Histone Deacetylase 5
| HDAC5 Protein | |
|---|---|
| Protein Name | Histone Deacetylase 5 |
| Gene | [HDAC5](/genes/hdac5) |
| UniProt ID | [Q9UQL6](https://www.uniprot.org/uniprot/Q9UQL6) |
| PDB Structures | 2VQM, 5A2U, 5VX9 |
| Protein Length | 1122 amino acids |
| Molecular Weight | ~112 kDa |
| Protein Class | Class IIa Histone Deacetylase |
| Subcellular Localization | Nucleus/Cytoplasm (signal-dependent shuttling) |
| Expression | Brain (high), heart, skeletal muscle |
| Chromosomal Location | 18q21.1 |
HDAC5 (Histone Deacetylase 5) is a Class IIa histone deacetylase that functions as a signal-dependent transcriptional regulator[1]. HDAC5 contains 1122 amino acids (~112 kDa) and shuttles dynamically between the nucleus and cytoplasm in response to cellular signals, allowing it to regulate both transcriptional programs and cytoplasmic signaling pathways. In the brain, HDAC5 plays critical roles in synaptic plasticity, memory formation, neuronal survival, and stress responses. Dysregulation of HDAC5 has been implicated in Alzheimer's disease, Parkinson's disease, and Huntington's disease, making it an attractive therapeutic target[2].
HDAC5 contains three major structural domains[3][4]:
N-terminal Regulatory Domain (aa 1-421):
Catalytic Domain (aa 482-680):
C-terminal Domain (aa 682-1022):
HDAC5 is extensively regulated by post-translational modifications that control its localization and activity[5][6]:
| Modification | Site | Kinase/Enzyme | Effect |
|---|---|---|---|
| Phosphorylation | Ser259 | CaMK, AMPK | Creates 14-3-3 binding site, promotes nuclear export |
| Phosphorylation | Ser498 | CaMK, AMPK | Creates 14-3-3 binding site, promotes nuclear export |
| Phosphorylation | Ser310 | PKD | Regulates nuclear-cytoplasmic shuttling |
| Phosphorylation | Ser275 | PKA | Modulates subcellular localization |
| Acetylation | Lys559 | p300/CBP | Alters HDAC5 transcriptional repressive activity |
| SUMOylation | Lys899 | SUMO E3 ligases | Modulates protein interactions |
| Ubiquitination | Multiple | E3 ligases | Proteasomal degradation |
Crystal structures of the HDAC4/5 catalytic domain (PDB: 2VQM) reveal[4:1]:
HDAC5 catalyzes the removal of acetyl groups from lysine residues, though with different substrate specificity than Class I HDACs[1:1]:
Histone substrates:
Non-histone substrates:
Mechanism: Zinc-dependent hydrolysis of acetyl-lysine side chains
HDAC5 is a paradigmatic signal-regulated deacetylase[5:1]:
Nucleus-to-Cytoplasm transport:
Cytoplasm-to-Nucleus transport:
Integration with neuronal activity:
HDAC5 represses gene transcription through multiple mechanisms[7]:
1. Direct chromatin modification:
2. Transcription factor interactions:
3. Corepressor complex formation:
HDAC5 alterations contribute to AD pathogenesis through multiple mechanisms[8][9]:
Transcriptional dysregulation:
Amyloid-beta effects:
Tau pathology connections:
Therapeutic potential:
In Parkinson's disease[2:1]:
Dopaminergic neuron vulnerability:
Alpha-synuclein interactions:
Neuroprotective potential:
HDAC5 is a compelling therapeutic target in Huntington's disease[10][11]:
Mutant huntingtin effects:
Therapeutic benefit:
Mechanisms:
Pan-HDAC inhibitors have shown therapeutic potential in neurodegeneration models[11:1]:
| Drug | HDAC Selectivity | Status | Neurological Use |
|---|---|---|---|
| Vorinostat (SAHA) | Pan-HDAC | Approved (CTCL) | Preclinical in AD/PD/HD |
| Entinostat (MS-275) | HDAC1/2/3 | Clinical trials | AD/HD models |
| Romidepsin | Pan-HDAC | Approved (CTCL) | Preclinical |
| Trichostatin A | Class I/II | Research only | Proof-of-concept |
| PCI-34051 | HDAC8 | Preclinical | HDAC5 indirectly affected |
Class IIa HDAC-selective compounds offer potential advantages[4:2]:
Development status:
Advantages:
Challenges:
HDAC5 interacts with numerous proteins to execute its functions[12][13]:
| Partner | Interaction Domain | Functional Consequence |
|---|---|---|
| MEF2A/C | N-terminal (aa 1-200) | Transcriptional repression of MEF2 targets |
| REST | N-terminal | Neuronal gene repression |
| NF-κB (p65) | N-terminal | Inflammatory gene suppression |
| HDAC3 | Catalytic domain (aa 500-680) | Corepressor complex formation |
| NCoR/SMRT | N-terminal | Transcriptional repression complex |
| 14-3-3 proteins | C-terminal (phospho-Ser259/498) | Cytoplasmic retention |
| CaMK | Cytoplasmic | Phosphorylation and nuclear export |
| PKD | Cytoplasmic | Phosphorylation and nuclear export |
| CRM1 | C-terminal | Nuclear export |
MEF2 Pathway:
CREB Pathway:
NF-κB Pathway:
p38 MAPK Pathway:
HDAC5 shows specific patterns of expression in the brain[14]:
High expression regions:
Cellular localization:
HDAC5 global knockout:
Neuron-specific knockdown:
AD models (APP/PS1, 3xTg-AD):
PD models (MPTP, 6-OHDA, alpha-synuclein transgenic):
HD models (N171-82Q, R6/1):
Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nature Reviews Genetics. 2009. ↩︎ ↩︎
Hu YB, Zou YL, Jia YB, et al. HDAC5: a promising therapeutic target in neurodegenerative diseases. Frontiers in Aging Neuroscience. 2022. ↩︎ ↩︎
Yang XJ, Seto E. The Rpd3/Hda1 family of histone deacetylases. Nature Reviews Molecular Cell Biology. 2003. ↩︎
Kirlic N, et al. HDAC5 structure and function: molecular basis for pharmacological intervention. Journal of Medicinal Chemistry. 2020. ↩︎ ↩︎ ↩︎
McKinsey TA, Zhang CL, Lu J, Olson EN. Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation. Nature. 2000. ↩︎ ↩︎
Grozinger CM, Schreiber SL. Regulation of histone deacetylase 4 and 5 and transcriptional activity by 14-3-3-dependent cellular localization. Proceedings of the National Academy of Sciences. 2000. ↩︎
Graff J, Tsai LH. Histone acetylation: molecular mnemonics on chromatin. Progress in Brain Research. 2013. ↩︎
Volakakis N, Kadkhodaei B, Joodmardi E, et al. HDAC5 is required for long-term memory formation. Neuron. 2016. ↩︎
Marathe HG, Mehta G, Zhang X, et al. HDAC5 represses the p38 MAPK signaling pathway by targeting MAPK14. Molecular and Cellular Biology. 2018. ↩︎ ↩︎
Bardai FH, Price V, Zaury L, et al. Diminished activity of HDAC5 in Huntington's disease disease brain contributes to the formation of polyglutamine aggregates. Acta Neuropathologica. 2019. ↩︎
Thomas EA, Coppola G, Desplats PA, et al. The HDAC inhibitor 4b ameliorates the disease phenotype in cellular and mouse models of Huntington disease. Journal of Clinical Investigation. 2008. ↩︎ ↩︎
Sando R 3rd, Gounko N, Pieraut S, et al. Regulation of dendritic branching and spine maturation by neuronal activity-dependent histone deacetylase 5. Neuron. 2012. ↩︎
Chawla S, Vanhoutte P, Arnold FJ, Huang CL, Bading H. Nuclear calcium-activated histone deacetylase 5 represses transcriptional activity. Journal of Physiology. 2003. ↩︎
Broide RS, Redwine JM, Aftahi N, et al. Distribution of histone deacetylases 1, 2, and 3 in rat brain. Journal of Comparative Neurology. 2007. ↩︎