HDAC6 (histone deacetylase 6; HGNC:14064, NCBI Gene ID 10013) is a human locus mapped to chromosome band Xp11.23 that encodes tandem-catalytic-domain Class IIb cytosolic deacetylase & ubiquitin binder HDAC6 (1,215 aa; 131 kDa; EC 3.5.1.98). HDAC6 acts in deacetylation of alpha-tubulin (Lys40), cortactin & HSP90 + dynein-driven aggresomal clearance of polyubiquitylated misfolded proteins, together with HDAC10 (Companion Class IIb Polyamine Deacetylase Paralog), SIRT2 (Companion Cytosolic Alpha-Tubulin Lys40 Deacetylase), and Tubulin (Deacetylated at Alpha-Tubulin Lys40 by HDAC6). Encodes the unique two-domain cytoplasmic Class IIb deacetylase HDAC6 that regulates microtubule axonal transport, HSP90 chaperone function, and aggresomal autophagy.
Deacetylation of alpha-tubulin (Lys40), cortactin & HSP90 + dynein-driven aggresomal clearance of polyubiquitylated misfolded proteins
Clinical / Therapeutic Role
X-linked dominant chondrodysplasia (3-prime UTR miR-433 mutation); target of selective HDAC6 inhibitors (ricolinostat, citarinostat, TYA-11631) in CMT, neuropathy & myeloma
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 29-exon X-linked gene at chromosome Xp11.23 (immediately adjacent to GATA1 and FOXP3), unique among all 11 zinc-dependent HDACs in possessing two tandem functional catalytic deacetylase domains (DD1 and DD2, where DD2 deacetylates alpha-tubulin and cortactin), a cytoplasmic-anchoring Ser-Glu-containing tetradecapeptide (SE14) repeat domain, and a C-terminal zinc-finger ubiquitin-binding domain (ZnF-UBP / BUZ) with high affinity for unanchored C-terminal diglycine ubiquitin.
Cellular & Tissue Expression Profile: Localized almost exclusively in the cytoplasm across central and peripheral nervous system neurons (especially long motor and sensory axons), cardiomyocytes, lymphocytes, and plasma cells.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Coordinates two major non-histone proteostasis and cytoskeletal pathways in the cytoplasm: (1) its DD2 catalytic domain deacetylates polymerized alpha-tubulin at Lys40 (opposing alpha-TAT1 acetyltransferase and regulating kinesin-1/dynein axonal transport of mitochondria and BDNF vesicles) and deacetylates the molecular chaperone HSP90 (enabling client oncoprotein folding and glucocorticoid receptor maturation); and (2) when the 26S proteasome is overwhelmed by misfolded proteins, its C-terminal ZnF-UBP domain binds polyubiquitylated protein aggregates and links them directly to cytoplasmic dynein motors for retrograde transport along microtubules into perinuclear aggresomes for autophagolysosomal degradation.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: A dominant point mutation in the 3-prime UTR of HDAC6 that abolishes post-transcriptional repression by miR-433 causes X-linked dominant chondrodysplasia with platyspondyly, whereas Hdac6-knockout mice are completely viable with hyperacetylated microtubules, enhanced axonal mitochondrial transport, and heightened FOXP3+ regulatory T-cell suppressive function.
Therapeutic & Clinical Pharmacology: Unlike Class I HDAC inhibitors (which cause thrombocytopenia and fatigue), selective DD2-pocket HDAC6 inhibitors (ricolinostat / ACY-1215, citarinostat, Regenacy/inka blockers, and TYA-11631) are well tolerated and restore axonal transport in Charcot-Marie-Tooth neuropathy, chemotherapy-induced peripheral neuropathy, BAG3/HFpEF cardiomyopathy, and proteasome-inhibitor-treated multiple myeloma.