KAT8
Function
Histone acetyltransferase that catalyzes histone H4 acetylation at 'Lys-5'- and 'Lys-8' (H4K5ac and H4K8ac) or 'Lys-16' (H4K16ac), depending on the context (PubMed:12397079, PubMed:16227571, PubMed:16543150, PubMed:20018852, PubMed:21217699, PubMed:22020126, PubMed:22547026, PubMed:31794431, PubMed:33837287). Catalytic component of the MSL histone acetyltransferase complex, a multiprotein complex that mediates the majority of histone H4 acetylation at 'Lys-16' (H4K16ac), an epigenetic mark that prevents chromatin compaction (PubMed:12397079, PubMed:16227571, PubMed:16543150, PubMed:21217699, PubMed:22020126, PubMed:22547026, PubMed:33657400, PubMed:33837287). H4K16ac constitutes the only acetylation mark intergenerationally transmitted and regulates key biological processes, such as oogenesis, embryonic stem cell pluripotency, hematopoiesis or glucose metabolism (By similarity). The MSL complex is required for chromosome stability and genome integrity by maintaining homeostatic levels of H4K16ac (PubMed:33837287). The MSL complex is also involved in gene dosage by promoting up-regulation of genes expressed by the X chromosome (By similarity). X up-regulation is required to compensate for autosomal biallelic expression (By similarity). The MSL complex also participates in gene dosage compensation by promoting expression of Tsix non-coding RNA (By similarity). As part of the NSL histone acetyltransferase complex, catalyzes histone H4 acetylation at 'Lys-5'- and 'Lys-8' (H4K5ac and H4K8ac) at transcription start sites and promotes transcription initiation (PubMed:20018852, PubMed:22547026, PubMed:33657400). The NSL complex also acts as a regulator of gene expression in mitochondria: KAT8 associates with mitochondrial DNA and controls expression of respiratory genes in an acetyltransferase-dependent mechanism (PubMed:27768893). Also functions as an acetyltransferase for non-histone targets, such as ALKBH5, COX17, IRF3, KDM1A/LSD1, LMNA, PAX7 or TP53/p53 (PubMed:17189187, PubMed:19854137, PubMed:37369679). Acts as an inhibitor of antiviral immunity by acetylating IRF3, preventing IRF3 recruitment to promoters (By similarity). Acts as a regulator of asymmetric division in muscle stem cells by mediating acetylation of PAX7 (By similarity). As part of the NSL complex, acetylates TP53/p53 at 'Lys-120' (PubMed:17189187, PubMed:19854137). Acts as a regulator of epithelial-to-mesenchymal transition as part of the NSL complex by mediating acetylation of KDM1A/LSD1 (PubMed:27292636). The NSL complex is required for nuclear architecture maintenance by mediating acetylation of LMNA (By similarity). Promotes mitochondrial integrity by catalyzing acetylation of COX17 (By similarity). In addition to protein acetyltransferase activity, able to mediate protein propionylation (PubMed:29321206).
Involvement in disease
Li-Ghorbani-Weisz-Hubshman syndrome
LIGOWS
An autosomal dominant disorder characterized by global developmental delay, mild to moderate intellectual disability, speech and language impairment, and variable facial dysmorphism. Some patients have seizures and autistic features. Brain imaging abnormalities are observed in some patients and include decreased white matter volume, enlarged ventricles, thin corpus callosum, and gray matter nodular heterotopia.
None
The disease is caused by variants affecting the gene represented in this entry.
Post-translational modifications
Acetylation at Lys-274 facilitates cognate substrate Lys-binding and acetylation (PubMed:22020126, PubMed:27382063). Although considered as an autoacetylation event, acetylation at Lys-274 probably takes place via a non-enzymatic process following acetyl-CoA-binding, which primes KAT8 for cognate protein-lysine acetylation (PubMed:27382063). Deacetylated by SIRT1 (PubMed:22918831).
Sequence Similarities
Belongs to the MYST (SAS/MOZ) family.
Cellular localization
- Nucleus
- Chromosome
- Mitochondrion
- Translocated into the nucleus via its association with importin-alpha-1 (KPNA2) (PubMed:28991411). As part of the NSL complex, associates with the proximal part of promoters and transcription start sites (PubMed:33657400). As part of the MSL complex, associates with gene bodies (By similarity). Also localizes to mitochondria; associates with mitochondrial DNA and regulates mitochondrial gene expression (PubMed:27768893).
Alternative names
MOF, MYST1, PP7073, KAT8, Histone acetyltransferase KAT8, Lysine acetyltransferase 8, Males-absent on the first protein homolog, Protein acetyltransferase KAT8, Protein propionyltransferase KAT8, MYST-1, hMOF