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Protein Post-translational Modifications in Signal Transduction and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 79642

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Dr. Mauro Salvi

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Guest Editor

Department of Biomedical Sciences, University of Padova, Padova, Italy
Interests: protein phosphorylation; acidic protein kinases; tyrosine kinases; kinase inhibitors; signal transduction; post-translational modifications; cancer; cystic fibrosis
Special Issues, Collections and Topics in MDPI journals

Dr. Claudio D‘Amore

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Guest Editor

Department of Biomedical Sciences, University of Padova, Padova, Italy
Interests: protein post-translational modifications

Special Issue Information

Dear Colleagues,

Post-translational modifications (PTMs) are well-known covalent processing events that can affect virtually all aspects of the functionality and the signalling of a protein, influencing its folding, stability, localization, and binding partners. It is therefore not surprising that altered levels of PTMs may be involved in different human diseases, including cancer, neurodegeneration, diabetes and inflammatory diseases, and the enzymes regulating their turnover are pharmacological targets of primary importance.

Among PTMs, protein phosphorylation is the most extensively studied, and its role in signalling transduction is widely accepted, but hundreds of other modifications have been identified to date, and new ones are still under identification. Notably, the complexity increases because the crosstalk between PTMs is widespread. The same amino acid can be modified by different competing PTMs—lysine residues, for example, can be modified by the addition of chemical groups, such as acetylation and methylation; the addition of complex molecules, such as glycation; or the addition of other protein molecules, such as ubiquitylation and sumoylation, and the biological outcome changes according the type of modification that prevails. Moreover, most commonly, the same protein is subjected to different PTMs in multiple sites, which can affect each other by simply changing either protein folding or chemical surface. The PhosphositePlus database indeed collects almost 500.000 PTMs in about 20,000 non-redundant proteins, which means an average of about 25 PTMs for protein.

The sum of the PTMs of a protein, functioning in a combinatory manner, define the so called PTM code, which, together with the dynamic nature of many PTMs, permits precisely fine-tuning any biological process, and transducing any microenvironment change into a rapid and specific cell response.

In this regard, we invite investigators to contribute original research and review articles that will stimulate the continuing efforts to understand how protein functions are affected by different types of PTMs, not limited to phosphorylation, in order to develop strategies for their identification and characterization, and to highlight the interactions between PTMs under normal and pathological processes.

The editors are particularly interested in the following topics:

Identification and characterization of PTMs
Structural and functional alteration of a protein following PTMs
Methodological developments in the PTMs field
Proteins involved in PTMs signalling: writers, erasers, and readers
PTMs crosstalk
Pato-physiological role of PTMs

Prof. Mauro Salvi
Dr. Claudio D‘Amore
Guest Editors

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Keywords

Methylation
sumoylation
ubiquitinylation
ubiquitination
acetylation
phosphorylation
nitrosylation
glycosylation
cysteinylation

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Published Papers (14 papers)

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Editorial

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4 pages, 194 KiB

Open AccessEditorial

Editorial of Special Issue “Protein Post-Translational Modifications in Signal Transduction and Diseases”

by Claudio D’Amore and Mauro Salvi

Int. J. Mol. Sci. 2021, 22(5), 2232; https://doi.org/10.3390/ijms22052232 - 24 Feb 2021

Cited by 2 | Viewed by 1791

Abstract

The making of a protein is based on the combination of 20 different monomers (22 considering selenocysteine and pyrrolysine, the latest present only in some archaea and bacteria) giving the possibility of building a variety of structures from the simplest to the most [...] Read more.

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

Research

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22 pages, 2944 KiB

Open AccessArticle

Angiotensin II Inhibits Insulin Receptor Signaling in Adipose Cells

by Citlaly Gutierrez-Rodelo, Araceli Arellano-Plancarte, Judith Hernandez-Aranda, Huguet V. Landa-Galvan, G. Karina Parra-Mercado, Nicole J. Moreno-Licona, Karla D. Hernandez-Gonzalez, Kevin J. Catt, Rafael Villalobos-Molina and J. Alberto Olivares-Reyes

Int. J. Mol. Sci. 2022, 23(11), 6048; https://doi.org/10.3390/ijms23116048 - 27 May 2022

Cited by 20 | Viewed by 3719

Abstract

Angiotensin II (Ang II) is a critical regulator of insulin signaling in the cardiovascular system and metabolic tissues. However, in adipose cells, the regulatory role of Ang II on insulin actions remains to be elucidated. The effect of Ang II on insulin-induced insulin receptor (IR) phosphorylation, Akt activation, and glucose uptake was examined in 3T3-L1 adipocytes. In these cells, Ang II specifically inhibited insulin-stimulated IR and insulin receptor substrate-1 (IRS-1) tyrosine-phosphorylation, Akt activation, and glucose uptake in a time-dependent manner. These inhibitory actions were associated with increased phosphorylation of the IR at serine residues. Interestingly, Ang II-induced serine-phosphorylation of IRS was not detected, suggesting that Ang II-induced desensitization begins from IR regulation itself. PKC inhibition by BIM I restored the inhibitory effect of Ang II on insulin actions. We also found that Ang II promoted activation of several PKC isoforms, including PKCα/βI/βII/δ, and its association with the IR, particularly PKCβII, showed the highest interaction. Finally, we also found a similar regulatory effect of Ang II in isolated adipocytes, where insulin-induced Akt phosphorylation was inhibited by Ang II, an effect that was prevented by PKC inhibitors. These results suggest that Ang II may lead to insulin resistance through PKC activation in adipocytes. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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19 pages, 3781 KiB

Open AccessArticle

Multi-Omics Integration Highlights the Role of Ubiquitination in CCl₄-Induced Liver Fibrosis

by Maria Mercado-Gómez, Fernando Lopitz-Otsoa, Mikel Azkargorta, Marina Serrano-Maciá, Sofia Lachiondo-Ortega, Naroa Goikoetxea-Usandizaga, Rubén Rodríguez-Agudo, David Fernández-Ramos, Maider Bizkarguenaga, Virginia Gutiérrez-de Juan, Benoît Lectez, Kerman Aloria, Jesus M. Arizmendi, Jorge Simon, Cristina Alonso, Juan J. Lozano, Matias A. Avila, Jesus M. Banales, Jose J. G. Marin, Naiara Beraza, José M. Mato, Félix Elortza, Rosa Barrio, James D. Sutherland, Ugo Mayor, María L. Martínez-Chantar and Teresa C. Delgado Show full author list Hide full author list

Int. J. Mol. Sci. 2020, 21(23), 9043; https://doi.org/10.3390/ijms21239043 - 27 Nov 2020

Cited by 17 | Viewed by 4817

Abstract

Liver fibrosis is the excessive accumulation of extracellular matrix proteins that occurs in chronic liver disease. Ubiquitination is a post-translational modification that is crucial for a plethora of physiological processes. Even though the ubiquitin system has been implicated in several human diseases, the role of ubiquitination in liver fibrosis remains poorly understood. Here, multi-omics approaches were used to address this. Untargeted metabolomics showed that carbon tetrachloride (CCl₄)-induced liver fibrosis promotes changes in the hepatic metabolome, specifically in glycerophospholipids and sphingolipids. Gene ontology analysis of public deposited gene array-based data and validation in our mouse model showed that the biological process “protein polyubiquitination” is enriched after CCl₄-induced liver fibrosis. Finally, by using transgenic mice expressing biotinylated ubiquitin (^bioUb mice), the ubiquitinated proteome was isolated and characterized by mass spectrometry in order to unravel the hepatic ubiquitinated proteome fingerprint in CCl₄-induced liver fibrosis. Under these conditions, ubiquitination appears to be involved in the regulation of cell death and survival, cell function, lipid metabolism, and DNA repair. Finally, ubiquitination of proliferating cell nuclear antigen (PCNA) is induced during CCl₄-induced liver fibrosis and associated with the DNA damage response (DDR). Overall, hepatic ubiquitome profiling can highlight new therapeutic targets for the clinical management of liver fibrosis. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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16 pages, 2682 KiB

Open AccessArticle

Mechanistic Insights into the Allosteric Regulation of the Clr4 Protein Lysine Methyltransferase by Autoinhibition and Automethylation

by Mina S. Khella, Alexander Bröhm, Sara Weirich and Albert Jeltsch

Int. J. Mol. Sci. 2020, 21(22), 8832; https://doi.org/10.3390/ijms21228832 - 22 Nov 2020

Cited by 5 | Viewed by 3242

Abstract

Clr4 is a histone H3 lysine 9 methyltransferase in Schizosaccharomyces pombe that is essential for heterochromatin formation. Previous biochemical and structural studies have shown that Clr4 is in an autoinhibited state in which an autoregulatory loop (ARL) blocks the active site. Automethylation of lysine residues in the ARL relieves autoinhibition. To investigate the mechanism of Clr4 regulation by autoinhibition and automethylation, we exchanged residues in the ARL by site-directed mutagenesis leading to stimulation or inhibition of automethylation and corresponding changes in Clr4 catalytic activity. Furthermore, we demonstrate that Clr4 prefers monomethylated (H3K9me1) over unmodified (H3K9me0) histone peptide substrates, similar to related human enzymes and, accordingly, H3K9me1 is more efficient in overcoming autoinhibition. Due to enzyme activation by automethylation, we observed a sigmoidal dependence of Clr4 activity on the AdoMet concentration, with stimulation at high AdoMet levels. In contrast, an automethylation-deficient mutant showed a hyperbolic Michaelis–Menten type relationship. These data suggest that automethylation of the ARL could act as a sensor for AdoMet levels in cells and regulate the generation and maintenance of heterochromatin accordingly. This process could connect epigenome modifications with the metabolic state of cells. As other human protein lysine methyltransferases (for example, PRC2) also use automethylation/autoinhibition mechanisms, our results may provide a model to describe their regulation as well. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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21 pages, 2646 KiB

Open AccessArticle

Insight into the Interactome of Intramitochondrial PKA Using Biotinylation-Proximity Labeling

by Yasmine Ould Amer and Etienne Hebert-Chatelain

Int. J. Mol. Sci. 2020, 21(21), 8283; https://doi.org/10.3390/ijms21218283 - 5 Nov 2020

Cited by 7 | Viewed by 3822

Abstract

Mitochondria are fully integrated in cell signaling. Reversible phosphorylation is involved in adjusting mitochondrial physiology to the cellular needs. Protein kinase A (PKA) phosphorylates several substrates present at the external surface of mitochondria to maintain cellular homeostasis. However, few targets of PKA located inside the organelle are known. The aim of this work was to characterize the impact and the interactome of PKA located inside mitochondria. Our results show that the overexpression of intramitochondrial PKA decreases cellular respiration and increases superoxide levels. Using proximity-dependent biotinylation, followed by LC-MS/MS analysis and in silico phospho-site prediction, we identified 21 mitochondrial proteins potentially targeted by PKA. We confirmed the interaction of PKA with TIM44 using coimmunoprecipitation and observed that TIM44-S80 is a key residue for the interaction between the protein and the kinase. These findings provide insights into the interactome of intramitochondrial PKA and suggest new potential mechanisms in the regulation of mitochondrial functions. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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16 pages, 2082 KiB

Open AccessArticle

GasPhos: Protein Phosphorylation Site Prediction Using a New Feature Selection Approach with a GA-Aided Ant Colony System

by Chi-Wei Chen, Lan-Ying Huang, Chia-Feng Liao, Kai-Po Chang and Yen-Wei Chu

Int. J. Mol. Sci. 2020, 21(21), 7891; https://doi.org/10.3390/ijms21217891 - 24 Oct 2020

Cited by 9 | Viewed by 3271

Abstract

Protein phosphorylation is one of the most important post-translational modifications, and many biological processes are related to phosphorylation, such as DNA repair, transcriptional regulation and signal transduction and, therefore, abnormal regulation of phosphorylation usually causes diseases. If we can accurately predict human phosphorylation sites, this could help to solve human diseases. Therefore, we developed a kinase-specific phosphorylation prediction system, GasPhos, and proposed a new feature selection approach, called Gas, based on the ant colony system and a genetic algorithm and used performance evaluation strategies focused on different kinases to choose the best learning model. Gas uses the mean decrease Gini index (MDGI) as a heuristic value for path selection and adopts binary transformation strategies and new state transition rules. GasPhos can predict phosphorylation sites for six kinases and showed better performance than other phosphorylation prediction tools. The disease-related phosphorylated proteins that were predicted with GasPhos are also discussed. Finally, Gas can be applied to other issues that require feature selection, which could help to improve prediction performance. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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17 pages, 2528 KiB

Open AccessArticle

Phosphoproteomics and Bioinformatics Analyses Reveal Key Roles of GSK-3 and AKAP4 in Mouse Sperm Capacitation

by Nailis Syifa, Jhih-Tian Yang, Chang-Shiann Wu, Miao-Hsia Lin, Wan-Ling Wu, Cheng-Wei Lai, Sheng-Hsuan Ku, Suh-Yuen Liang, Yu-Chun Hung, Chia-Te Chou, Chien-Sheng Wang, Yasushi Ishihama, Jiahn-Haur Liao, Shih-Hsiung Wu and Tzu-Hua Wu

Int. J. Mol. Sci. 2020, 21(19), 7283; https://doi.org/10.3390/ijms21197283 - 2 Oct 2020

Cited by 6 | Viewed by 4603

Abstract

Protein phosphorylation can induce signal transduction to change sperm motility patterns during sperm capacitation. However, changes in the phosphorylation of sperm proteins in mice are still incompletely understood. Here, capacitation-related phosphorylation in mouse sperms were firstly investigated by label-free quantitative (LFQ) phosphoproteomics coupled with bioinformatics analysis using ingenuity pathway analysis (IPA) methods such as canonical pathway, upstream regulator, and network analysis. Among 1632 phosphopeptides identified at serine, threonine, and tyrosine residues, 1050 novel phosphosites, corresponding to 402 proteins, were reported. Gene heatmaps for IPA canonical pathways showed a novel role for GSK-3 in GP6 signaling pathways associated with capacitation for 60 min. At the same time, the reduction of the abundant isoform-specific GSK-3α expression was shown by western blot (WB) while the LFQ pY of this isoform slightly decreased and then increased. The combined results from WB and LFQ methods explain the less inhibitory phosphorylation of GSK-3α during capacitation and also support the predicted increases in its activity. In addition, pAKAP4 increased at the Y156 site but decreased at the Y811 site in a capacitated state, even though IPA network analysis and WB analysis for overall pAKAP revealed upregulated trends. The potential roles of GSK-3 and AKAP4 in fertility are discussed. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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21 pages, 2642 KiB

Open AccessArticle

Proteomic Investigation of S-Nitrosylated Proteins During NO-Induced Adventitious Rooting of Cucumber

by Lijuan Niu, Jihua Yu, Weibiao Liao, Jianming Xie, Jian Yu, Jian Lv, Xuemei Xiao, Linli Hu and Yue Wu

Int. J. Mol. Sci. 2019, 20(21), 5363; https://doi.org/10.3390/ijms20215363 - 28 Oct 2019

Cited by 41 | Viewed by 4061

Abstract

Nitric oxide (NO) acts an essential signaling molecule that is involved in regulating various physiological and biochemical processes in plants. However, whether S-nitrosylation is a crucial molecular mechanism of NO is still largely unknown. In this study, 50 μM S-nitrosoglutathione (GSNO) treatment was found to have a maximum biological effect on promoting adventitious rooting in cucumber. Meanwhile, removal of endogenous NO significantly inhibited the development of adventitious roots implying that NO is responsible for promoting the process of adventitious rooting. Moreover, application of GSNO resulted in an increase of intracellular S-nitrosothiol (SNO) levels and endogenous NO production, while decreasing the S-nitrosoglutathione reductase (GSNOR) activity during adventitious rooting, implicating that S-nitrosylation might be involved in NO-induced adventitious rooting in cucumber. Furthermore, the identification of S-nitrosylated proteins was performed utilizing the liquid chromatography/mass spectrometry/mass spectrometry (LC-MS/MS) and biotin-switch technique during the development of adventitious rooting. Among these proteins, the activities and S-nitrosylated level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), tubulin alpha chain (TUA), and glutathione reductase (GR) were further analyzed as NO direct targets. Our results indicated that NO might enhance the S-nitrosylation level of GAPDH and GR, and was found to subsequently reduce these activities and transcriptional levels. Conversely, S-nitrosylation of TUA increased the expression level of TUA. The results implied that S-nitrosylation of key proteins seems to regulate various pathways through differential S-nitrosylation during adventitious rooting. Collectively, these results suggest that S-nitrosylation could be involved in NO-induced adventitious rooting, and they also provide fundamental evidence for the molecular mechanism of NO signaling during adventitious rooting in cucumber explants. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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Review

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27 pages, 2937 KiB

Open AccessReview

Role of Host-Mediated Post-Translational Modifications (PTMs) in RNA Virus Pathogenesis

by Ramesh Kumar, Divya Mehta, Nimisha Mishra, Debasis Nayak and Sujatha Sunil

Int. J. Mol. Sci. 2021, 22(1), 323; https://doi.org/10.3390/ijms22010323 - 30 Dec 2020

Cited by 87 | Viewed by 11904

Abstract

Being opportunistic intracellular pathogens, viruses are dependent on the host for their replication. They hijack host cellular machinery for their replication and survival by targeting crucial cellular physiological pathways, including transcription, translation, immune pathways, and apoptosis. Immediately after translation, the host and viral proteins undergo a process called post-translational modification (PTM). PTMs of proteins involves the attachment of small proteins, carbohydrates/lipids, or chemical groups to the proteins and are crucial for the proteins’ functioning. During viral infection, host proteins utilize PTMs to control the virus replication, using strategies like activating immune response pathways, inhibiting viral protein synthesis, and ultimately eliminating the virus from the host. PTM of viral proteins increases solubility, enhances antigenicity and virulence properties. However, RNA viruses are devoid of enzymes capable of introducing PTMs to their proteins. Hence, they utilize the host PTM machinery to promote their survival. Proteins from viruses belonging to the family: Togaviridae, Flaviviridae, Retroviridae, and Coronaviridae such as chikungunya, dengue, zika, HIV, and coronavirus are a few that are well-known to be modified. This review discusses various host and virus-mediated PTMs that play a role in the outcome during the infection. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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26 pages, 2626 KiB

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Putative Role of Protein Palmitoylation in Cardiac Lipid-Induced Insulin Resistance

by Francesco Schianchi, Jan F. C. Glatz, Artur Navarro Gascon, Miranda Nabben, Dietbert Neumann and Joost J. F. P. Luiken

Int. J. Mol. Sci. 2020, 21(24), 9438; https://doi.org/10.3390/ijms21249438 - 11 Dec 2020

Cited by 14 | Viewed by 4838

Abstract

In the heart, inhibition of the insulin cascade following lipid overload is strongly associated with contractile dysfunction. The translocation of fatty acid transporter CD36 (SR-B2) from intracellular stores to the cell surface is a hallmark event in the lipid-overloaded heart, feeding forward to intracellular lipid accumulation. Yet, the molecular mechanisms by which intracellularly arrived lipids induce insulin resistance is ill-understood. Bioactive lipid metabolites (diacyl-glycerols, ceramides) are contributing factors but fail to correlate with the degree of cardiac insulin resistance in diabetic humans. This leaves room for other lipid-induced mechanisms involved in lipid-induced insulin resistance, including protein palmitoylation. Protein palmitoylation encompasses the reversible covalent attachment of palmitate moieties to cysteine residues and is governed by protein acyl-transferases and thioesterases. The function of palmitoylation is to provide proteins with proper spatiotemporal localization, thereby securing the correct unwinding of signaling pathways. In this review, we provide examples of palmitoylations of individual signaling proteins to discuss the emerging role of protein palmitoylation as a modulator of the insulin signaling cascade. Second, we speculate how protein hyper-palmitoylations (including that of CD36), as they occur during lipid oversupply, may lead to insulin resistance. Finally, we conclude that the protein palmitoylation machinery may offer novel targets to fight lipid-induced cardiomyopathy. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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18 pages, 2458 KiB

Open AccessReview

Post-Translational Modifications of Circulating Alpha-1-Antitrypsin Protein

by Urszula Lechowicz, Stefan Rudzinski, Aleksandra Jezela-Stanek, Sabina Janciauskiene and Joanna Chorostowska-Wynimko

Int. J. Mol. Sci. 2020, 21(23), 9187; https://doi.org/10.3390/ijms21239187 - 2 Dec 2020

Cited by 40 | Viewed by 6562

Abstract

Alpha-1-antitrypsin (AAT), an acute-phase protein encoded by the SERPINA1 gene, is a member of the serine protease inhibitor (SERPIN) superfamily. Its primary function is to protect tissues from enzymes released during inflammation, such as neutrophil elastase and proteinase 3. In addition to its antiprotease activity, AAT interacts with numerous other substances and has various functions, mainly arising from the conformational flexibility of normal variants of AAT. Therefore, AAT has diverse biological functions and plays a role in various pathophysiological processes. This review discusses major molecular forms of AAT, including complex, cleaved, glycosylated, oxidized, and S-nitrosylated forms, in terms of their origin and function. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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20 pages, 2406 KiB

Open AccessReview

Post-Translational Modifications of Cytochrome c in Cell Life and Disease

by Alejandra Guerra-Castellano, Inmaculada Márquez, Gonzalo Pérez-Mejías, Antonio Díaz-Quintana, Miguel A. De la Rosa and Irene Díaz-Moreno

Int. J. Mol. Sci. 2020, 21(22), 8483; https://doi.org/10.3390/ijms21228483 - 11 Nov 2020

Cited by 36 | Viewed by 5159

Abstract

Mitochondria are the powerhouses of the cell, whilst their malfunction is related to several human pathologies, including neurodegenerative diseases, cardiovascular diseases, and various types of cancer. In mitochondrial metabolism, cytochrome c is a small soluble heme protein that acts as an essential redox carrier in the respiratory electron transport chain. However, cytochrome c is likewise an essential protein in the cytoplasm acting as an activator of programmed cell death. Such a dual role of cytochrome c in cell life and death is indeed fine-regulated by a wide variety of protein post-translational modifications. In this work, we show how these modifications can alter cytochrome c structure and functionality, thus emerging as a control mechanism of cell metabolism but also as a key element in development and prevention of pathologies. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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22 pages, 4710 KiB

Open AccessReview

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease

by Rui Wang, Hongyang Sun, Guanghui Wang and Haigang Ren

Int. J. Mol. Sci. 2020, 21(19), 7182; https://doi.org/10.3390/ijms21197182 - 29 Sep 2020

Cited by 34 | Viewed by 7433

Abstract

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. The neuropathological features of PD are selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta, deficiencies in striatal dopamine levels, and the presence of intracellular Lewy bodies. Interactions among aging and genetic and environmental factors are considered to underlie the common etiology of PD, which involves multiple changes in cellular processes. Recent studies suggest that changes in lysine acetylation and deacetylation of many proteins, including histones and nonhistone proteins, might be tightly associated with PD pathogenesis. Here, we summarize the changes in lysine acetylation of both histones and nonhistone proteins, as well as the related lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), in PD patients and various PD models. We discuss the potential roles and underlying mechanisms of these changes in PD and highlight that restoring the balance of lysine acetylation/deacetylation of histones and nonhistone proteins is critical for PD treatment. Finally, we discuss the advantages and disadvantages of different KAT/KDAC inhibitors or activators in the treatment of PD models and emphasize that SIRT1 and SIRT3 activators and SIRT2 inhibitors are the most promising effective therapeutics for PD. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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22 pages, 4513 KiB

Open AccessReview

Histone H1 Post-Translational Modifications: Update and Future Perspectives

by Marta Andrés, Daniel García-Gomis, Inma Ponte, Pedro Suau and Alicia Roque

Int. J. Mol. Sci. 2020, 21(16), 5941; https://doi.org/10.3390/ijms21165941 - 18 Aug 2020

Cited by 60 | Viewed by 11931

Abstract

Histone H1 is the most variable histone and its role at the epigenetic level is less characterized than that of core histones. In vertebrates, H1 is a multigene family, which can encode up to 11 subtypes. The H1 subtype composition is different among cell types during the cell cycle and differentiation. Mass spectrometry-based proteomics has added a new layer of complexity with the identification of a large number of post-translational modifications (PTMs) in H1. In this review, we summarize histone H1 PTMs from lower eukaryotes to humans, with a particular focus on mammalian PTMs. Special emphasis is made on PTMs, whose molecular function has been described. Post-translational modifications in H1 have been associated with the regulation of chromatin structure during the cell cycle as well as transcriptional activation, DNA damage response, and cellular differentiation. Additionally, PTMs in histone H1 that have been linked to diseases such as cancer, autoimmune disorders, and viral infection are examined. Future perspectives and challenges in the profiling of histone H1 PTMs are also discussed. Full article

(This article belongs to the Special Issue Protein Post-translational Modifications in Signal Transduction and Diseases)

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