HDAC11 Protein

HDAC11 Protein

Overview

HDAC11 (Histone Deacetylase 11) is the sole member of the Class IV histone deacetylases, representing the smallest and most recently characterized HDAC enzyme. It catalyzes the removal of acetyl groups from lysine residues on histones and non-histone proteins, regulating gene expression, immune responses, and cellular metabolism. In the brain, HDAC11 may regulate neuronal gene expression and immune responses in glial cells. [@gaofeng2016]

HDAC11 Protein

Overview

HDAC11 (Histone Deacetylase 11) is the sole member of the Class IV histone deacetylases, representing the smallest and most recently characterized HDAC enzyme. It catalyzes the removal of acetyl groups from lysine residues on histones and non-histone proteins, regulating gene expression, immune responses, and cellular metabolism. In the brain, HDAC11 may regulate neuronal gene expression and immune responses in glial cells. [@gaofeng2016]

<div class="infobox infobox-protein">
<table>
<tr><th colspan="2" style="background:#e8f4f8; text-align:center; font-size:1.1em;">Histone Deacetylase 11 Protein</th></tr>
<tr><td><strong>Protein Name</strong></td><td>Histone Deacetylase 11 (HDAC11)</td></tr>
<tr><td><strong>Gene</strong></td><td>[HDAC11](/genes/hdac11)</td></tr>
<tr><td><strong>UniProt ID</strong></td><td>[Q9P0K5](https://www.uniprot.org/uniprot/Q9P0K5)</td></tr>
<tr><td><strong>PDB Structure</strong></td><td>4RUI, 5ICR</td></tr>
<tr><td><strong>Molecular Weight</strong></td><td>39 kDa</td></tr>
<tr><td><strong>Subcellular Localization</strong></td><td>Nucleus, Cytoplasm</td></tr>
<tr><td><strong>Protein Family</strong></td><td>Class IV Histone Deacetylase</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/huntington" style="color:#ef9a9a">Huntington</a>, <a href="/wiki/inflammation" style="color:#ef9a9a">Inflammation</a>, <a href="/wiki/ms" style="color:#ef9a9a">Ms</a>, <a href="/wiki/neurodegeneration" style="color:#ef9a9a">Neurodegeneration</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">58 edges</a></td>
</tr>
</table>
</div>

Structure

Domain Architecture

HDAC11 is a 347 amino acid protein containing a catalytic domain distinct from Class I, II, and III enzymes. The structure reveals a Rossmann-fold-like catalytic core with a unique zinc-binding motif. HDAC11 is the smallest [HDAC](/entities/hdac-enzymes) with unique structural features.

Structural Features

| Feature | Function |
|---------|----------|
| Rossmann-fold catalytic core | Central deacetylase activity |
| Zinc-binding motif | Required for catalytic function |
| N-terminal regulatory region | Protein-protein interactions |
| L1 and L2 loops | Substrate specificity |

Normal Function

Epigenetic Regulation

HDAC11 catalyzes the removal of acetyl groups from lysine residues on histones, primarily H3 and H4 tails. This modifies chromatin structure and regulates gene transcription. [@grunstein1997]

Histone acetylation dynamics:

• Hyperacetylation: Open chromatin, active transcription
• Deacetylation: Compact chromatin, gene silencing
• HDAC11 substrate specificity: Prefers H4 at specific lysine residues

Non-histone Protein Deacetylation

HDAC11 also deacetylates non-histone proteins, including:

• Transcription factors: Modulates their DNA binding and activity
• Signal transduction proteins: Regulates signaling pathway activity
• Metabolic enzymes: Affects metabolic flux

Immune Regulation

In immune cells, HDAC11 regulates: [@park2016]

• T cell differentiation: Influences Th1/Th2 balance
• Cytokine production: Controls inflammatory responses
• macrophage activation: Modulates innate immunity
• Autoimmune responses: Maintains immune tolerance

Brain Expression and Function

In the central nervous system:

• Neuronal gene expression: Regulates neuronal-specific genes
• Glial cell function: Modulates astrocyte and microglia activity
• Synaptic plasticity: May affect learning and memory
• Inflammatory responses: Controls neuroinflammation

Role in Disease

Cancer

| Cancer Type | HDAC11 Role | Evidence |
|-------------|-------------|----------|
| Breast cancer | Overexpression promotes growth | High HDAC11 correlates with poor prognosis |
| Prostate cancer | Androgen receptor regulation | Tumor-specific expression |
| Colorectal cancer | Cell cycle progression | Knockdown reduces proliferation |
| Glioma | Stem cell maintenance | Expressed in glioma stem cells |

HDAC11 is frequently overexpressed in various cancers and promotes tumor growth through epigenetic and non-epigenetic mechanisms. [@khan2018]

Autoimmune Disorders

• Multiple sclerosis: Altered immune cell gene expression
• Rheumatoid arthritis: Dysregulated cytokine production
• Systemic lupus erythematosus: T cell hyperactivity

Neurodegenerative Disease

While HDAC11 is the least studied HDAC in neurodegeneration, emerging evidence suggests important roles:

Alzheimer's Disease:

• Possible regulation of tau acetylation
• May affect amyloid processing
• Potential role in neuroinflammation

• May regulate alpha-synuclein acetylation
• Possible involvement in mitochondrial function
• Could modulate neuroinflammation

• Potential regulation of TDP-43 function
• May affect SOD1 aggregation
• Could modulate motor neuron inflammation

Epigenetic Dysregulation in Neurodegeneration

The balance of histone acetylation/deacetylation is critical for neuronal health: [@shen2015]

Therapeutic Targeting

HDAC11-Selective Inhibitors

| Compound | Selectivity | Stage | Application |
|----------|-------------|-------|-------------|
| HDAC11-IN-1 | HDAC11-specific | Preclinical | Tool compound |
| HDAC11-IN-2 | HDAC11-selective | Discovery | Lead optimization |
| JH-X-01-02 | HDAC11>others | Preclinical | Cancer |

Broader HDAC Inhibitors

Pan-HDAC inhibitors that target HDAC11:

• Vorinostat (SAHA): FDA-approved for CTCL
• Panobinostat: Approved for multiple myeloma
• Romidepsin: FDA-approved for CTCL

• Neurodegeneration: Reduce protein aggregation
• Cancer therapy: Tumor-selective targeting
• Autoimmune diseases: Immune modulation

Potential Neurodegeneration Applications

• Tau acetylation modulation: Influence tau pathology
• Neuroinflammation: Reduce glial activation
• Synaptic plasticity: Enhance cognitive function

HDAC Family Comparison

| HDAC Class | Members | Subcellular Location | Function |
|------------|---------|---------------------|----------|
| Class I | HDAC1,2,3,8 | Nucleus | Corepressor complexes |
| Class IIa | HDAC4,5,7,9 | Nucleus/Cytoplasm | Signal-dependent |
| Class IIb | HDAC6,10 | Cytoplasm | Cytoplasmic proteins |
| Class III | SIRT1-7 | Multiple | NAD+-dependent |
| Class IV | HDAC11 | Nucleus/Cytoplasm | Unique substrates |

Cross-linking to Related Pages

• [HDAC11 Gene](/genes/hdac11)
• [HDAC Enzymes](/entities/hdac-enzymes)
• [Epigenetic Mechanisms](/mechanisms/epigenetic-regulation-neurodegeneration)
• [Neuroinflammation](/mechanisms/neuroinflammation)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)
• [Amyotrophic Lateral Sclerosis](/diseases/als)

See Also

• [HDAC11 Gene](/genes/hdac11)
• [Epigenetic Mechanisms](/mechanisms/epigenetic-regulation-neurodegeneration)
• [Immune Response](/mechanisms/neuroinflammation)
• [Histone Modifications](/mechanisms/histone-modifications)
• [Transcription Regulation](/mechanisms/transcription-regulation)

External Links

• [UniProt: HDAC11](https://www.uniprot.org/uniprot/Q9P0K5)
• [PDB: HDAC11 Structure](https://www.rcsb.org/structure/4RUI)
• [GeneCards: HDAC11](https://www.genecards.org/cgi-bin/carddisp.pl?gene=HDAC11)
• [NCBI Gene: HDAC11](https://www.ncbi.nlm.nih.gov/gene/79804)

References