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.

Keywords: Cell signaling; Epigenetics; Histone deacetylase; Phosphorylation.

Fig. 1

Increased deacetylase activity of HDAC1 upon phosphorylation. Phosphorylation of HDAC1 at S421 and S423 by CK2 has been demonstrated to be necessary for its activity in deacetylating histones. Histone deacetylation leads to tighter binding of the DNA and histone proteins in a “closed conformation,” such that gene transcription is repressed [24]. P phosphate, Ac acetyl group

Fig. 2

14-3-3-mediated nuclear export of phosphorylated Class IIa HDACs. One of the general mechanisms by which Class IIa HDACs are regulated is phosphorylation-dependent change in subcellular localization. Though the phosphorylation of Class IIa HDACs can promote their nuclear import or export under specific stimuli and cellular contexts, many studies have presented the finding that the phosphorylation of Class IIa HDACs promotes their binding to 14-3-3 proteins and nuclear export under a wide variety of stimuli and contexts. As a consequence of their localization in the cytoplasm, Class IIa HDACs are unable to repress MEF2-mediated gene transcription [–54]. P phosphate

Fig. 3

Phosphorylation of HDAC2 influences its stability. Phosphorylation of HDAC2 can have different effects on its stability depending on the cellular context. HDAC2 phosphorylation by CK2 in lung epithelial cells, macrophages, and mouse lungs following exposure to cigarette smoke leads to its ubiquitination and proteasomal degradation. Loss of HDAC2 through this mechanism is proposed to play a role in inflammation and steroid resistance associated with asthma and chronic obstructive pulmonary disease (COPD) [29]. In neurons, loss of HDAC2 phosphorylation at Y222 leads to the proteasomal degradation of HDAC2, releasing its repression of the transcription of neuronal genes that otherwise occurs in Alzheimer’s disease [68]. P phosphate, Ub ubiquitin

Fig. 4

Relationship between SIRT1 phosphorylation and p53-mediated apoptosis. a Phosphorylation of SIRT1 at T344 by AMPK can have opposing effects on p53 acetylation, depending on the cellular context. SIRT1 phosphorylation in hepatocellular carcinoma cells inhibits its activity in deacetylating p53 and promotes apoptosis [48]. In contrast, its phosphorylation in osteosarcoma cells disrupts its interaction with its inhibitor, DBC1, allowing SIRT1 to deacetylate p53 and inhibit apoptosis [84]. b Genotoxic stress leads to the phosphorylation of SIRT1 at different sites by several kinases, including CK2, DYRK1A, DYRK3, and HIPK2, which influences the ability of SIRT1 to deacetylate p53. CK2- and DYRK-mediated phosphorylation of SIRT1 support its ability to deacetylate p53 and inhibit apoptosis [45, 46]. In contrast, SIRT1 phosphorylation by HIPK2 disrupts its interaction with its activator, AROS, which inhibits the deacetylation of p53 and leads to apoptosis [47]. P phosphate, Ac acetyl group