HDAC11 (Histone Deacetylase 11 Sole Class IV Long-Chain Fatty-Acyl Deacylase & Thermogenesis Brake Gene)
HDAC11 (histone deacetylase 11; HGNC:19086, NCBI Gene ID 79885) is a human locus mapped to chromosome band 3p25.1 that encodes class IV Zn2+-dependent lysine long-chain fatty-acyl deacylase (demyristoylase/depalmitoylase) HDAC11 (347 aa; 39 kDa; EC 3.5.1.-). HDAC11 acts in lysine demyristoylation of SHMT2/GRAIL, BRD2-linked repression of brown fat UCP1/PPARGC1A & IL-10 repression in antigen-presenting cells, together with UCP1 (Brown Adipose Thermogenin Repressed by HDAC11-BRD2), PPARGC1A (PGC-1alpha Coactivator Repressed by HDAC11), and SIRT6 (NAD+-Dependent Long-Chain Demyristoylase Counterpart). Encodes the sole Class IV enzyme HDAC11, a potent lysine long-chain fatty-acyl deacylase that restrains brown adipose thermogenesis and modulates anti-tumor immunity.
Approved Symbol
HDAC11
Chromosomal Locus
3p25.1
Encoded Product
Class IV Zn2+-dependent lysine long-chain fatty-acyl deacylase (demyristoylase/depalmitoylase) HDAC11 (347 aa; 39 kDa; EC 3.5.1.-)
Primary Pathway
Lysine demyristoylation of SHMT2/GRAIL, BRD2-linked repression of brown fat UCP1/PPARGC1A & IL-10 repression in antigen-presenting cells
Clinical / Therapeutic Role
Smallest HDAC & sole Class IV member; deletion unleashes UCP1 brown/beige thermogenesis, enhances muscle regeneration & boosts CD8+ T-cell anti-tumor immunity
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: 9-exon gene on chromosome 3p25.1 encoding the smallest human zinc-dependent histone deacetylase (347 amino acids), consisting almost entirely of a conserved catalytic domain with minimal N- and C-terminal tails and an internal hydrophobic cavity that hydrolyzes long-chain myristoyl and dodecanoyl (C12–C14) fatty-acyl-lysine bonds >10,000-fold more efficiently than acetyl-lysine.
Cellular & Tissue Expression Profile: Selectively enriched in the brain, skeletal muscle fibers, cardiac myocytes, brown and white adipocytes, renal tubules, and myeloid antigen-presenting cells / T lymphocytes.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Functions biochemically as the principal Zn2+-dependent lysine fatty-acyl deacylase (complementing NAD+-dependent SIRT6): in the cytoplasm it demyristoylates serine hydroxymethyltransferase 2 (SHMT2 at Lys245, preventing ubiquitin-specific protease BRCC36 degradation of the type I interferon receptor IFNAR1) and A-kinase anchoring protein AKAP12; in the nucleus of adipocytes and myocytes, HDAC11 physically associates with the bromodomain protein BRD2 to repress the UCP1 and PGC-1alpha (PPARGC1A) enhancers; and in myeloid antigen-presenting cells it represses the anti-inflammatory IL-10 promoter.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Hdac11-knockout mice are completely viable and exhibit striking metabolic protection: they display expanded UCP1-positive brown adipose tissue, widespread "beiging" of subcutaneous white adipose tissue, elevated oxygen consumption, resistance to high-fat-diet obesity and hepatic steatosis, accelerated skeletal muscle satellite cell regeneration (via IL-10 induction), and hyper-functional Eomes/T-bet+ CD8+ cytotoxic T cells.
Therapeutic & Clinical Pharmacology: Selective long-chain hydroxamate and hydrazide HDAC11 inhibitors (such as FT895 and SIS17) are in preclinical development to stimulate UCP1 thermogenic energy expenditure in metabolic syndrome and to augment CAR-T and checkpoint immunotherapy.