International Journal of Molecular Sciences Review The Role of Post-Translational Acetylation and Deacetylation of Signaling Proteins and Transcription Factors after Cerebral Ischemia: Facts and Hypotheses Svetlana Demyanenko 1,* and Svetlana Sharifulina 1,2 1 Laboratory of Molecular Neurobiology, Academy of Biology and Biotechnology, Southern Federal University, pr. Stachki 194/1, 344090 Rostov-on-Don, Russia; [email protected] 2 Neuroscience Center HiLife, University of Helsinki, Haartmaninkatu 8, P.O. Box 63, 00014 Helsinki, Finland * Correspondence: [email protected]; Tel.: +7-918-5092185; Fax: +7-863-2230837 Abstract: Histone deacetylase (HDAC) and histone acetyltransferase (HAT) regulate transcription and the most important functions of cells by acetylating/deacetylating histones and non-histone proteins. These proteins are involved in cell survival and death, replication, DNA repair, the cell cycle, and cell responses to stress and aging. HDAC/HAT balance in cells affects gene expression and cell signaling. There are very few studies on the effects of stroke on non-histone protein acetylation/deacetylation in brain cells. HDAC inhibitors have been shown to be effective in protecting the brain from ischemic damage. However, the role of different HDAC isoforms in the survival and death of brain cells after stroke is still controversial. HAT/HDAC activity depends on the acetylation site and the acetylation/deacetylation of the main proteins (c-Myc, E2F1, p53, Citation: Demyanenko, S.; ERK1/2, Akt) considered in this review, that are involved in the regulation of cell fate decisions. Sharifulina, S. The Role of Post-Translational Acetylation and Our review aims to analyze the possible role of the acetylation/deacetylation of transcription factors Deacetylation of Signaling Proteins and signaling proteins involved in the regulation of survival and death in cerebral ischemia. and Transcription Factors after Cerebral Ischemia: Facts and Keywords: cerebral ischemia; histone acetylation; histone deacetylases; histone deacetylase in- Hypotheses. Int. J. Mol. Sci. 2021, 22, hibitors; non-histone proteins 7947. https://doi.org/10.3390/ ijms22157947 Academic Editors: Anuska 1. Introduction V. Andjelkovic, Richard F. Keep and Acetylation of histones and non-histone proteins modulates gene expression and Michael M. Wang signaling in cells. Changes in the secondary structure of proteins by acetylation leads to a change in their enzymatic activity, subcellular localization and protein-protein Received: 23 June 2021 interactions [1]. Accepted: 22 July 2021 Published: 26 July 2021 The study of non-histone protein acetylation/deacetylation began after the success of the clinical use of histone deacetylase inhibitors (HDACs) in the treatment of various forms of cancer and was driven by the search for the causes of cytotoxicity of nonselective Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in HDAC inhibitors (HDACi) [2]. Non-histone substrates of HDAC and acetyltransferases published maps and institutional affil- (HAT) have been identified, which are tumor suppressors, signaling mediators, steroid iations. receptors and transcription factors [3,4]. The number of identified proteins in which activity is regulated by acetylation/deacetylation to date is certainly lower than the actual amount represented by acetylome in vivo. There are very few studies on the non-histone protein acetylation/deacetylation in brain cells, and there is apparently no data on these processes in stroke. Our review aims to Copyright: © 2021 by the authors. analyze the possible role of acetylation/deacetylation of transcription factors and signaling Licensee MDPI, Basel, Switzerland. This article is an open access article proteins involved in the regulation of apoptosis in ischemia. distributed under the terms and 2. Protein Acetylation and Deacetylation Enzymes conditions of the Creative Commons Attribution (CC BY) license (https:// Acetylation and deacetylation of histones and non-histone proteins is carried out by creativecommons.org/licenses/by/ histone deacetylase (HDAC) and histone acetyltransferase (HAT). Histone acetyltrans- 4.0/). ferases (HATs) transfer acetyl groups from acetyl coenzyme A (Acetyl Co-A) to the "-amino Int. J. Mol. Sci. 2021, 22, 7947. https://doi.org/10.3390/ijms22157947 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, 7947 2 of 16 Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 17 group of lysine residues, while histone deacetylases (HDACs), on the contrary, catalyze the removal of acetyl groups. Since histones were the first identified targets of deacetylases and acetyltransferases,2. Protein Acetylation theseand Deacetylation enzymes were Enzymes named histone deacetylases and histone acetyltrans- ferases.Acetylation However, and deacetylation in addition of to histones regulating and non-histone transcription, proteins HAT/HDAC is carried out by regulate the most histone deacetylase (HDAC) and histone acetyltransferase (HAT). Histone acetyltransfer- important functions of cells by acetylating/deacetylating a huge number of non-histone ases (HATs) transfer acetyl groups from acetyl coenzyme A (Acetyl Co-A) to the ε-amino proteins,group of lysine which residues, have while always histone been deacet theirylases evolutionarily (HDACs), on primarythe contrary, targets catalyze [3 ]. These proteins regulatethe removal cell of survivalacetyl groups. and Since death, histones replication, were the DNAfirst identified repair, targets the cell of cycle,deacety- and cell responses tolases stress and acetyltransferases, and aging. these enzymes were named histone deacetylases and histone acetyltransferases. However, in addition to regulating transcription, HAT/HDAC regulate 3.the Histone most important Acetyltransferases functions of cells by acetylating/deacetylating a huge number of non- histone proteins, which have always been their evolutionarily primary targets [3]. These proteinsDepending regulate cell on survival the intracellular and death, replication, localization, DNA repair, HATs the arecell cycle, classified and cell into types A or B, whichresponses either to stress contain and aging. or do not contain a bromodomain [5] (Figure1). Type A HATs are mainly responsible for acetylation associated with transcription. Type B cytoplasmic HATs 3. Histone Acetyltransferases acetylate de novo synthesized histones and non-histone proteins. Based on sequence ho- Depending on the intracellular localization, HATs are classified into types A or B, mologywhich either as wellcontain as or common do not contain structural a bromodomain features and[5] (Figure functions, 1). Type HATs A HATs have are been grouped into threemainly main responsible categories: for acetylation GNAT (GCN5-relatedassociated with transcription. N-Acetyltransferases), Type B cytoplasmic EP300/CREBBP (E1A bindingHATs acetylate protein de p300/CREB-bindingnovo synthesized histones protein), and non-hist andone the proteins. MYST Based family. on se- PCAF (P300/CBP- associatedquence homology factor), as well belonging as common to structural the GNAT features family, and functions, is the HATs most have important been enzyme that grouped into three main categories: GNAT (GCN5-related N-Acetyltransferases), acetylates non-histone proteins [6]. In addition, PCAF is the only HAT in which, even with EP300/CREBBP (E1A binding protein p300/CREB-binding protein), and the MYST family. aPCAF complete (P300/CBP-associated knockout, no factor), phenotypic belonging changes to the GNAT are observed family, is the [7 ].most In important the model of photothrom- boticenzyme stroke that acetylates (PTS), itnon-histone was shown proteins that [6]. PCAF In addition, is poorly PCAF expressed is the only inHAT normal in neurons and astrocyteswhich, even ofwith the a complete rat cerebral knockout, cortex. no ph However,enotypic changes the protein are observed level increased[7]. In the in neurons and especiallymodel of photothrombotic in the astrocytes stroke of(PTS), the it penumbrawas shown that 4–24 PCAF hafter is poorly PTS expressed [8]. Intracellular in localiza- normal neurons and astrocytes of the rat cerebral cortex. However, the protein level in- tioncreased and in activityneurons and of PCAFespecially is in regulated the astrocytes by of its the acetylation. penumbra 4–24 Autoacetylation h after PTS [8]. of PCAF, or its acetylationIntracellular localization by p300, enhancesand activitythe of PCAF acetyltransferase is regulated by its activity acetylation. of the Autoacety- enzyme and leads to its translocationlation of PCAF, intoor itsthe acetylation nucleus. by Deacetylationp300, enhances the of acetyltransferase PCAF by HDAC3 activity decreases of the the activity of theenzyme enzyme and leads and to promotes its translocation its cytoplasmic into the nucleus. localization Deacetylation [9 of]. PCAF by HDAC3 decreases the activity of the enzyme and promotes its cytoplasmic localization [9]. Figure 1. Histone acetyltransferase (HAT) and histone deacetylase (HDAC) classification. The chro- Figurematin conformation 1. Histone in the acetyltransferasecell according to the HAT/HDAC (HAT) and balance. histone The different deacetylase families (HDAC) and classification. The chromatin conformation in the cell according to the HAT/HDAC balance. The different families and classes of enzymes are noted. Type A HATs responsible for acetylation associated with transcrip- tion. Type B cytoplasmic HATs acetylate de novo synthesized