Regulation of histone deacetylase activities and functions by phosphorylation and its physiological relevance.

Abstract

Histone deacetylases (HDACs) are conserved enzymes that regulate many cellular processes by catalyzing the removal of acetyl groups from lysine residues on histones and non-histone proteins. As appropriate for proteins that occupy such an essential biological role, HDAC activities and functions are in turn highly regulated. Overwhelming evidence suggests that the dysregulation of HDACs plays a major role in many human diseases. The regulation of HDACs is achieved by multiple different mechanisms, including posttranslational modifications. One of the most common posttranslational modifications on HDACs is reversible phosphorylation. Many HDAC phosphorylations are context-dependent, occurring in specific tissues or as a consequence of certain stimuli. Additionally, whereas phosphorylation can regulate some HDACs in a non-specific manner, many HDAC phosphorylations result in specific consequences. Although some of these modifications support normal HDAC function, aberrations can contribute to disease development. Here we review and critically evaluate how reversible phosphorylation activates or deactivates HDACs and, thereby, regulates their many functions under various cellular and physiological contexts.