HDAC5

Histone deacetylase 5 (HDAC5) is a member of the class IIa histone deacetylases. Class IIa HDACs are zinc-dependent enzymes that generally show relatively weak intrinsic catalytic activity when studied in isolation. HDAC5 functions primarily as a transcriptional corepressor by deacetylating histones and non-histone proteins in cooperation with transcription factors such as MEF2, thereby modulating gene expression. The human HDAC5 gene encodes the protein widely expressed in multiple tissues.

Structure and regulation: HDAC5 contains an N-terminal catalytic deacetylase domain characteristic of class IIa enzymes, though substitutions in the active site reduce its catalytic efficiency. A C-terminal regulatory region includes phosphorylation sites and a nuclear export signal that control its subcellular localization and interaction with cofactors.

Localization and signaling: HDAC5 shuttles between the nucleus and cytoplasm. Calcium-dependent signaling activates kinases such as CaMK and PKD, which phosphorylate HDAC5 and promote binding of 14-3-3 proteins, triggering nuclear export. Dephosphorylation leads to nuclear re-accumulation and transcriptional repression resumes.

Biological roles: In muscle and heart, HDAC5 represses MEF2-dependent gene expression and is involved in myogenesis and cardiac hypertrophy; nuclear export relieves repression under hypertrophic stimuli. In the nervous system, HDAC5 regulates neuronal development and synaptic plasticity through similar MEF2- and activity-dependent pathways.

Clinical and research relevance: HDAC5 has been studied in contexts such as cardiac disease, neurodevelopment, and cognitive function. It is a target of interest in epigenetic therapy, with class IIa HDAC inhibitors under investigation, though achieving specificity for HDAC5 remains a challenge.