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[0,1,24,19,31]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,11,32,39,7]},{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[15,24,44,47]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[1,25,31,45]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[42,44,45,48]}],"complexes":["NuRSERY (HDAC5/GATA1/EKLF/pERK)","HDAC4/5-DREAM complex","AhRR/ANKRA2/HDAC5 co-repressor"],"partners":["MEF2A","MEF2C","GATA1","YY1","P53","PPARA","RB1","FLNA"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UQL6","full_name":"Histone deacetylase 5","aliases":["Antigen NY-CO-9"],"length_aa":1122,"mass_kda":122.0,"function":"Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Serves as a corepressor of RARA and causes its deacetylation (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758)","subcellular_location":"Nucleus; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q9UQL6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/HDAC5","classification":"Not Classified","n_dependent_lines":4,"n_total_lines":1208,"dependency_fraction":0.0033112582781456954},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/HDAC5","total_profiled":1310},"omim":[{"mim_id":"613880","title":"BROMO-ADJACENT HOMOLOGY DOMAIN-CONTAINING PROTEIN 1; BAHD1","url":"https://www.omim.org/entry/613880"},{"mim_id":"613418","title":"BONE MINERAL DENSITY QUANTITATIVE TRAIT LOCUS 15; BMND15","url":"https://www.omim.org/entry/613418"},{"mim_id":"613405","title":"MICRO RNA 2861; MIR2861","url":"https://www.omim.org/entry/613405"},{"mim_id":"611508","title":"CALMODULIN-BINDING TRANSCRIPTION ACTIVATOR 2; CAMTA2","url":"https://www.omim.org/entry/611508"},{"mim_id":"611192","title":"ANKYRIN REPEAT DOMAIN-CONTAINING PROTEIN 11; ANKRD11","url":"https://www.omim.org/entry/611192"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nuclear speckles","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/HDAC5"},"hgnc":{"alias_symbol":["KIAA0600","NY-CO-9","FLJ90614"],"prev_symbol":[]},"alphafold":{"accession":"Q9UQL6","domains":[{"cath_id":"3.40.800.20","chopping":"684-1082","consensus_level":"medium","plddt":94.1878,"start":684,"end":1082}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQL6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQL6-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UQL6-F1-predicted_aligned_error_v6.png","plddt_mean":63.59},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=HDAC5","jax_strain_url":"https://www.jax.org/strain/search?query=HDAC5"},"sequence":{"accession":"Q9UQL6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UQL6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UQL6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UQL6"}},"corpus_meta":[{"pmid":"19920351","id":"PMC_19920351","title":"A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans.","date":"2009","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/19920351","citation_count":389,"is_preprint":false},{"pmid":"12578979","id":"PMC_12578979","title":"Regulation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha ) and mitochondrial function by MEF2 and HDAC5.","date":"2003","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12578979","citation_count":343,"is_preprint":false},{"pmid":"24209626","id":"PMC_24209626","title":"Injury-induced HDAC5 nuclear export is essential for axon regeneration.","date":"2013","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/24209626","citation_count":259,"is_preprint":false},{"pmid":"12641737","id":"PMC_12641737","title":"Neuronal activity-dependent nucleocytoplasmic shuttling of HDAC4 and HDAC5.","date":"2003","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12641737","citation_count":250,"is_preprint":false},{"pmid":"22692128","id":"PMC_22692128","title":"HDAC5 is a novel injury-regulated tubulin deacetylase controlling axon regeneration.","date":"2012","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/22692128","citation_count":178,"is_preprint":false},{"pmid":"10748098","id":"PMC_10748098","title":"mHDA1/HDAC5 histone deacetylase interacts with and represses MEF2A transcriptional activity.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10748098","citation_count":175,"is_preprint":false},{"pmid":"33414476","id":"PMC_33414476","title":"METTL14-regulated PI3K/Akt signaling pathway via PTEN affects HDAC5-mediated epithelial-mesenchymal transition of renal tubular cells in diabetic kidney disease.","date":"2021","source":"Cell death & 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The repression is independent of the HDAC5 deacetylase domain; the N-terminal non-deacetylase domain is sufficient for repression. The MADS box/MEF2-domain region of MEF2A interacts with a limited region in the N-terminal part of HDAC5.\",\n      \"method\": \"Co-immunoprecipitation (in vivo and in vitro), domain mapping, transcriptional reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP (in vivo and in vitro), domain-mapping mutagenesis, functional reporter assay; replicated in multiple subsequent studies\",\n      \"pmids\": [\"10748098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HDAC5 represses PGC-1α transcription through MEF2-binding sites in the PGC-1α promoter. Transgenic expression of a signal-resistant (phosphorylation-defective) HDAC5 in mouse heart causes loss of cardiac mitochondria, down-regulation of mitochondrial enzymes, and down-regulation of PGC-1α, placing HDAC5 as a repressor of the MEF2/PGC-1α axis controlling cardiac mitochondrial biogenesis.\",\n      \"method\": \"Transgenic mouse model (signal-resistant HDAC5), promoter analysis, transcriptional reporter assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo transgenic model with defined phenotype plus promoter mechanistic analysis; multiple orthogonal methods in single study\",\n      \"pmids\": [\"12578979\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Neuronal activity controls the nucleocytoplasmic distribution of HDAC5 in hippocampal neurons. HDAC5 nuclear export requires stimulation of calcium flux through synaptic NMDA receptors or L-type calcium channels and is sensitive to the CaM kinase inhibitor KN-62, establishing that CaMK signaling drives HDAC5 cytoplasmic translocation in neurons.\",\n      \"method\": \"Live-cell imaging of GFP-tagged HDAC5, pharmacological inhibitors (KN-62), calcium channel blockers\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct localization imaging with functional consequence, multiple pharmacological dissections, replicated across papers\",\n      \"pmids\": [\"12641737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"HDAC5 directly associates with GATA-1 and co-localizes with it in the nucleus of murine erythroleukemia (MEL) cells. Co-expression of HDAC5 suppresses GATA-1 transcriptional activity. During HMBA-induced erythroid differentiation a portion of HDAC5 relocates to the cytoplasm, correlated with de-repression of GATA-1.\",\n      \"method\": \"Co-immunoprecipitation, co-localization by immunofluorescence, transcriptional reporter assay, subcellular fractionation\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and localization data in a single lab, supported by functional reporter assay\",\n      \"pmids\": [\"14668799\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Gβγ subunit of heterotrimeric G proteins directly binds HDAC5 through its C-terminal domain. This interaction occurs in a signal-dependent manner, can be blocked by Gαo overexpression and reversed by α2A-adrenergic receptor activation. Formation of the Gβ1γ2–HDAC5 complex inhibits HDAC5-mediated transcriptional co-repression of MEF2C, indicating that G protein signaling directly controls HDAC5 co-repressor function.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation in mammalian cells, MEF2C transcriptional reporter assay, Gβγ scavenger overexpression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus Co-IP in mammalian cells plus functional reporter, single lab\",\n      \"pmids\": [\"16221676\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"HDAC5 localization in H9C2 cells is controlled by CaMKIV and/or PKD (which maintain cytoplasmic HDAC5 in undifferentiated cells) and by PP2A phosphatase (which promotes nuclear HDAC5 in differentiated cells). In differentiated cells, nuclear HDAC5 interacts with YY1 transcription factor and is required for YY1 repressor function.\",\n      \"method\": \"GFP-fusion live imaging, co-immunoprecipitation, dominant-negative kinase/phosphatase constructs\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell localization imaging with mechanistic follow-up (Co-IP, kinase/phosphatase inhibition), single lab\",\n      \"pmids\": [\"16822951\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"HDAC5 is recruited as a co-repressor to the CYP1A1 promoter via interaction with AhRR and the adaptor protein ANKRA2 (which bridges HDAC4/5 to AhRR). RNA interference of ANKRA2 or AhRR reduces this repression, establishing an AhRR/ANKRA2/HDAC5 co-repressor axis.\",\n      \"method\": \"Yeast two-hybrid, RNAi knockdown, chromatin immunoprecipitation, transcriptional reporter assay\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid identification, functional siRNA validation, ChIP confirmation, single lab\",\n      \"pmids\": [\"17949687\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SIK1 (salt-inducible kinase 1) phosphorylates HDAC5 causing its nuclear export and activation of MEF2C in AICAR-treated C2C12 myoblasts. GSK-3β contributes to sustained SIK1 activity, and this pathway drives PGC-1α expression in a HDAC5/MEF2C-dependent manner.\",\n      \"method\": \"In vitro kinase assay, GFP-HDAC5 nuclear export imaging, dominant-negative constructs, pharmacological inhibitors\",\n      \"journal\": \"Endocrine journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay plus live imaging, single lab\",\n      \"pmids\": [\"18946175\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"YY1 transcription factor interacts with HDAC5 via the HDAC5 phosphorylation domain and prevents HDAC5 nuclear export in response to hypertrophic stimuli in cardiac myocytes. The interaction is required for YY1 to function as a transcription repressor; YY1 overexpression reduces HDAC5 phosphorylation in response to hypertrophic stimuli.\",\n      \"method\": \"Co-immunoprecipitation, GFP-HDAC5 localization, siRNA knockdown, dominant-negative and deletion constructs, luciferase reporter assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, live-cell localization, and functional reporter; single lab with multiple methods\",\n      \"pmids\": [\"18632988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"GIT1 scaffold protein mediates Ang II-induced phosphorylation of HDAC5 at Ser498 in vascular smooth muscle cells through a Src–PLCγ–CaMKII signaling pathway. Knockdown of GIT1 decreases Ang II-induced HDAC5 phosphorylation and MEF2 transcriptional activity.\",\n      \"method\": \"siRNA knockdown, phospho-specific antibodies, co-immunoprecipitation of GIT1-CaMKII, MEF2 reporter assays\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, targeted siRNA knockdown, phospho-site specific antibody validation, single lab\",\n      \"pmids\": [\"18292392\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"HDAC5 interacts with GEF (GLUT4 enhancer factor) in the absence of MEF2 proteins and specifically inhibits GLUT4 promoter activity through this interaction.\",\n      \"method\": \"Co-immunoprecipitation, GLUT4 promoter luciferase reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — single Co-IP plus reporter assay, single lab\",\n      \"pmids\": [\"18216015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Fluid shear stress stimulates CaMK-dependent phosphorylation of HDAC5 at Ser259/Ser498 and its nuclear export in endothelial cells, causing dissociation from MEF2 and MEF2-driven expression of KLF2 and eNOS. A phosphorylation-defective HDAC5 mutant (S259A/S498A) blocks these effects and attenuates the anti-inflammatory response.\",\n      \"method\": \"Adenoviral overexpression of HDAC5-S/A mutant, phospho-specific immunoblotting, MEF2 reporter assay, cell adhesion assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-site mutagenesis with defined functional phenotype, multiple orthogonal readouts; consistent with independent replications in other systems\",\n      \"pmids\": [\"20042720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Alpha-adrenergic receptor activation by phenylephrine causes PKD-dependent HDAC5 nuclear efflux in slow soleus skeletal muscle fibers. PKD1 redistribution and HDAC5 export are transient (reflecting receptor desensitization), whereas phorbol ester (PMA) causes continuous PKD-dependent export. This HDAC5 export increases histone H3 acetylation and MEF2 reporter activity.\",\n      \"method\": \"Live-cell imaging of HDAC5-GFP and PKD1-mPlum in isolated adult muscle fibers, pharmacological inhibition, histone acetylation immunoblot, MEF2 reporter assay\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell localization with functional readouts, single lab, multiple methods\",\n      \"pmids\": [\"19124542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In vascular smooth muscle cells (VSMCs), CaMKIIδ2 mediates Ca2+-dependent phosphorylation of both HDAC4 and HDAC5 in response to AngII and PDGF. HDAC5 regulation depends on HDAC4: suppression of HDAC4 expression and activity prevents AngII/PDGF-dependent phosphorylation of HDAC5. This regulates MEF2 DNA-binding and target gene expression (Nur77, MCP1).\",\n      \"method\": \"CaMKIIδ2 siRNA/dominant-negative, HDAC4 siRNA, phospho-HDAC immunoblots, MEF2 DNA-binding ELISA, qPCR\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"22360269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Calpain-generated free catalytic domain of PKCα (PKCα-CT) constitutively localizes to nuclei and directly drives nucleocytoplasmic shuttling of HDAC5, inducing MEF2-dependent inflammatory pathway gene expression. This occurs independently of PKD, which is required for receptor-mediated (phorbol ester) HDAC5 export.\",\n      \"method\": \"Confocal imaging of nuclear/cytoplasmic HDAC5, adenoviral PKCα-CT expression, PKD inhibition, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging plus mechanistic kinase dissection, single lab\",\n      \"pmids\": [\"21642422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HDAC5 is associated with actively replicating pericentric heterochromatin during late S phase. RNAi-mediated depletion of HDAC5 disrupts heterochromatin structure, slows replication forks, triggers DNA damage checkpoint activation, and induces autophagy and apoptosis in cancer cells in vitro and in vivo.\",\n      \"method\": \"RNAi knockdown, BrdU incorporation/replication fork assay, immunofluorescence, xenograft tumor assay\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi with defined molecular and cellular phenotype, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"22301920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"HDAC5 functions as an injury-regulated tubulin deacetylase in peripheral neurons. Axon injury induces calcium influx that activates PKC-mediated HDAC5 activity at the injury site, leading to localized tubulin deacetylation. This is required for growth cone dynamics and axon regeneration in vitro and in vivo; central neurons fail to activate this pathway.\",\n      \"method\": \"In vitro axon regeneration assays, in vivo sciatic nerve injury model, pharmacological PKC inhibition, HDAC5 knockdown/overexpression, acetylated tubulin immunostaining\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vitro and in vivo loss-of-function with defined molecular substrate (tubulin deacetylation), multiple orthogonal methods\",\n      \"pmids\": [\"22692128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"NOX2-derived reactive oxygen species (ROS) drive HDAC5 nuclear efflux during intense (50 Hz) repetitive stimulation of fast skeletal muscle fibers. This is completely blocked by ROS scavenger NAC and absent in NOX2 knockout fibers, in contrast to HDAC4 efflux which is additionally regulated by CaMK.\",\n      \"method\": \"GFP-HDAC5 live imaging in isolated muscle fibers, NAC scavenger treatment, NOX2 knockout mice, KN-62 CaMK inhibition\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout plus pharmacological inhibition with direct imaging readout, mechanistically dissects ROS vs. CaMK contributions\",\n      \"pmids\": [\"22648949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Axon injury in peripheral sensory neurons elicits a back-propagating calcium wave that causes PKCμ-dependent nuclear export of HDAC5, thereby enhancing histone acetylation and activating a pro-regenerative gene-expression program. A nuclear-trapped HDAC5 mutant prevents axon regeneration; enhancing HDAC5 nuclear export promotes regeneration in vitro and in vivo. This pathway fails to activate in central nervous system injury.\",\n      \"method\": \"Calcium imaging, PKCμ inhibition/knockdown, HDAC5 nuclear-trap mutant expression, in vivo sciatic nerve injury regeneration assay, gene expression profiling\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic dissection (calcium → PKCμ → HDAC5 nuclear export) with in vitro and in vivo loss-of-function, nuclear-trap mutant, multiple readouts; high-impact venue\",\n      \"pmids\": [\"24209626\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HDAC5 binds to p53 and abrogates acetylation of p53 at K120. This prevents p53 recruitment to pro-apoptotic gene promoters at early phases of genotoxic stress, promoting arrest/antioxidant gene expression. Upon prolonged stress, HDAC5 undergoes nuclear export, p53 becomes K120-acetylated, and pro-apoptotic genes are selectively transactivated.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, acetylation assays, HDAC5 knockdown in mice, gene expression analysis\",\n      \"journal\": \"Molecular cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct Co-IP, ChIP, acetylation assay, in vivo mouse knockdown, multiple orthogonal methods establishing mechanism of p53 K120 deacetylation by HDAC5\",\n      \"pmids\": [\"24120667\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HDAC5 interacts with Tbx3 transcription factor via two critical motifs (585LFSYPYT591 and 604HRH606) and mediates Tbx3-driven repression of E-cadherin and HCC cell migration/metastasis. An HDAC inhibitor blocks Tbx3-mediated E-cadherin downregulation.\",\n      \"method\": \"Glycine scan mutagenesis, deletion assays, co-immunoprecipitation, E-cadherin promoter reporter, in vitro migration assay, in vivo metastasis assay\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus mutagenesis plus functional assays in vitro and in vivo, single lab\",\n      \"pmids\": [\"30151243\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HDAC5 is required for the interaction of HDAC1/2/Sin3a co-repressor complexes with transcription factors Nkx2.5 and YY1 at the Ncx1 and Bnp promoters in heart. HDAC5 knockout prevents pressure overload-induced Ncx1 upregulation and prevents recruitment of HDAC1/Sin3a co-repressor to these promoters, supporting a non-canonical scaffolding role for HDAC5.\",\n      \"method\": \"HDAC5 knockout mouse, pressure overload model, co-immunoprecipitation, chromatin immunoprecipitation\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with ChIP and Co-IP, single lab, novel mechanism of scaffold function\",\n      \"pmids\": [\"26704971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HDAC5-deficient mice have reduced cardiac PTB protein abundance. HDAC inhibition in myocytes reduces cFLIP expression, enabling caspase-dependent PTB cleavage. This pathway controls alternative splicing of tropomyosin-1, tropomyosin-2, and MEF2 in the developing heart.\",\n      \"method\": \"HDAC5 knockout mouse, cFLIP overexpression, caspase inhibition, in vitro caspase cleavage assay, RT-PCR for alternative splicing\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with defined molecular cascade and splicing phenotype, single lab\",\n      \"pmids\": [\"23424201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"HDAC5 in erythroid cells forms a novel complex (NuRSERY) with GATA1, EKLF, and pERK, as identified by pull-down experiments. ERK phosphorylation is required for complex formation; inhibition of ERK phosphorylation reduces nuclear content of HDAC5, GATA1, and EKLF by >90%. The complex is erythroid-specific and regulates globin gene expression.\",\n      \"method\": \"Co-immunoprecipitation/pulldown, pharmacological ERK inhibition, class IIa-selective HDAC inhibitor, RT-PCR for globin expression\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies complex, ERK inhibition validates requirement, functional globin readout, single lab\",\n      \"pmids\": [\"24594363\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HDAC5 negatively regulates sclerostin (SOST) expression in osteocytes by binding and inhibiting MEF2C. ChIP mapping identified MEF2C binding at a distal SOST enhancer 45 kb downstream of the transcription start site. HDAC5 deficiency increases MEF2C chromatin association at this enhancer, increases H3K27ac, and decreases NCoR/HDAC3 co-repressor recruitment. HDAC5 knockout mice show increased SOST mRNA and sclerostin protein, decreased Wnt activity, and reduced bone mass.\",\n      \"method\": \"HDAC5 shRNA/overexpression, HDAC5 knockout mice, chromatin immunoprecipitation (ChIP), MEF2C knockdown rescue experiment\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP mapping, genetic KO mouse, shRNA rescue with MEF2C double KD, multiple orthogonal methods in single study\",\n      \"pmids\": [\"25271055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"HDAC5 deacetylates cytosolic Hsp70, which reduces Hsp70 affinity for HIF-1α, thereby decreasing HIF-1α degradation and enabling its nuclear accumulation. AMPK activation promotes cytoplasmic shuttling of HDAC5 which is necessary for this activity under hypoxia or low glucose. HDAC5 knockdown impairs hypoxia-induced HIF-1α accumulation.\",\n      \"method\": \"HDAC5 knockdown/overexpression, Hsp70 co-immunoprecipitation, acetylation assay of Hsp70, AMPK inhibition, HIF-1α nuclear fractionation\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct substrate identification (Hsp70 deacetylation) plus functional consequence on HIF-1α, single lab\",\n      \"pmids\": [\"26061431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Ketamine rapidly stimulates HDAC5 phosphorylation and nuclear export in rat hippocampal neurons through CaMKII- and PKD-dependent pathways, enhancing MEF2 transcriptional activity. A phosphorylation-defective HDAC5 mutant (S259A/S498A) blocks ketamine-induced MEF2 activation. Hippocampal knockdown of HDAC5 blocks the antidepressant-like effects of ketamine in rats.\",\n      \"method\": \"Phospho-specific immunoblotting, GFP-HDAC5 nuclear export imaging, HDAC5-S/A adenovirus, viral-mediated hippocampal knockdown, behavioral assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phospho-site mutagenesis, in vivo knockdown with behavioral phenotype, multiple orthogonal methods; consistent with established HDAC5 phosphorylation biology\",\n      \"pmids\": [\"26647181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Filamin A interacts with HDAC5 via its C-terminal domain and is required for HDAC5-dependent tubulin deacetylation at the injury site. Filamin A axonal expression increases after nerve injury in a protein synthesis-dependent manner. Disruption of the HDAC5–filamin A interaction prevents injury-induced tubulin deacetylation and reduces axon regeneration.\",\n      \"method\": \"Co-immunoprecipitation, filamin A knockdown, axon regeneration assay, acetylated tubulin immunostaining\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies interaction, knockdown with defined molecular and functional phenotype, single lab\",\n      \"pmids\": [\"26157139\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"AMPK loss in muscle does not affect HDAC5 phosphorylation during exercise; instead, compensatory PKD activation (32.6% increase) maintains HDAC5 phosphorylation. When HDAC5 phosphorylation is blocked in the context of active PKD, alternative post-transcriptional reduction of HDAC5 mRNA and protein occurs, activating a subset of metabolic genes.\",\n      \"method\": \"AMPK knockout mouse, exercise protocol, PKD activity assay, C2C12 cell overexpression, metabolic gene expression analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout mouse plus cell-based mechanistic studies, single lab\",\n      \"pmids\": [\"24732133\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"HDAC5 physically interacts with LSD1 through its domain containing nuclear localization sequence and phosphorylation sites. HDAC5 stabilizes LSD1 protein and promotes USP28 (a deubiquitinase of LSD1) protein stability, decreasing LSD1 ubiquitination/degradation. Loss of HDAC5 diminishes LSD1 demethylase activity and reduces H3K4me1/me2 nuclear levels.\",\n      \"method\": \"Co-immunoprecipitation, HDAC5 deletion mutants, in vitro acetylation assays, siRNA knockdown, LSD1 ubiquitination assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with deletion mapping, ubiquitination/acetylation assays, siRNA, single lab\",\n      \"pmids\": [\"27212032\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Dephosphorylated, nuclear HDAC5 in the nucleus accumbens associates with an activity-sensitive enhancer of the Npas4 gene and negatively regulates NPAS4 expression. HDAC5 nuclear activity reduces cocaine reward-context associations; conditional Npas4 deletion in NAc reduces cocaine CPP and delayed drug-reinforced learning.\",\n      \"method\": \"Chromatin immunoprecipitation, conditional Npas4 knockout, viral-mediated HDAC5 overexpression, cocaine self-administration and CPP behavioral paradigms\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — ChIP identifies HDAC5 at Npas4 enhancer, conditional KO with specific behavioral phenotype, multiple experimental approaches in single study\",\n      \"pmids\": [\"28957664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Fasting glucagon promotes dephosphorylation and nuclear translocation of HDAC5 in liver. Nuclear HDAC5 interacts with PPARα and promotes PPARα transcriptional activity and fatty acid oxidation gene expression. ER stress activates CaMKII-mediated phosphorylation of HDAC5, causing its cytoplasmic retention and impairing fatty acid oxidation. A phosphorylation-deficient HDAC5 mutant (2SA) protects against hepatic steatosis in HFD-fed mice.\",\n      \"method\": \"HDAC5 co-immunoprecipitation with PPARα, liver-specific HDAC5 overexpression/knockdown, phospho-deficient HDAC5 2SA mutant mouse, HFD model, gene expression analysis\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifies PPARα as binding partner, phospho-mutant defines mechanism, in vivo overexpression/knockdown with metabolic phenotype\",\n      \"pmids\": [\"29229738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"β-Adrenergic stimulation induces HDAC5 nuclear accumulation in cardiomyocytes via a β1-AR/PKA-dependent mechanism. This requires B55α-PP2A-mediated dephosphorylation of Ser259/Ser498 (not Ser279). Co-immunoprecipitation revealed a specific HDAC5–B55α interaction that increases >3-fold with isoproterenol. B55α knockdown attenuates isoproterenol-induced HDAC5 dephosphorylation.\",\n      \"method\": \"3D confocal microscopy, site-directed mutagenesis (Ser259/279/498), pharmacological PKA/PP2A inhibitors, Co-IP, B55α siRNA knockdown\",\n      \"journal\": \"Journal of the American Heart Association\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP identifies B55α as PP2A targeting subunit for HDAC5, phospho-site mutagenesis, 3D imaging, siRNA validation; multiple orthogonal methods\",\n      \"pmids\": [\"28343149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CD13 interacts with HDAC5 via co-immunoprecipitation to promote HDAC5 protein stability. Stabilized HDAC5 then deacetylates LSD1, promoting LSD1 stability, which decreases NF-κB p65 methylation and increases p65 stability, activating NF-κB signaling.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS proteomic analysis, LSD1 deacetylation assay, p65 methylation assay\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus MS identification, deacetylation/methylation assays; single lab\",\n      \"pmids\": [\"33377659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC5 interacts with GCM1 transcription factor in placental cells, facilitating GCM1 deacetylation and suppression of its transcriptional activity and syncytin-1 expression/cell fusion. Epac1/Rap1/CaMKI signaling phosphorylates HDAC5 at Ser259/Ser498, causing its nuclear export and de-repression of GCM1 activity.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, phospho-specific antibodies, RNA interference, cell fusion assay, constitutively active Epac1/CaMKI constructs\",\n      \"journal\": \"Molecular human reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and phospho-site specific evidence with functional cell fusion readout, single lab\",\n      \"pmids\": [\"23867755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"KSHV viral IRF3 (vIRF3) physically interacts with HDAC5 (identified by mass spectrometry) and blocks phosphorylation-dependent cytoplasmic translocation of HDAC5 in lymphatic endothelial cells (LECs), altering global gene expression specifically in LECs (not BECs) and inducing hypersprouting/lymphangiogenesis.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, immunofluorescence, ΔvIRF3 KSHV mutant infection, gene expression analysis\",\n      \"journal\": \"mBio\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-confirmed interaction, viral mutant validation, cell-type specific phenotype; single lab\",\n      \"pmids\": [\"29339432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"HDAC5 deacetylates SOX9, which is required for SOX9 nuclear translocation in tamoxifen-resistant breast cancer cells. HDAC5 physically interacts with SOX9 as shown by co-immunoprecipitation. C-MYC transcriptionally promotes HDAC5 expression in resistant cells.\",\n      \"method\": \"Co-immunoprecipitation, acetylation immunoprecipitation, subcellular fractionation, qRT-PCR, siRNA knockdown\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP plus acetylation assay defining HDAC5 as the specific deacetylase for SOX9, single lab\",\n      \"pmids\": [\"31690832\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC4 and HDAC5 form a complex with DREAM transcription factor that is recruited to the ncx3 promoter, causing histone deacetylation and NCX3 gene silencing after stroke. DREAM knockdown prevents HDAC4/5 recruitment to the ncx3 promoter. Pharmacological class IIa HDAC inhibition (MC1568) increases NCX3 expression and reduces neuronal stroke damage.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation, siRNA knockdown, in vitro OGD model, in vivo tMCAO rat model, class IIa HDAC inhibitor\",\n      \"journal\": \"Journal of cerebral blood flow and metabolism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, siRNA in vitro and in vivo models, single lab\",\n      \"pmids\": [\"31696766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PTHrP inhibits chondrocyte hypertrophy partly through HDAC5. In mice, HDAC5 KO in addition to HDAC4 KO is required to fully block PTHrP action on chondrocyte differentiation at birth. PTHrP reduces HDAC4 phosphorylation at 14-3-3-binding sites and promotes nuclear translocation of HDAC4/5, which then repress MEF2 activity and Runx2 mRNA expression needed for hypertrophy.\",\n      \"method\": \"Multiple mouse genetic knockout models (Hdac4-KO, Hdac5-KO, double-KO), PTHrP-KO epistasis, phospho-immunoblotting, immunofluorescence\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo double genetic KO epistasis establishes HDAC5 as mediator of PTHrP signaling, replicated in multiple mouse models within single study\",\n      \"pmids\": [\"30843886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FAK directly phosphorylates HDAC5 at tyrosine 642, a post-translational modification that controls HDAC5 subcellular localization in osteocytes. Fluid flow shear stress triggers FAK dephosphorylation, driving class IIa HDAC (HDAC4/5) nuclear translocation, which is required for loading-induced SOST suppression and bone formation.\",\n      \"method\": \"Phospho-tyrosine immunoblotting, FAK catalytic inhibitor (in vitro and in vivo), site-directed mutagenesis of Tyr642, Ocy454 cell line FFSS model, mouse loading model\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct PTM identification (Y642 phosphorylation by FAK), pharmacological FAK inhibition in vitro and in vivo, site-directed mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"32612176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC5 promotes optic nerve regeneration in RGCs when in its cytoplasmic form. An HDAC5 mutant with Ser259/488 replaced by Ala (predominantly cytoplasmic) stimulates RGC survival and optic nerve regeneration in vivo by activating the mTOR pathway, an effect not seen with wild-type HDAC5.\",\n      \"method\": \"AAV-mediated in vivo HDAC5 and HDAC5AA expression in RGCs, optic nerve crush model, mTOR pathway immunoblotting, immunofluorescence of pS6/RGC markers\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic manipulation with defined molecular pathway (mTOR activation), single lab\",\n      \"pmids\": [\"30910408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HDAC5 regulates SOX10 expression by directly binding to the promoter region of the Sox10 gene (as shown by ChIP), thereby upregulating SOX10 and promoting spinal neuronal sensitization in neuropathic pain models.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), lentiviral HDAC5 overexpression/knockdown, mechanical allodynia/thermal hyperalgesia behavioral testing, immunoblotting\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP demonstrates direct promoter binding, lentiviral gain/loss-of-function with behavioral phenotype, single lab\",\n      \"pmids\": [\"29447134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"HDAC5 regulates PD-L1 expression by directly interacting with NF-κB p65 and deacetylating p65 at lysine-310, which reduces p65 transcriptional activity. This interaction is suppressed by p65 phosphorylation at serine-311. HDAC5 silencing/inhibition sensitizes pancreatic cancer to immune checkpoint blockade in syngeneic and KPC mouse models.\",\n      \"method\": \"Co-immunoprecipitation, p65 deacetylation assay, phospho-mutant p65, syngeneic/KPC allograft tumor models, immune checkpoint blockade combination treatment\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct deacetylation assay for p65-K310, Co-IP, phospho-mutant dissection, in vivo syngeneic models; multiple orthogonal methods\",\n      \"pmids\": [\"35265200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Cyclic AMP (cAMP)/PKA signaling causes nuclear retention and hypo-phosphorylation of HDAC5 (at Ser259/498) and HDAC9 in cardiomyocytes but not non-myocytes, via PKA-dependent inhibition of PKD. Endogenous HDAC5 (but not HDAC9) specifically contributes to repression of endogenous MEF2 activity; cardiomyocytes deficient in both HDAC5 and HDAC4 show blunted cAMP-induced repression of cellular hypertrophy.\",\n      \"method\": \"HDAC5/HDAC9/HDAC4 knockout neonatal cardiomyocytes, 3D confocal localization imaging, PKD inhibition, MEF2 reporter assay, cell size measurement\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic HDAC mouse models used to dissect endogenous contributions, multiple orthogonal methods (imaging, reporter, PKD inhibition), single lab with strong experimental design\",\n      \"pmids\": [\"32485181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"HDAC5 interacts with RB tumor suppressor through an FXXXV motif (with RB-N) and also with RB-C; these interactions are diminished by RB phosphorylation at Ser249/Thr252 and Thr821. HDAC5 loss increases H3K27 acetylation and circumvents RB-mediated repression of cell-cycle-related pro-oncogenic genes, conferring CDK4/6 inhibitor resistance.\",\n      \"method\": \"Co-immunoprecipitation, HDAC5 LXCXE/FXXXV motif mutagenesis, H3K27ac ChIP, HDAC5 KO in prostate/breast cancer cells and in vivo xenograft models\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — motif mutagenesis defines interaction surfaces, ChIP quantifies downstream histone acetylation, in vitro and in vivo genetic models, single rigorous study\",\n      \"pmids\": [\"33419772\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC5 deacetylates GATA1, which represses cPLA2 expression. HDAC5 knockdown results in hyperacetylation of GATA1, enabling upregulation of cPLA2 and overproduction of arachidonic acid (AA) in pancreatic cancer. This renders HDAC5-deficient tumors sensitive to cPLA2 inhibition.\",\n      \"method\": \"GATA1 acetylation assay by Co-IP/immunoblot, ChIP, cPLA2 promoter analysis, nontargeted metabolomics, cPLA2 genetic/pharmacologic inhibition, in vivo xenograft/dietary manipulation\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct deacetylation substrate identification (GATA1), ChIP, metabolomics, in vivo models; multiple orthogonal methods\",\n      \"pmids\": [\"36102738\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC5 interacts with MEF2A and suppresses MEF2A binding to the Smad7 promoter, resulting in Smad7 repression, sustained Smad2/3 phosphorylation, and fibroblast activation in hypertrophic scar. LMK235 (HDAC4/5 inhibitor) alleviates scar formation. Smad7 knockdown rescues the phenotype of HDAC5 deficiency.\",\n      \"method\": \"Co-immunoprecipitation, chromatin immunoprecipitation (ChIP-qPCR), luciferase reporter assay, Smad7 rescue knockdown, in vivo hypertrophic scar model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, ChIP, luciferase reporter, rescue experiment in vivo and in vitro, single lab\",\n      \"pmids\": [\"36263180\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"HDAC5 reduces the enrichment of H3K9/K14ac on the miR-142 promoter, suppressing miR-142-5p expression and upregulating ARMC8 in osteosarcoma. METTL3 increases m6A on HDAC5 mRNA, stabilizing it and promoting HDAC5-mediated miR-142 repression and OS cell proliferation.\",\n      \"method\": \"m6A-methylation assay, HDAC5 knockdown/overexpression, H3K9/K14ac ChIP, miR-142-5p expression analysis, xenograft tumor model\",\n      \"journal\": \"Cell death discovery\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP defines histone modification substrate, in vivo xenograft model, single lab\",\n      \"pmids\": [\"35396379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SIK1 phosphorylates HDAC5 at Ser498, promoting its interaction with 14-3-3 protein and protecting it from TRIM28-mediated ubiquitylation/degradation. SIK1-stabilized HDAC5 deacetylates STAT6, enhancing STAT6 transcriptional activity and upregulating SLC7A11, conferring ferroptosis resistance in pancreatic cancer.\",\n      \"method\": \"In vitro kinase assay (SIK1 phosphorylation of HDAC5), co-immunoprecipitation (14-3-3, TRIM28), STAT6 deacetylation assay, SLC7A11 promoter analysis, organoid and PDX models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — in vitro kinase assay, Co-IP, deacetylation assay with multiple downstream readouts; single lab, preprint-level novelty but peer-reviewed\",\n      \"pmids\": [\"40250791\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"HDAC5 is a signal-responsive class IIa histone deacetylase that functions primarily as a transcriptional co-repressor by binding MEF2 family transcription factors (MEF2A/C) and other partners (p53, PPARα, GATA1, SOX9, YY1, GCM1, RB), with its activity and gene-regulatory output controlled by phosphorylation-dependent nucleocytoplasmic shuttling: kinases including CaMKII, PKD, PKC, FAK, and SIK1 phosphorylate Ser259/Ser498 (and Tyr642) to promote cytoplasmic export, while PP2A/B55α-mediated dephosphorylation drives nuclear retention and MEF2 repression; in the cytoplasm HDAC5 additionally acts as a tubulin deacetylase (promoting axon regeneration via filamin A-dependent activity) and deacetylates non-histone substrates including Hsp70, STAT6, and GATA1, placing HDAC5 at the intersection of calcium signaling, energy sensing (AMPK), mechanical transduction (FAK), and epigenetic control of differentiation, metabolism, and stress responses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"HDAC5 is a signal-responsive class IIa histone deacetylase that functions principally as a transcriptional co-repressor, binding MEF2 family transcription factors through its N-terminal non-deacetylase domain to inhibit their activity in a deacetylase-independent manner [#0]. This MEF2 axis governs diverse differentiation and stress programs: HDAC5 represses the PGC-1\\u03b1 promoter to control cardiac mitochondrial biogenesis [#1], suppresses a distal SOST enhancer in osteocytes to regulate bone mass [#24], and mediates PTHrP repression of chondrocyte hypertrophy [#38]. The gene-regulatory output of HDAC5 is set by phosphorylation-dependent nucleocytoplasmic shuttling: multiple kinases\\u2014CaMK [#2, #11], PKD [#12], SIK1 [#7], PKC\\u03b1/PKC\\u03bc [#14, #18], and FAK (at Tyr642) [#39]\\u2014phosphorylate Ser259/Ser498 to drive cytoplasmic export and MEF2 de-repression, while B55\\u03b1/PP2A-mediated dephosphorylation promotes nuclear retention [#32]. Beyond MEF2, HDAC5 acts as a co-repressor or scaffold for numerous partners including GATA1 [#3], YY1 [#8], p53 [#19], PPAR\\u03b1 [#31], and RB [#44]. In the cytoplasm HDAC5 functions as an injury-regulated tubulin deacetylase, acting through filamin A to drive growth cone dynamics and peripheral axon regeneration [#16, #27]. HDAC5 additionally deacetylates non-histone substrates including p53 at K120 [#19], Hsp70 to stabilize HIF-1\\u03b1 [#25], NF-\\u03baB p65 at K310 [#42], GATA1 [#45], and STAT6 [#48], placing it at the intersection of calcium signaling, energy sensing, mechanotransduction, and epigenetic control of metabolism, differentiation, and stress responses.\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established the founding mechanism of HDAC5 as a MEF2 co-repressor and showed, unexpectedly, that repression does not require the catalytic deacetylase domain.\",\n      \"evidence\": \"Reciprocal Co-IP, domain mapping, and reporter assays defining the HDAC5\\u2013MEF2A interaction\",\n      \"pmids\": [\"10748098\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of deacetylase-independent repression not resolved\", \"Did not address how the interaction is regulated by signaling\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected HDAC5 to a physiological output by showing it represses the MEF2/PGC-1\\u03b1 axis controlling cardiac mitochondrial biogenesis, and that signal-resistant HDAC5 produces a defined in vivo phenotype.\",\n      \"evidence\": \"Transgenic mouse expressing phosphorylation-defective HDAC5 plus PGC-1\\u03b1 promoter analysis\",\n      \"pmids\": [\"12578979\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the kinase(s) normally relieving repression\", \"Restricted to cardiac tissue\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that signaling (calcium/CaMK) physically relocates HDAC5 between nucleus and cytoplasm, establishing the shuttling paradigm that governs its co-repressor function.\",\n      \"evidence\": \"Live imaging of GFP-HDAC5 in neurons with calcium channel and CaMK pharmacology; Co-IP/co-localization with GATA1 in erythroleukemia cells\",\n      \"pmids\": [\"12641737\", \"14668799\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Exact phospho-acceptor residues not yet mapped in these studies\", \"GATA1 work was correlative for differentiation\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that HDAC5 co-repressor activity is gated by direct protein binding as well as phosphorylation, expanding the regulatory repertoire to G protein and additional transcription factor inputs.\",\n      \"evidence\": \"Y2H, Co-IP, and MEF2C reporter assays for G\\u03b2\\u03b3 binding; Co-IP and kinase/phosphatase manipulation for YY1, GEF, and AhRR/ANKRA2 partnerships\",\n      \"pmids\": [\"16221676\", \"16822951\", \"17949687\", \"18216015\", \"18632988\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Several partner interactions rest on single-lab Co-IP\", \"Relative physiological weighting of these partners unclear\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapped the regulated phospho-acceptor sites (Ser259/Ser498) and tied diverse upstream signals\\u2014shear stress, adrenergic, salt-inducible kinase\\u2014to HDAC5 export and target gene activation.\",\n      \"evidence\": \"Phospho-site mutant (S259A/S498A) analysis with functional readouts in endothelial cells, muscle fibers, and myoblasts; SIK1/GIT1 kinase pathway dissection\",\n      \"pmids\": [\"20042720\", \"18946175\", \"18292392\", \"19124542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Combinatorial logic among kinases not fully resolved\", \"Site-specific phosphatase activity not yet defined here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Revealed cytoplasmic catalytic functions of HDAC5 distinct from transcriptional repression, including injury-induced tubulin deacetylation driving axon regeneration and a role in heterochromatin replication.\",\n      \"evidence\": \"In vitro and in vivo nerve injury models with PKC inhibition and acetylated-tubulin readout; RNAi with replication fork and DNA damage assays\",\n      \"pmids\": [\"22692128\", \"22301920\", \"22648949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why peripheral but not central neurons activate the pathway not mechanistically resolved at this stage\", \"Heterochromatin role lacks direct substrate identification\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established HDAC5 as a non-histone substrate deacetylase and scaffold, deacetylating p53 at K120 to gate apoptosis and bridging HDAC1/Sin3a co-repressors to cardiac transcription factors.\",\n      \"evidence\": \"Co-IP, ChIP, acetylation assays, and in vivo knockdown for p53; HDAC5 KO mice with ChIP/Co-IP for Nkx2.5/YY1 scaffolding and alternative splicing\",\n      \"pmids\": [\"24120667\", \"26704971\", \"23424201\", \"24209626\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrate specificity determinants for K120 deacetylation not defined\", \"Scaffold versus catalytic contributions not cleanly separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined HDAC5 as a node coupling energy/mechanical signaling to epigenetic and non-histone outputs, including Hsp70 deacetylation stabilizing HIF-1\\u03b1 and filamin A-dependent tubulin deacetylation.\",\n      \"evidence\": \"AMPK manipulation with Hsp70 deacetylation and HIF-1\\u03b1 fractionation; ChIP at the SOST enhancer with KO mice; filamin A Co-IP and axon regeneration assays\",\n      \"pmids\": [\"26061431\", \"25271055\", \"26157139\", \"24732133\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Compensation by PKD when AMPK is lost complicates pathway assignment\", \"Direct structural basis of substrate engagement unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Identified the phosphatase arm of the shuttling switch (B55\\u03b1/PP2A) and extended the regulatory output to liver fatty acid oxidation via PPAR\\u03b1 and to behavioral/addiction circuits via Npas4.\",\n      \"evidence\": \"Co-IP and B55\\u03b1 knockdown defining the dephosphorylation step; PPAR\\u03b1 Co-IP with phospho-mutant mice; ChIP at Npas4 enhancer with conditional KO and behavior\",\n      \"pmids\": [\"28343149\", \"29229738\", \"28957664\", \"26647181\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific selection of phosphatase versus kinase inputs incompletely mapped\", \"How nuclear HDAC5 distinguishes activating versus repressive partners unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Added a tyrosine-phosphorylation arm (FAK at Tyr642) controlling localization in mechanically loaded osteocytes and resolved redundancy with HDAC4 across cardiac, skeletal, and developmental contexts.\",\n      \"evidence\": \"Phospho-Tyr immunoblotting, Tyr642 mutagenesis, and FAK inhibition in vitro and in vivo; HDAC4/HDAC5 single and double KO models\",\n      \"pmids\": [\"32612176\", \"30843886\", \"32485181\", \"31696766\", \"30910408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crosstalk between Ser and Tyr phosphorylation not integrated\", \"Degree of HDAC4/HDAC5 functional overlap is context-dependent and not generalized\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Cemented HDAC5 as a cancer-relevant deacetylase acting on RB, NF-\\u03baB p65, GATA1, and STAT6 to drive proliferation, immune evasion, metabolic rewiring, and therapy resistance.\",\n      \"evidence\": \"Motif mutagenesis and H3K27ac ChIP for RB; deacetylation assays and in vivo models for p65-K310, GATA1, and SOX9; SIK1/14-3-3/TRIM28 stabilization with STAT6 deacetylation\",\n      \"pmids\": [\"33419772\", \"35265200\", \"36102738\", \"31690832\", \"40250791\", \"30151243\", \"27212032\", \"33377659\", \"35396379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which substrates dominate in a given tumor context unresolved\", \"Catalytic versus scaffolding contributions to oncogenic output not always separated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How HDAC5 selects among its many partners and substrates within a single cell, and the structural basis for its deacetylase-independent repression, remain unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model for partner/substrate discrimination\", \"Integration of Ser259/Ser498 versus Tyr642 phosphorylation codes not defined\", \"Catalytic versus scaffolding roles not cleanly partitioned across contexts\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [16, 19, 25, 42, 45, 48]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [0, 1, 24, 19, 31, 44]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [24, 47]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [21, 6]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [0, 2, 3, 19, 31, 32]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 16, 25, 27, 40]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [0, 1, 24, 19, 31]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 11, 32, 39, 7]},\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [15, 24, 44, 47]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [1, 25, 31, 45]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [42, 44, 45, 48]}\n    ],\n    \"complexes\": [\n      \"NuRSERY (HDAC5/GATA1/EKLF/pERK)\",\n      \"HDAC4/5-DREAM complex\",\n      \"AhRR/ANKRA2/HDAC5 co-repressor\"\n    ],\n    \"partners\": [\n      \"MEF2A\",\n      \"MEF2C\",\n      \"GATA1\",\n      \"YY1\",\n      \"p53\",\n      \"PPARA\",\n      \"RB1\",\n      \"FLNA\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}