HDAC5 (histone deacetylase 5; HGNC:14068, NCBI Gene ID 10014) is a human locus mapped to chromosome band 17q21.31 that encodes class IIa signal-responsive nucleocytoplasmic shuttle protein HDAC5 (1,122 aa; 122 kDa). HDAC5 acts in AMPK/CaMKII phosphorylation at Ser259/Ser498 -> 14-3-3 nuclear export -> derepression of MEF2, GLUT4 (SLC2A4) & PPARGC1A in exercising muscle, together with HDAC4 (Partner Class IIa Shuttle Gene), HDAC9 (Partner Class IIa Cardiac Hypertrophy Brake Gene), and AMPK (Directly Phosphorylates HDAC5 Ser259/Ser498 During Exercise). Encodes Class IIa histone deacetylase 5, which is phosphorylated and exported from the nucleus by AMPK and CaMKII during exercise to unlock GLUT4 and PGC-1alpha transcription.
Approved Symbol
HDAC5
Chromosomal Locus
17q21.31
Encoded Product
Class IIa signal-responsive nucleocytoplasmic shuttle protein HDAC5 (1,122 aa; 122 kDa)
Primary Pathway
AMPK/CaMKII phosphorylation at Ser259/Ser498 -> 14-3-3 nuclear export -> derepression of MEF2, GLUT4 (SLC2A4) & PPARGC1A in exercising muscle
Clinical / Therapeutic Role
Acts redundantly with HDAC4 to suppress pathological cardiac hypertrophy; exercise-induced nuclear export drives skeletal muscle GLUT4 & mitochondrial adaptation
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 26-exon gene on chromosome 17q21.31 closely paralogous to HDAC4 and HDAC9, encoding a 1,122-amino-acid protein featuring an N-terminal MEF2-binding domain, nuclear localization signal flanked by two critical AMPK/CaMKII/PKD phosphorylation sites (Ser259 and Ser498), and a C-terminal His-substituted pseudo-deacetylase domain that recruits NCoR1/SMRT-HDAC3.
Cellular & Tissue Expression Profile: Abundantly expressed in cardiac myocytes, skeletal muscle fibers, brain neurons (including hypothalamic arcuate leptin-responsive neurons and nucleus accumbens), and vascular endothelial cells.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: In resting skeletal muscle, nuclear HDAC5 binds MEF2A/MEF2D on the promoters of the insulin-regulated glucose transporter GLUT4 (SLC2A4) and PGC-1alpha (PPARGC1A) to keep them repressed; during acute endurance exercise, rising AMP:ATP activates nuclear AMPK (PRKAA2) and rising Ca2+ activates CaMKII, both of which directly phosphorylate HDAC5 at Ser259 and Ser498 to trigger 14-3-3 binding and CRM1-dependent nuclear export—explaining how physical exercise transcriptionally up-regulates muscle GLUT4 and insulin sensitivity; in the hypothalamus, HDAC5 de-repression of STAT3 mediates leptin satiety signaling.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Double knockout of Hdac5 and Hdac9 (or Hdac4) in cardiomyocytes causes severe stress-induced pathological cardiac hypertrophy via unrestrained MEF2 activation of fetal cardiac gene programs (ANP, BNP, beta-MHC), while human GWAS variants in HDAC5 are associated with bone mineral density and blood pressure regulation.
Therapeutic & Clinical Pharmacology: Endurance exercise and pharmacological AMPK activators (metformin, AICAR) act through HDAC5 Ser259/Ser498 phosphorylation to restore skeletal muscle GLUT4 expression in insulin-resistant type 2 diabetes.