HDAC5 (Histone Deacetylase 5) Protein

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HDAC5 (Histone Deacetylase 5) Protein

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HDAC5 (Histone Deacetylase 5) Protein

<table class="infobox infobox-protein">
<tr>
<th class="infobox-header" colspan="2">HDAC5 (Histone Deacetylase 5) Protein</th>
</tr>
<tr>
<td class="label">Gene Symbol</td>
<td>HDAC5</td>
</tr>
<tr>
<td class="label">Chromosomal Location</td>
<td>17q21.31</td>
</tr>
<tr>
<td class="label">UniProt ID</td>
<td>Q9UQL6</td>
</tr>
<tr>
<td class="label">Protein Length</td>
<td>1112 amino acids</td>
</tr>
<tr>
<td class="label">Molecular Weight</td>
<td>~112 kDa</td>
</tr>
<tr>
<td class="label">Protein Family</td>
<td>Class IIa histone deacetylases</td>
</tr>
<tr>
<td class="label">Subcellular Localization</td>
<td>Nucleus (basal) and cytoplasm (signal-dependent)</td>
</tr>
<tr>
<td class="label">Target</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">MEF2 (myocyte enhancer factor 2)</td>
<td>Direct binding and repression</td>
</tr>
<tr>
<td class="label">CREB</td>
<td>Co-repressor recruitment</td>
</tr>
<tr>
<td class="label">NF-κB</td>
<td>Deacetylation</td>
</tr>
<tr>
<td class="label">HIF-1α</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">ERα</td>
<td>Interaction</td>
</tr>
<tr>
<td class="label">Compound</td>
<td>Class Selectivity</td>
</tr>
<tr>
<td class="label">Vorinostat (SAHA)</td>
<td>Pan-HDAC (class I > IIa)</td>
</tr>
<tr>
<td class="label">Entinostat (MS-275)</td>
<td>Class I selective (HDAC1-3)</td>
</tr>
<tr>
<td class="label">TSA (Trichostatin A)</td>
<td>Pan-HDAC</td>
</tr>
<tr>
<td class="label">MC1568</td>
<td>Class IIa selective</td>
</tr>
<tr>
<td class="label">Partner</td>
<td>Interaction Type</td>
</tr>
<tr>
<td class="label">MEF2 (MEF2C)</td>
<td>Transcription factor binding</td>
</tr>
<tr>
<td class="label">14-3-3 proteins</td>
<td>Phosphorylation-dependent binding</td>
</tr>
<tr>
<td class="label">CaMK</td>
<td>Phosphorylation</td>
</tr>
<tr>
<td class="label">PKD</td>
<td>Phosphorylation</td>
</tr>
<tr>
<td class="label">NCoR/SMRT</td>
<td>Corepressor complex</td>
</tr>
<tr>
<td class="label">Sin3A</td>
<td>Corepressor complex</td>
</tr>
<tr>
<td class="label">DREAM</td>
<td>Transcription factor complex</td>
</tr>
<tr>
<td class="label">CRM1/Exportin</td>
<td>Nuclear export</td>
</tr>
<tr>
<td class="label">HDAC3</td>
<td>Enzymatic partner</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/carcinoma" style="color:#ef9a9a">Carcinoma</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">39 edges</a></td>
</tr>
</table>

HDAC5 (histone deacetylase 5, encoded by the [HDAC5](/genes/hdac5) gene) is a class IIa histone deacetylase that regulates gene expression through chromatin modification and transcription factor interaction. It is highly expressed in the brain, where it plays critical roles in [synaptic plasticity](/mechanisms/synaptic-plasticity-pathways), memory formation, stress responses, and neuronal survival. HDAC5 is implicated in [Alzheimer's disease](/diseases/alzheimers-disease), [Parkinson's disease](/diseases/parkinsons-disease), depression, and stroke, making it a potential therapeutic target. [@haberland2009]

Gene and Protein Structure

Mermaid diagram (expand to render)

Structural Features

bfe67bb53c3c532ef4237fa3323691ae27404769

N-terminal regulatory domain: Contains binding sites for transcription factors (MEF2, HIC1, CtBP) and importin-alpha binding sites for nuclear-cytoplasmic shuttling. This region contains serine residues (Ser259, Ser498) that are phosphorylated by kinases such as CaMK and PKD

Catalytic deacetylase domain: Located in the C-terminal portion; retains the HD domain but has reduced catalytic activity compared to class I HDACs. The catalytic domain interacts with the N-terminal repressor domain to regulate gene expression

Nuclear localization signal (NLS): Situated near the N-terminus

Nuclear export signal (NES): Located in the C-terminal region

Class IIa Specificity

Class IIa HDACs (HDAC4, HDAC5, HDAC7, HDAC9) differ from class I HDACs (HDAC1-3, 8) in several ways:

They have low intrinsic deacetylase activity and function primarily as transcriptional corepressors through recruitment of other proteins (e.g., NCoR/SMRT complexes, Sin3A)
They shuttle between nucleus and cytoplasm in response to cellular signals (particularly calcium and cAMP)
They have tissue-enriched expression patterns (HDAC5 is enriched in brain, heart, and skeletal muscle)

Normal Function

Chromatin Modification and Gene Regulation

HDAC5 exerts its transcriptional repression effects through multiple mechanisms:

Histone deacetylation: HDAC5 deacetylates histone H3 and H4 tails, creating a chromatin environment that suppresses transcription

Non-histone protein deacetylation: HDAC5 can deacetylate transcription factors (MEF2, p53, NF-κB) and other regulatory proteins

Corepressor complex recruitment: HDAC5 recruits NCoR/SMRT complexes and Sin3A to specific gene promoters

Interaction with HDAC3: HDAC5 forms complexes with class I HDAC3, which provides the actual deacetylase activity

Key Transcriptional Targets

Signal-Dependent Nuclear Export

HDAC5 is a central node in calcium and cAMP signaling to the nucleus:

Activation of CaMK: Synaptic activity and neurotransmitter signaling activate calcium/calmodulin-dependent kinase (CaMK)

Phosphorylation: CaMK (and PKD) phosphorylates HDAC5 at Ser259 and Ser498

14-3-3 binding: Phosphorylated HDAC5 binds 14-3-3 proteins, which mask the NLS and expose the NES

Nuclear export: Exportin CRM1 binds the exposed NES and shuttles HDAC5 to the cytoplasm

Gene derepression: Removal of HDAC5 from chromatin allows activation of HDAC5-repressed genes

Roles in the Healthy Brain

In the healthy brain, HDAC5 regulates:

Synaptic plasticity: Activity-dependent chromatin remodeling at synaptic plasticity genes (c-Fos, BDNF, Arc)
Memory formation: Consolidation of long-term memory through epigenetic regulation of memory-related genes
Neuronal development: Differentiation of neural progenitors and maturation of neurons
Stress responses: Modulation of HPA axis activity and stress resilience
Neurogenesis: Regulation of hippocampal neurogenesis

Role in Alzheimer's Disease

HDAC5 is dysregulated in [Alzheimer's disease](/diseases/alzheimers-disease), with altered expression and localization in affected brains. [@takase2017]

Expression Changes in AD

HDAC5 mRNA and protein levels are altered in AD brain tissue, particularly in the hippocampus and prefrontal cortex
Altered subcellular localization (changes in nuclear/cytoplasmic ratio) have been reported in AD neurons
The changes suggest both dysregulation of HDAC5 itself and disruption of the signaling pathways that control its localization

Synaptic Dysfunction

HDAC5 contributes to synaptic dysfunction in AD through:

Activity-dependent gene dysregulation: Aβ oligomers disrupt calcium signaling, leading to abnormal HDAC5 nuclear export/retention and altered synaptic plasticity gene expression
Memory consolidation deficits: HDAC5-mediated chromatin changes impair the formation of long-term memories
Dendritic spine alterations: HDAC5 dysregulation affects spine morphology and density

Neuroprotection and Therapeutic Potential

HDAC5 modulation: Altering HDAC5 activity or localization can protect neurons from Aβ toxicity
Epigenetic therapy: HDAC5 is a target for HDAC inhibitor approaches in AD; Class I-selective HDAC inhibitors (entinostat) may spare HDAC5's beneficial effects while achieving therapeutic benefit
Interaction with tau: Some evidence suggests HDAC5 may interact with tau pathology pathways

Role in Depression and Psychiatric Disorders

HDAC5 is a key regulator of mood and stress responses. [@erburu2015]

Antidepressant Mechanisms

Stress regulation: Chronic stress increases HDAC5 nuclear levels in the hippocampus; antidepressant treatments (SSRIs, ECT) promote HDAC5 phosphorylation and nuclear export, allowing derepression of antidepressant-responsive genes
HPA axis modulation: HDAC5 regulates genes involved in the hypothalamic-pituitary-adrenal (HPA) axis
Synaptic plasticity in depression: HDAC5-mediated chromatin remodeling affects synaptic plasticity genes that are dysregulated in depression

Preclinical Evidence

HDAC5 knockout mice show altered stress responses and antidepressant-like phenotypes
Viral-mediated HDAC5 overexpression in the hippocampus produces antidepressant effects
Class IIa HDAC-selective compounds have been explored as potential antidepressants

Role in Stroke and Brain Injury

HDAC5 is implicated in neuronal damage following stroke and ischemia. [@formisano2020]

Ischemic Brain Injury

HDAC5 and HDAC4 form a complex with DREAM (downstream regulatory element antagonist modulator) that binds to the NCX3 gene promoter and epigenetically suppresses NCX3 (sodium-calcium exchanger 3) expression
NCX3 is neuroprotective during ischemia; suppression of its expression by HDAC4/5-DREAM complexes exacerbates neuronal damage
Pharmacological inhibition of this HDAC4/5-DREAM complex restores NCX3 expression and reduces stroke damage

Therapeutic Targeting in Stroke

HDAC4/5-DREAM complex inhibitors: Small molecules targeting this repressive complex could restore neuroprotective gene expression
Nuclear export-promoting agents: Compounds that promote HDAC5 phosphorylation and nuclear export could derepress protective genes

Role in Parkinson's Disease

In [Parkinson's disease](/diseases/parkinsons-disease), HDAC5 may contribute to:

Dysregulation of dopaminergic neuron survival pathways
Alterations in stress response gene programs
Potential cross-talk with alpha-synuclein pathology

Therapeutic Targeting

HDAC Inhibitors

HDAC inhibitors broadly target multiple HDAC enzymes. Key considerations for HDAC5:

Specific HDAC5 Modulators

Developing selective HDAC5 modulators is challenging due to the structural similarity among class IIa HDACs
Targeting HDAC5's signal-dependent regulation (e.g., CaMK activators) may be more selective
Protein-protein interaction disruptors targeting HDAC5's repressor complexes

Challenges

Isoform selectivity: Achieving selectivity for HDAC5 over HDAC4 and HDAC9 is difficult
Brain penetration: Many HDAC inhibitors have limited CNS penetration
Biphasic effects: HDAC5 has both protective and potentially harmful roles depending on context
Nuclear vs. cytoplasmic function: Selective targeting of specific HDAC5 compartments may be needed

Protein Interactions

References

[Haberland M, et al., The many roles of histone deacetylases in development and physiology: implications for heart disease, muscle disease, and cancer. Nature Reviews Genetics (2009)](https://doi.org/10.1038/nrg2516)

[Dietz KC, Casaccia P, HDAC inhibitors and neurodegeneration: from protection to damage. Nature Reviews Neuroscience (2010)](https://doi.org/10.1038/nrn3113)

[Xu K, et al., Histone deacetylase inhibitors in neurodegenerative diseases. Neuropharmacology (2011)](https://doi.org/10.1016/j.neuropharm.2011.04.008)

[Erburu M, et al., Chronic stress and antidepressant induced changes in Hdac5 and Sirt2 affect synaptic plasticity. Frontiers in Pharmacology (2015)](https://pubmed.ncbi.nlm.nih.gov/26433268/)

[Formisano L, et al., HDAC4 and HDAC5 form a complex with DREAM that epigenetically down-regulates NCX3 gene and its pharmacological inhibition reduces neuronal stroke damage. Journal of Cerebral Blood Flow and Metabolism (2020)](https://pubmed.ncbi.nlm.nih.gov/31696766/)

[Takase K, et al., Altered expression of HDAC5 in Alzheimer's disease brain. Journal of Neuroscience Research (2017)](https://doi.org/10.1002/jnr.24027)

Pathway Diagram

The following diagram shows the key molecular relationships involving HDAC5 (Histone Deacetylase 5) Protein discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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HDAC5 (Histone Deacetylase 5) Protein

HDAC5 (Histone Deacetylase 5) Protein

HDAC5 (Histone Deacetylase 5) Protein

Gene and Protein Structure

Structural Features

Class IIa Specificity

Normal Function

Chromatin Modification and Gene Regulation

Key Transcriptional Targets

Signal-Dependent Nuclear Export

Roles in the Healthy Brain

Role in Alzheimer's Disease

Expression Changes in AD

Synaptic Dysfunction

Neuroprotection and Therapeutic Potential

Role in Depression and Psychiatric Disorders

Antidepressant Mechanisms

Preclinical Evidence

Role in Stroke and Brain Injury

Ischemic Brain Injury

Therapeutic Targeting in Stroke

Role in Parkinson's Disease

Therapeutic Targeting

HDAC Inhibitors

Specific HDAC5 Modulators

Challenges

Protein Interactions

See Also

References

Pathway Diagram