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Viruses Jan 2024Influenza A virus (IAV) is one of the most circulated human pathogens, and influenza disease, commonly known as the flu, remains one of the most recurring and prevalent... (Review)
Review
Influenza A virus (IAV) is one of the most circulated human pathogens, and influenza disease, commonly known as the flu, remains one of the most recurring and prevalent infectious human diseases globally. IAV continues to challenge existing vaccines and antiviral drugs via its ability to evolve constantly. It is critical to identify the molecular determinants of IAV pathogenesis to understand the basis of flu severity in different populations and design improved antiviral strategies. In recent years, acetylation has been identified as one of the determinants of IAV pathogenesis. Acetylation was originally discovered as an epigenetic protein modification of histones. But, it is now known to be one of the ubiquitous protein modifications of both histones and non-histone proteins and a determinant of proteome complexity. Since our first observation in 2007, significant progress has been made in understanding the role of acetylation during IAV infection. Now, it is becoming clearer that acetylation plays a pro-IAV function via at least three mechanisms: (1) by reducing the host's sensing of IAV infection, (2) by dampening the host's innate antiviral response against IAV, and (3) by aiding the stability and function of viral and host proteins during IAV infection. In turn, IAV antagonizes the host deacetylases, which erase acetylation, to facilitate its replication. This review provides an overview of the research progress made on this subject so far and outlines research prospects for the significance of IAV-acetylation interplay.
Topics: Humans; Acetylation; Histones; Epigenesis, Genetic; Influenza A virus; Influenza, Human; Antiviral Agents
PubMed: 38257831
DOI: 10.3390/v16010131 -
European Journal of Pharmacology Sep 2022Deregulation of protein post-translational modifications is intensively involved in the etiology of diseases, including degenerative diseases, inflammatory injuries, and... (Review)
Review
Deregulation of protein post-translational modifications is intensively involved in the etiology of diseases, including degenerative diseases, inflammatory injuries, and cancers. Acetylation is one of the most common post-translational modifications of proteins, and the acetylation levels are controlled by two mutually antagonistic enzyme families, histone acetyl transferases (HATs) and histone deacetylases (HDACs). HATs loosen the chromatin structure by neutralizing the positive charge of lysine residues of histones; whereas HDACs deacetylate certain histones, thus inhibiting gene transcription. Compared with HATs, HDACs have been more intensively studied, particularly regarding their clinical significance. HDACs extensively participate in the regulation of proliferation, migration, angiogenesis, immune escape, and therapeutic resistance of cancer cells, thus emerging as critical targets for clinical cancer therapy. Compared to HATs, inhibitors of HDAC have been clinically used for cancer treatment. Here, we enumerate and integratethe mechanisms of HDAC family members in tumorigenesis and cancer progression, and address the new and exciting therapeutic implications of single or combined HDAC inhibitor (HDACi) treatment.
Topics: Acetylation; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Humans; Neoplasms
PubMed: 35988787
DOI: 10.1016/j.ejphar.2022.175216 -
Biochimica Et Biophysica Acta. Gene... Sep 2023Circadian rhythm is a roughly 24-h wake and sleep cycle that almost all of the organisms on the earth follow when they execute their biological functions and... (Review)
Review
Circadian rhythm is a roughly 24-h wake and sleep cycle that almost all of the organisms on the earth follow when they execute their biological functions and physiological activities. The circadian clock is mainly regulated by the transcription-translation feedback loop (TTFL), consisting of the core clock proteins, including BMAL1, CLOCK, PERs, CRYs, and a series of accessory factors. The circadian clock and the downstream gene expression are not only controlled at the transcriptional and translational levels but also precisely regulated at the post-translational modification level. Recently, it has been discovered that CLOCK exhibits lysine acetyltransferase activities and could acetylate protein substrates. Core clock proteins are also acetylated, thereby altering their biological functions in the regulation of the expression of downstream genes. Studies have revealed that many protein acetylation events exhibit oscillation behavior. However, the biological function of acetylation on circadian rhythm has only begun to explore. This review will briefly introduce the acetylation and deacetylation of the core clock proteins and summarize the proteins whose acetylation is regulated by CLOCK and circadian rhythm. Then, we will also discuss the crosstalk between lysine acetylation and the circadian clock or other post-translational modifications. Finally, we will briefly describe the possible future perspectives in the field.
Topics: CLOCK Proteins; Lysine; Acetylation; Circadian Rhythm; Protein Processing, Post-Translational
PubMed: 37453648
DOI: 10.1016/j.bbagrm.2023.194958 -
American Journal of Physiology.... Jul 2023Lysine acetylation of proteins has emerged as a key posttranslational modification (PTM) that regulates mitochondrial metabolism. Acetylation may regulate energy...
Lysine acetylation of proteins has emerged as a key posttranslational modification (PTM) that regulates mitochondrial metabolism. Acetylation may regulate energy metabolism by inhibiting and affecting the stability of metabolic enzymes and oxidative phosphorylation (OxPhos) subunits. Although protein turnover can be easily measured, due to the low abundance of modified proteins, it has been difficult to evaluate the effect of acetylation on the stability of proteins in vivo. We applied HO-metabolic labeling coupled with immunoaffinity and high-resolution mass spectrometry method to measure the stability of acetylated proteins in mouse liver based on their turnover rates. As a proof-of-concept, we assessed the consequence of high-fat diet (HFD)-induced altered acetylation in protein turnover in LDL receptor-deficient (LDLR) mice susceptible to diet-induced nonalcoholic fatty liver disease (NAFLD). HFD feeding for 12 wk led to steatosis, the early stage of NAFLD. A significant reduction in acetylation of hepatic proteins was observed in NAFLD mice, based on immunoblot analysis and label-free quantification with mass spectrometry. Compared with control mice on a normal diet, NAFLD mice had overall increased turnover rates of hepatic proteins, including mitochondrial metabolic enzymes (0.159 ± 0.079 vs. 0.132 ± 0.068 day), suggesting their reduced stability. Also, acetylated proteins had slower turnover rates (increased stability) than native proteins in both groups (0.096 ± 0.056 vs. 0.170 ± 0.059 day in control, and 0.111 ± 0.050 vs. 0.208 ± 0.074 day in NAFLD). Furthermore, association analysis revealed a relationship between the HFD-induced decrease in acetylation and increased turnover rates for hepatic proteins in NAFLD mice. These changes were associated with increased expressions of the hepatic mitochondrial transcriptional factor (TFAM) and complex II subunit without any changes to other OxPhos proteins, suggesting that enhanced mitochondrial biogenesis prevented restricted acetylation-mediated depletion of mitochondrial proteins. We conclude that decreased acetylation of mitochondrial proteins may contribute to adaptive improved hepatic mitochondrial function in the early stages of NAFLD. This is the first method to quantify acetylome dynamics in vivo. This method revealed acetylation-mediated altered hepatic mitochondrial protein turnover in response to a high-fat diet in a mouse model of NAFLD.
Topics: Animals; Mice; Non-alcoholic Fatty Liver Disease; Diet, High-Fat; Acetylation; Liver; Protein Processing, Post-Translational; Mitochondrial Proteins; Mitochondrial Turnover; Mice, Inbred C57BL
PubMed: 37224468
DOI: 10.1152/ajpendo.00310.2022 -
Journal of Neurochemistry Aug 2022Lysine acetylation is a reversible post-translational modification (PTM) involved in multiple physiological functions. Recent studies have demonstrated the involvement...
Lysine acetylation is a reversible post-translational modification (PTM) involved in multiple physiological functions. Recent studies have demonstrated the involvement of protein acetylation in modulating the biology of Schwann cells (SCs) and regeneration of the peripheral nervous system (PNS). However, the mechanisms underlying these processes remain partially understood. Here, we characterized the acetylome of the mouse sciatic nerve (SN) and investigated the cellular distribution of acetylated proteins. We identified 483 acetylated proteins containing 1442 acetylation modification sites in the SN of adult C57BL/6 mice. Bioinformatics suggested that these acetylated SN proteins were mainly located in the myelin sheath, mitochondrial inner membrane, and cytoskeleton, and highlighted the significant differences between the mouse SN and brain acetylome. Manual annotation further indicated that most acetylated proteins (> 45%) were associated with mitochondria, energy metabolism, and cytoskeleton and cell adhesion. We verified three newly discovered acetylation-modified proteins, including neurofilament light polypeptide (NEFL), neurofilament medium/high polypeptide (NFM/H), and periaxin (PRX). Immunofluorescence illustrated that the acetylated proteins, including acetylated alpha-tubulin, were mainly co-localized with S100-positive SCs. Herein, we provided a comprehensive acetylome for the mouse SN and demonstrated that acetylated proteins in the SN were predominantly located in SCs. These results will extend our understanding and promote further study of the role and mechanism of protein acetylation in SC development and PNS regeneration.
Topics: Acetylation; Animals; Lysine; Mice; Mice, Inbred C57BL; Protein Processing, Post-Translational; Proteome; Sciatic Nerve
PubMed: 35585794
DOI: 10.1111/jnc.15648 -
Comprehensive Reviews in Food Science... Jan 2021Meat quality plays an important role in the purchase decision of consumers, affecting producers and retailers. The formation mechanisms determining meat quality are... (Review)
Review
Meat quality plays an important role in the purchase decision of consumers, affecting producers and retailers. The formation mechanisms determining meat quality are intricate, as several endogenous and exogenous factors contribute during antemortem and postmortem periods. Abundant research has been performed on meat quality; however, unexpected variation in meat quality remains an issue in the meat industry. Protein posttranslational modifications (PTMs) regulate structures and functions of proteins in living tissues, and recent reports confirmed their importance in meat quality. The objective of this review was to provide a summary of the research on the effects of PTMs on meat quality. The effects of four common PTMs, namely, protein phosphorylation, acetylation, S-nitrosylation, and ubiquitination, on meat quality were discussed, with emphasis on the effects of protein phosphorylation on meat tenderness, color, and water holding capacity. The mechanisms and factors that may affect the function of protein phosphorylation are also discussed. The current research confirms that meat quality traits are regulated by multiple PTMs. Cross talk between different PTMs and interactions of PTMs with postmortem biochemical processes need to be explored to improve our understanding on factors affecting meat quality.
Topics: Acetylation; Meat; Phosphorylation; Protein Processing, Post-Translational; Proteins
PubMed: 33443799
DOI: 10.1111/1541-4337.12668 -
Nature Communications Sep 2023The histone acetyltransferase p300/CBP is composed of several conserved domains, among which, the TAZ2 domain is known as a protein-protein interaction domain that binds...
The histone acetyltransferase p300/CBP is composed of several conserved domains, among which, the TAZ2 domain is known as a protein-protein interaction domain that binds to E1A and various transcription factors. Here we show that TAZ2 has a HAT autoinhibitory function. Truncating p300/CBP at TAZ2 leads to hyperactive HAT and elevated histone H3K27 and H3K18 acetylation in cells. Mechanistically, TAZ2 cooperates with other HAT neighboring domains to maintain the HAT active site in a 'closed' state. Truncating TAZ2 or binding of transcription factors to TAZ2 induces a conformational change that 'opens' the active site for substrate acetylation. Importantly, genetic mutations that lead to p300/CBP TAZ2 truncations are found in human cancers, and cells with TAZ2 truncations are vulnerable to histone deacetylase inhibitors. Our study reveals a function of the TAZ2 domain in HAT autoinhibitory regulation and provides a potential therapeutic strategy for the treatment of cancers harboring p300/CBP TAZ2 truncations.
Topics: Humans; Acetylation; Histone Deacetylase Inhibitors; Histones; Inhibition, Psychological; Transcription Factors
PubMed: 37660055
DOI: 10.1038/s41467-023-41245-2 -
Biochimica Et Biophysica Acta. Gene... Feb 2021General Control Non-repressed 5 protein (GCN5), encoded by the mammalian gene Kat2a, is the first histone acetyltransferase discovered to link histone acetylation to... (Review)
Review
General Control Non-repressed 5 protein (GCN5), encoded by the mammalian gene Kat2a, is the first histone acetyltransferase discovered to link histone acetylation to transcriptional activation [1]. The enzymatic activity of GCN5 is linked to cellular metabolic and energetic states regulating gene expression programs. GCN5 has a major impact on energy metabolism by i) sensing acetyl-CoA, a central metabolite and substrate of the GCN5 catalytic reaction, and ii) acetylating proteins such as PGC-1α, a transcriptional coactivator that controls genes linked to energy metabolism and mitochondrial biogenesis. PGC-1α is biochemically associated with the GCN5 protein complex during active metabolic reprogramming. In the first part of the review, we examine how metabolism can change GCN5-dependent histone acetylation to regulate gene expression to adapt cells. In the second part, we summarize the GCN5 function as a nutrient sensor, focusing on non-histone protein acetylation, mainly the metabolic role of PGC-1α acetylation across different tissues.
Topics: Acetyl Coenzyme A; Acetylation; Adipose Tissue; Animals; Energy Metabolism; Glucose; Histones; Humans; Liver; Mitochondria; Nutrients; Organelle Biogenesis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Thermogenesis; Trans-Activators; Transcriptional Activation; p300-CBP Transcription Factors
PubMed: 32827753
DOI: 10.1016/j.bbagrm.2020.194626 -
Journal of Magnetic Resonance (San... Apr 2022Selective detection of biomolecules and their modifications in cells is essential for understanding cell functions and diseases. We have developed an NMR pulse sequence,...
Selective detection of biomolecules and their modifications in cells is essential for understanding cell functions and diseases. We have developed an NMR pulse sequence, Ac-FIND (Acetylation-FIltered aNd eDited), which uses isotope editing/filtering techniques for selective detection of protein acetylation. Acetylation of the N-terminus and lysine side chains by N-succinimidyl acetate was selectively observed for intrinsically disordered α-synuclein and well-ordered ubiquitin. Furthermore, when nonacetylated C/N-enriched α-synuclein was introduced into live HEK293 cells, intracellular N-terminal acetylation of α-synuclein was detected by the appearance of a single peak using Ac-FIND. This work demonstrates the utility of NMR to detect a specific protein modification both in vitro and in live cells.
Topics: Acetylation; HEK293 Cells; Humans; Magnetic Resonance Spectroscopy; Protein Structure, Secondary; alpha-Synuclein
PubMed: 35255256
DOI: 10.1016/j.jmr.2022.107169 -
Journal of Microbiology (Seoul, Korea) Dec 2020Protein lysine acetylation influences many physiological functions, such as gene regulation, metabolism, and disease in eukaryotes. Although little is known about the... (Review)
Review
Protein lysine acetylation influences many physiological functions, such as gene regulation, metabolism, and disease in eukaryotes. Although little is known about the role of lysine acetylation in bacteria, several reports have proposed its importance in various cellular processes. Here, we discussed the function of the protein lysine acetylation and the post-translational modifications (PTMs) of histone-like proteins in bacteria focusing on Salmonella pathogenicity. The protein lysine residue in Salmonella is acetylated by the Pat-mediated enzymatic pathway or by the acetyl phosphate-mediated non-enzymatic pathway. In Salmonella, the acetylation of lysine 102 and lysine 201 on PhoP inhibits its protein activity and DNA-binding, respectively. Lysine acetylation of the transcriptional regulator, HilD, also inhibits pathogenic gene expression. Moreover, it has been reported that the protein acetylation patterns significantly differ in the drug-resistant and -sensitive Salmonella strains. In addition, nucleoid-associated proteins such as histone-like nucleoid structuring protein (H-NS) are critical for the gene silencing in bacteria, and PTMs in H-NS also affect the gene expression. In this review, we suggest that protein lysine acetylation and the post-translational modifications of H-NS are important factors in understanding the regulation of gene expression responsible for pathogenicity in Salmonella.
Topics: Acetylation; Bacteria; Bacterial Proteins; DNA-Binding Proteins; Gene Expression Regulation, Bacterial; Gene Silencing; Lysine; Protein Processing, Post-Translational; Salmonella; Salmonella typhimurium; Transcription Factors; Virulence
PubMed: 33201432
DOI: 10.1007/s12275-020-0483-8