GCN5 maintains muscle integrity by acetylating YY1 to promote dystrophin expression

Protein lysine acetylation is a post-translational modification that regulates protein structure and function. It is targeted to proteins by lysine acetyltransferases (KATs) or removed by lysine deacetylases. This work identifies a role for the KAT enzyme general control of amino acid synthesis protein 5 (GCN5; KAT2A) in regulating muscle integrity by inhibiting DNA binding of the transcription factor/repressor Yin Yang 1 (YY1). Here we report that a muscle-specific mouse knockout of GCN5 (Gcn5skm−/−) reduces the expression of key structural muscle proteins, including dystrophin, resulting in myopathy. GCN5 was found to acetylate YY1 at two residues (K392 and K393), disrupting the interaction between the YY1 zinc finger region and DNA. These findings were supported by human data, including an observed negative correlation between YY1 gene expression and muscle fiber diameter. Collectively, GCN5 positively regulates muscle integrity through maintenance of structural protein expression via acetylation-dependent inhibition of YY1. This work implicates the role of protein acetylation in the regulation of muscle health and for consideration in the design of novel therapeutic strategies to support healthy muscle during myopathy or aging.

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Role of the DksA-Like Protein in the Pathogenesis and Diverse Metabolic Activity of Campylobacter jejuni

Journal of Bacteriology ◽

10.1128/jb.00105-08 ◽

2008 ◽

Vol 190 (13) ◽

pp. 4512-4520 ◽

Cited By ~ 18

Author(s):

Jiae Yun ◽

Byeonghwa Jeon ◽

Yi-Wen Barton ◽

Paul Plummer ◽

Qijing Zhang ◽

...

Keyword(s):

Amino Acid ◽

Campylobacter Jejuni ◽

Pathogenic Bacteria ◽

Acid Metabolism ◽

Acid Synthesis ◽

Regulatory Role ◽

Intestinal Cells ◽

Amino Acid Synthesis ◽

Metabolic Reactions

ABSTRACT DksA is well known for its regulatory role in the transcription of rRNA and genes involved in amino acid synthesis in many bacteria. DksA has also been reported to control expression of virulence genes in pathogenic bacteria. Here, we elucidated the roles of a DksA-like protein (CJJ81176_0160, Cj0125c) in the pathogenesis of Campylobacter jejuni. As in other bacteria, transcription of stable RNA was repressed by the DksA-like protein under stress conditions in C. jejuni. Transcriptomic and proteomic analyses of C. jejuni 81-176 and an isogenic mutant lacking the DksA-like protein showed differential expression of many genes involved in amino acid metabolism, iron-related metabolism, and other metabolic reactions. Also, the C. jejuni DksA-like protein mutant exhibited a decreased ability to invade intestinal cells and induce release of interleukin-8 from intestinal cells. These results suggest that the DksA-like protein plays an important regulatory role in diverse metabolic events and the virulence of C. jejuni.

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Microbial amino acid synthesis and utilization in rats: the role of coprophagy

British Journal Of Nutrition ◽

10.1079/bjn19960077 ◽

1996 ◽

Vol 76 (5) ◽

pp. 701-709 ◽

Cited By ~ 28

Author(s):

David Torrallardona ◽

C. Ian Harris ◽

Malcolm F. Fuller

Keyword(s):

Body Weight ◽

Isotope Ratio Mass Spectrometry ◽

Acid Synthesis ◽

Exchange Chromatography ◽

The Body ◽

Amino Acid Synthesis ◽

Low Protein ◽

N Enrichment ◽

Fermentable Carbohydrates

Four rats were housed in cages with mesh floors; another four rats were housed in tubular anti-coprophagy cages, in which they could not turn round to reach their own faeces. Both groups were fed for 6 d on a low-protein diet containing fermentable carbohydrates and 15NH4Cl. At the end of the experiment the rats were killed and their carcasses were homogenized, lysine was isolated by ion-exchange chromatography and its 15N enrichment measured by isotope-ratio mass spectrometry. The 15N enrichment in the lysine of the microbial fraction of faeces and the total amount of lysine in the body were also determined in order to estimate the amount of microbial lysine absorbed. The 15N enrichment in body lysine of non-coprophagic rats was not different from that previously measured in rats given unlabelled NH4Cl, but in coprophagic rats it was significantly higher. The daily absorption of microbial lysine by the coprophagic rats accounted for 20·7 (SE 2·55) mg/kg body weight0·75 but was only 0·5 (SE 1·04) mg/kg body weight0·75 for the non-coprophagic rats. This value was not significantly different from zero. The utilization of microbial amino acids via coprophagy resulted in a higher weight gain (adjusted for intake) in the coprophagic group (15·5 g/6 d) than in the non-coprophagic rats (3·1 g/6 d). It was concluded that, in rats, the utilization of microbial lysine occurred exclusively via coprophagy.

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Identification the role of mono-ADP-ribosylation in colorectal cancer by integrated Transcriptome analysis

10.21203/rs.3.rs-212814/v1 ◽

2021 ◽

Author(s):

Shuxian Zhang ◽

Jiale Duan ◽

Yanping Yang ◽

Hanjuan Gong ◽

Yi Tang ◽

...

Keyword(s):

Colorectal Cancer ◽

Endoplasmic Reticulum ◽

Alternative Splicing ◽

Enrichment Analysis ◽

Drug Candidate ◽

Post Translational Modification ◽

Lentiviral Infection ◽

Whole Transcriptome Sequencing ◽

And Function

Abstract Purpose Our previous study has clarified the carcinogenic properties of arginine-specific mono-ADP ribosyltransferase 1(ART1), which is considered to be a critical post-translational modification that changes the structure and function of proteins and is widely involved in important processes. This study provides, for the first time, a comprehensive insight of transcriptomic analysis for colorectal cancer cells interfered with ART1 silencing by Illumina RNA-Seq and related verification experiments. Methods Lentiviral infection was used to construct a CT-26 cell line that stably knocks down the ART1 gene, a whole transcriptome sequencing technique was performed to identify differentially expressed genes (DEGs). GO and KEGG classification/enrichment analysis and verification experiments were performed to determine the role of ART1 in the progression of colorectal cancer. Results a total of 5552 DEGs, GO function and KEGG pathway with highest enrichment, forms of SNP and diverse splicing patterns were able to be identified. Importantly, knockdown of ART1 affected the occurrence of the splicing of certain key genes related to tumor cell growth, also down-regulated expression of the key gene PTBP1 for alternative splicing. The overall attenuation of the endoplasmic reticulum unfolded protein response (UPR) signaling pathway caused by ART1 inhibition would unbalance UPR signaling, leading to the occurrence of apoptosis to impede tumorigenesis. Conclusion ART1, which clustered in organelles, may promote the development of colorectal cancer by participating in a variety of new mechanisms including endoplasmic reticulum stress regulation, metabolic process or alternative splicing, which may provide a good clinical drug candidate closer to targeted therapy of CRC.

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Transcriptomic Bioinformatic Analyses of Atria Uncover Involvement of Pathways Related to Strain and Post-translational Modification of Collagen in Increased Atrial Fibrillation Vulnerability in Intensely Exercised Mice

Frontiers in Physiology ◽

10.3389/fphys.2020.605671 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yena Oh ◽

Sibao Yang ◽

Xueyan Liu ◽

Sayantan Jana ◽

Farzad Izaddoustdar ◽

...

Keyword(s):

Atrial Fibrillation ◽

Cardiovascular Health ◽

Venous Pressure ◽

Post Translational Modification ◽

Time Points ◽

Ventricular Structure ◽

And Function ◽

Collagen Genes ◽

Necrosis Factor

Atrial Fibrillation (AF) is the most common supraventricular tachyarrhythmia that is typically associated with cardiovascular disease (CVD) and poor cardiovascular health. Paradoxically, endurance athletes are also at risk for AF. While it is well-established that persistent AF is associated with atrial fibrosis, hypertrophy and inflammation, intensely exercised mice showed similar adverse atrial changes and increased AF vulnerability, which required tumor necrosis factor (TNF) signaling, even though ventricular structure and function improved. To identify some of the molecular factors underlying the chamber-specific and TNF-dependent atrial changes induced by exercise, we performed transcriptome analyses of hearts from wild-type and TNF-knockout mice following exercise for 2 days, 2 or 6 weeks of exercise. Consistent with the central role of atrial stretch arising from elevated venous pressure in AF promotion, all 3 time points were associated with differential regulation of genes in atria linked to mechanosensing (focal adhesion kinase, integrins and cell-cell communications), extracellular matrix (ECM) and TNF pathways, with TNF appearing to play a permissive, rather than causal, role in gene changes. Importantly, mechanosensing/ECM genes were only enriched, along with tubulin- and hypertrophy-related genes after 2 days of exercise while being downregulated at 2 and 6 weeks, suggesting that early reactive strain-dependent remodeling with exercise yields to compensatory adjustments. Moreover, at the later time points, there was also downregulation of both collagen genes and genes involved in collagen turnover, a pattern mirroring aging-related fibrosis. By comparison, twofold fewer genes were differentially regulated in ventricles vs. atria, independently of TNF. Our findings reveal that exercise promotes TNF-dependent atrial transcriptome remodeling of ECM/mechanosensing pathways, consistent with increased preload and atrial stretch seen with exercise. We propose that similar preload-dependent mechanisms are responsible for atrial changes and AF in both CVD patients and athletes.

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Post Translational Modification and its pathologic association in Rheumatoid Arthritis: A brief perspective

Current Protein and Peptide Science ◽

10.2174/1389203722666210215152433 ◽

2021 ◽

Vol 22 ◽

Author(s):

Vishnupreetha Vasudevan ◽

Prachi Agnihotri ◽

Sagarika Biswas

Keyword(s):

Rheumatoid Arthritis ◽

Bone Pain ◽

Cyclic Peptide ◽

Delayed Diagnosis ◽

Living System ◽

The Body ◽

Post Translational Modification ◽

And Function ◽

Inflammatory Autoimmune Disease

: Post Translational Modification (PTM) is the process in which covalent addition of functional groups on protein happens to maintain their structure, function and stability. Every PTM process in our living system happens to increase the functional diversity of protein. But sometimes it happens without any regulation and occurrence of this specific change in proteins are leading to autoimmunity. Rheumatoid arthritis (RA) is one such chronic, inflammatory, autoimmune disease that affects joints. Proper treatment can be manageable for RA, but it is not completely curable. Delayed diagnosis of RA can cause severe bone pain, stiffness, inflammation, redness in joints and affect other parts of the body such as liver, kidney etc. Early diagnosis of disease is preferable to cure it effectively. Currently, Rheumatoid factor (RF) and anti-citrullinated cyclic peptide (Anti-CCP) are considered as biomarkers to diagnose RA. Other than citrullination several other PTM’s are also involved in generation of autoantibodies such as, carbamylation, glycosylation, glycation, acetylation, ubiquitination, proteolysis, phosphorylation, lipidation. Aim of this review is to elucidate several considerable changes in form, nature and function of above PTMs in RA, affecting joints and day to day life. This review will give a recent overview on the role of PTMs in the pathogenesis of RA, focusing on the modifications.

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Role of O-acetylhomoserine sulfhydrylase in sulfur amino acid synthesis in various yeasts

Yeast ◽

10.1002/yea.320091207 ◽

1993 ◽

Vol 9 (12) ◽

pp. 1335-1342 ◽

Cited By ~ 12

Author(s):

Jerzy Brzywczy ◽

Andrzej Paszewski

Keyword(s):

Amino Acid ◽

Acid Synthesis ◽

Sulfur Amino Acid ◽

Amino Acid Synthesis

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Molecular Dynamics of SARS-CoV-2 Nsp1 Structural Changes Associated with Variant Mutations

10.21203/rs.3.rs-781636/v1 ◽

2021 ◽

Author(s):

Shokouh Rezaei ◽

Yahya Sefidbakht ◽

Filipe Pereira

Keyword(s):

Molecular Dynamics ◽

Conformational Changes ◽

Structural Changes ◽

Structure And Function ◽

Dynamics Simulation ◽

Structural Protein ◽

Wild Type ◽

Deletion Mutations ◽

And Function

Abstract SARS-CoV-2 non-structural protein 1 (Nsp1) is a virulence factor that inhibits the translation of host mRNAs and interact with viral RNA. Despite the relevance of Nsp1, few studies have been conducted to understand the effect of mutations on Nsp1 structure and function. Here, we provide a molecular dynamics simulation of SARS-CoV-2 Nsp1, wild type and variants. We found that SARS-CoV-2 Nsp1 has a more Rg value than SARS-CoV-1 Nsp1, with indicate an effect on the folding protein. This result suggest that SARS-CoV-2 Nsp1 can more easily approach the active site of the ribosome compared to SARS-CoV-1 Nsp1. In addition, we found that the C-terminal of the SARS-CoV-2 Nsp1, in particular residues 164 to 170, are more flexible than other regions of SARS-CoV-2 Nsp1 and SARS-CoV-1 Nsp1, confirming the role of this region in the interaction with the 40S subunit. Moreover, multiple deletion mutations have been found in the N/C-terminal of the SARS-CoV-2 Nsp1, which seems the effect of SARS-CoV-2 Nsp1 multiple deletions is greater than that of substitutions. Among all deletions, D156-158 and D80-90 may destabilize the protein structure and possibly increase the virulence of the SARS-CoV-2. Overall, our findings reinforce the importance of studying Nsp1 conformational changes in new variants and its effect on virulence of SARS-CoV-2.

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Comprehensive Proteomic Analysis of Lysine Acetylation in Nicotiana benthamiana After Sensing CWMV Infection

Frontiers in Microbiology ◽

10.3389/fmicb.2021.672559 ◽

2021 ◽

Vol 12 ◽

Author(s):

Bowen Yuan ◽

Tingting Liu ◽

Ye Cheng ◽

Shiqi Gao ◽

Linzhi Li ◽

...

Keyword(s):

Nicotiana Benthamiana ◽

Lysine Acetylation ◽

Biological Processes ◽

Post Translational Modification ◽

Cellular Regulation ◽

Histone 3 ◽

Protein Lysine Acetylation ◽

Related Proteins ◽

Chinese Wheat

Protein lysine acetylation (Kac) is an important post-translational modification mechanism in eukaryotes that is involved in cellular regulation. To investigate the role of Kac in virus-infected plants, we characterized the lysine acetylome of Nicotiana benthamiana plants with or without a Chinese wheat mosaic virus (CWMV) infection. We identified 4,803 acetylated lysine sites on 1,964 proteins. A comparison of the acetylation levels of the CWMV-infected group with those of the uninfected group revealed that 747 sites were upregulated on 422 proteins, including chloroplast localization proteins and histone H3, and 150 sites were downregulated on 102 proteins. Nineteen conserved motifs were extracted and 51 percent of the acetylated proteins located on chloroplast. Nineteen Kac sites were located on histone proteins, including 10 Kac sites on histone 3. Bioinformatics analysis results indicated that lysine acetylation occurs on a large number of proteins involved in biological processes, especially photosynthesis. Furthermore, we found that the acetylation level of chloroplast proteins, histone 3 and some metabolic pathway-related proteins were significantly higher in CWMV-infected plants than in uninfected plants. In summary, our results reveal the regulatory roles of Kac in response to CWMV infection.

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Inhibition of SENP2-mediated Akt deSUMOylation promotes cardiac regeneration via activating Akt pathway

Clinical Science ◽

10.1042/cs20201408 ◽

2021 ◽

Vol 135 (6) ◽

pp. 811-828

Author(s):

Yijin Chen ◽

Tong Xu ◽

Mengsha Li ◽

Chuling Li ◽

Yusheng Ma ◽

...

Keyword(s):

Heart Development ◽

Cardiac Regeneration ◽

Akt Pathway ◽

Post Translational Modification ◽

Specific Protease ◽

Differentiation And Proliferation ◽

Novel Therapeutic Strategies

AbstractPost-translational modification (PTM) by small ubiquitin-like modifier (SUMO) is a key regulator of cell proliferation and can be readily reversed by a family of SUMO-specific proteases (SENPs), making SUMOylation an ideal regulatory mechanism for developing novel therapeutic strategies for promoting a cardiac regenerative response. However, the role of SUMOylation in cardiac regeneration remains unknown. In the present study, we assessed whether targeting protein kinase B (Akt) SUMOylation can promote cardiac regeneration. Quantitative PCR and Western blotting results showed that small ubiquitin-like modifier-specific protease 2 (SENP2) is up-regulated during postnatal heart development. SENP2 deficiency promoted P7 and adult cardiomyocyte (CM) dedifferentiation and proliferation both in vitro and in vivo. Mice with SENP2 deficiency exhibited improved cardiac function after MI due to CM proliferation and angiogenesis. Mechanistically, the loss of SENP2 up-regulated Akt SUMOylation levels and increased Akt kinase activity, leading to a decrease in GSK3β levels and subsequently promoting CM proliferation and angiogenesis. In summary, inhibition of SENP2-mediated Akt deSUMOylation promotes CM differentiation and proliferation by activating the Akt pathway. Our results provide new insights into the role of SUMOylation in cardiac regeneration.

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The nuclear factor-kappaB (NF-kappaB): from a versatile transcription factor to a ubiquitous therapeutic target.

Acta Biochimica Polonica ◽

10.18388/abp.2006_3293 ◽

2006 ◽

Vol 53 (4) ◽

pp. 651-662 ◽

Cited By ~ 21

Author(s):

Laura L Yates ◽

Dariusz C Górecki

Keyword(s):

Nuclear Factor Kappab ◽

Specific Response ◽

Nuclear Factor ◽

Therapeutic Approaches ◽

Altered Regulation ◽

Nf Kappab ◽

Novel Therapeutic Strategies ◽

And Function

The nuclear factor-kappaB (NF-kappaB) transcription factors regulate a plethora of cellular pathways and processes including the immune response, inflammation, proliferation, apoptosis and calcium homeostasis. In addition to the complexity of its physiological roles, the composition and function of this family of proteins is very complicated. While the basic understanding of NF-kappaB signalling is extensive, relatively little is know of the in vivo dynamics of this pathway or what controls the balance between various outcomes. Although we know a large number of NF-kappaB-responsive genes, the contribution of these genes to a specific response is not always clear. Finally, the involvement of NF-kappaB in pathological processes is only now beginning to be unravelled. In addition to cancer and immunodeficiency disorders, altered regulation of NF-kappaB has been associated with several inherited diseases. These findings indicate that modulation of the NF-kappaB pathways may be beneficial. However, our limited knowledge of NF-kappaB signalling hinders therapeutic approaches: in many situations it is not clear whether the enhancement or inhibition of NF-kappaB activity would be beneficial or which pathways to interfere with and what the required level of activation is. Further studies of the role of NF-kappaB are needed as these may result in novel therapeutic strategies for a wide variety of diseases.

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