The Dynamic Phosphorylation of Class IIa Histone Deacetylases is Implicated in Both Conserved and Divergent Functions

摘要

Class IIa histone deacetylases (HDACs) are a family of essential transcriptional regulators that function as components of multi-protein complexes to modulate transcription by removing acetyl groups from target substrates. Emerging evidence supports roles for class IIa HDACs (HDACs 4, 5, 7, and 9) in human disease progression and response to viral infection. Class IIa HDACs shuttle between the nucleus and the cytoplasm, resulting in a localization-dependent mechanism of transcriptional control determined, in part, by site-specific phosphorylation. Phosphorylation-dependent interaction with 14-3-3 proteins is essential for nuclear export and regulation of shuttling. Interaction of HDACs with the NCoR complex potentiates transcriptional repression within the nucleus. The dynamic localization of these enzymes additionally suggests that class IIa HDACs may target yet-unidentified nuclear and cytoplasmic substrates. Here, we map the phosphorylation of class IIa HDACs and examine the contribution of individual phosphorylation sites in regulating conserved or divergent functions of these enzymes. Our lab recently reported in vivo phosphorylation of HDAC5 at 17 sites, of which 13 are novel. Class IIa HDACs exhibit high sequence conservation, suggesting that novel shared phosphorylations may be important in determining regulation of this class of enzymes. Moreover, the dynamic localization of class IIa HDACs suggests that these enzymes may possess yet-unidentified nuclear and cytoplasmic substrates.