Explore the vast range of titles available.

Protein post‐translational modifications (PTMs) allow the cell to regulate protein activity and play a crucial role in the response to changes in external conditions or internal states. Advances in mass spectrometry now enable proteome wide characterization of PTMs and have revealed a broad functional role for a range of different types of modifications. Here we review advances in the study of the evolution and function of PTMs that were spurred by these technological improvements. We provide an overview of studies focusing on the origin and evolution of regulatory enzymes as well as the evolutionary dynamics of modification sites. Finally, we discuss different mechanisms of altering protein activity via post‐translational regulation and progress made in the large‐scale functional characterization of PTM function. Graphical Abstract Advances in proteomics have opened new avenues for the analysis of the evolution of protein post‐translational modifications (PTMs) and have enabled the large‐scale functional characterization of a range of different modifications types.

Histones are DNA‐binding basic proteins found in chromosomes. After the histone translation, its amino tail undergoes various modifications, such as methylation, acetylation, phosphorylation, ubiquitination, malonylation, propionylation, butyrylation, crotonylation, and lactylation, which together constitute the “histone code.” The relationship between their combination and biological function can be used as an important epigenetic marker. Methylation and demethylation of the same histone residue, acetylation and deacetylation, phosphorylation and dephosphorylation, and even methylation and acetylation between different histone residues cooperate or antagonize with each other, forming a complex network. Histone‐modifying enzymes, which cause numerous histone codes, have become a hot topic in the research on cancer therapeutic targets. Therefore, a thorough understanding of the role of histone post‐translational modifications (PTMs) in cell life activities is very important for preventing and treating human diseases. In this review, several most thoroughly studied and newly discovered histone PTMs are introduced. Furthermore, we focus on the histone‐modifying enzymes with carcinogenic potential, their abnormal modification sites in various tumors, and multiple essential molecular regulation mechanism. Finally, we summarize the missing areas of the current research and point out the direction of future research. We hope to provide a comprehensive understanding and promote further research in this field. Histone tails are subject to a variety of post‐translational modifications. We have introduced histone acetylation, methylation, phosphorylation, ubiquitination, malonylation, crotonylation, propionylation, butyrylation, and so forth. They participate in many life activities through different related histone sites.

Skeletal muscle makes up 30–40% of the total body mass. It is of great significance in maintaining digestion, inhaling and exhaling, sustaining body posture, exercising, protecting joints and many other aspects. Moreover, muscle is also an important metabolic organ that helps to maintain the balance of sugar and fat. Defective skeletal muscle function not only limits the daily activities of the elderly but also increases the risk of disability, hospitalization and death, placing a huge burden on society and the healthcare system. Sarcopenia is a progressive decline in muscle mass, muscle strength and muscle function with age caused by environmental and genetic factors, such as the abnormal regulation of protein post‐translational modifications (PTMs). To date, many studies have shown that numerous PTMs, such as phosphorylation, acetylation, ubiquitination, SUMOylation, glycosylation, glycation, methylation, S‐nitrosylation, carbonylation and S‐glutathionylation, are involved in the regulation of muscle health and diseases. This article systematically summarizes the post‐translational regulation of muscle growth and muscle atrophy and helps to understand the pathophysiology of muscle aging and develop effective strategies for diagnosing, preventing and treating sarcopenia.

Brain tumors are one of the most severe types of malignant tumors and glioma accounts for ~80% of malignant brain tumors. The current treatment methods for glioma are limited and patients with glioma often experience relapse following treatment, which leads to a poor prognosis for these patients. Therefore, novel therapeutic targets and methods urgently need to be explored. The present review screened studies that mainly focused on the epigenetic regulation of small guanosine triphosphate (GTP)ase in glioma. These small GTPases participate in most cellular biological processes, including differentiation, proliferation, cell migration, apoptosis, vesicle and organelle dynamics and transport, nuclear dynamics and cytoskeleton regulation. Due to the diversity and importance of the biological functions of small GTPases, an increasing number of studies have focused on them; however, the incidence of changes in the gene structure of small GTPases is considered to be low in glioma. Several studies have shown that the abnormal expression of genes encoding small GTPases is often influenced by epigenetic regulation in glioma. Epigenetic regulation is a dynamic and reversible process, which implies that the reversal of abnormal epigenetic modifications is a potential treatment strategy for glioma. These previous studies, which are summarized in the present review, not only provide new therapeutic targets and prognostic markers, but also provide information regarding the treatment of glioma. The current review may provide valuable insights for future research and promote the clinical translation of relevant research results.

A gas chromatography-mass spectrometry (GC–MS) method was developed and validated in relevant concentration ranges for the simultaneous measurement of l-lysine (Lys, L) and its Nε- and Nα-methylated (M), Nε- and Nα-acetylated (Ac), Nε-carboxymethylated (CM) and Nε-carboxyethylated (CE) metabolites in human urine. Analyzed Lys metabolites were the post-translational modification (PTM) products Nε-mono-, di- and trimethyllsine, Nε-MML, Nε-DML, Nε-TML, respectively, Nα-ML, Nε-AcL, Nα-AcL, and its advanced glycation end-products (AGEs) Nε-CML, Nε-CM-[2,4,4-2H3]Lys (d3-CML), Nε-CEL and furosine. AGEs of arginine (Arg) and cysteine (Cys) were also analyzed. De novo synthesized trideutero-methyl esters (R-COOCD3) from unlabelled amino acids and derivatives were used as internal standards. Native urine samples (10 µL aliquots) were evaporated to dryness under a stream of nitrogen. Analytes were esterified using 2 M HCl in methanol (60 min, 80 °C) and subsequently amidated by pentafluoropropionic anhydride in ethyl acetate (30 min, 65 °C). The generated methyl ester-pentafluoropropionyl (Me-PFP) derivatives were reconstituted in borate buffer and extracted immediately with toluene. GC–MS analyses were performed by split-less injection of 1-µL aliquots, oven-programmed separation and negative-ion chemical ionization (NICI). Mass spectra were generated in the scan mode (range, m/z 50–1000). Quantification was performed in the selected-ion monitoring (SIM) mode using a dwell time of 50 or 100 ms for each ion. The GC–MS method was suitable for the measurement of Lys and all of its metabolites, except for the quaternary ammonium cation Nε-TML. The Me-PFP derivatives of Lys, Arg and Cys and its metabolites eluted in the retention time window of 9 to 14 min. The derivatization of Nε-CML, d3-CML and Nε-CEL was accompanied by partial Nε-decarboxylation and formation of the Me-PFP Lys derivative. The lowest derivatization yield was observed for Nε-DML, indicating a major role of the Nε-DML group in Lys derivatization. The GC–MS method enables precise (relative standard deviation, RSD < 20%) and accurate (bias, < ± 20%) simultaneous measurement of 33 analytes in human urine in relevant concentration ranges. We used the method to measure the urinary excretion rates of Lys and its PTM metabolites and AGEs in healthy black (n = 39) and white (n = 41) boys of the Arterial Stiffness in Offspring Study (ASOS). No remarkable differences were found indicating no ethnic-related differences in PTM metabolites and AGEs except for Nε-monomethyllysine and S-(2-carboxymethylcysteine).

Backgroud Glioblastoma multiforme (GBM) is among the most aggressive cancers, with current treatments limited in efficacy. A significant hurdle in the treatment of GBM is the resistance to the chemotherapeutic agent temozolomide (TMZ). The methylation status of the MGMT promoter has been implicated as a critical biomarker of response to TMZ. Methods To explore the mechanisms underlying resistance, we developed two TMZ‐resistant GBM cell lines through a gradual increase in TMZ exposure. Transcriptome sequencing of TMZ‐resistant cell lines revealed that alterations in histone post‐translational modifications might be instrumental in conferring TMZ resistance. Subsequently, multi‐omics analysis suggests a strong association between histone H3 lysine 9 acetylation (H3K9ac) levels and TMZ resistance. Results We observed a significant correlation between the expression of H3K9ac and MGMT, particularly in the unmethylated MGMT promoter samples. More importantly, our findings suggest that H3K9ac may enhance MGMT transcription by facilitating the recruitment of the SP1 transcription factor to the MGMT transcription factor binding site. Additionally, by analyzing single‐cell transcriptomics data from matched primary and recurrent GBM tumors treated with TMZ, we modeled the molecular shifts occurring upon tumor recurrence. We also noted a reduction in tumor stem cell characteristics, accompanied by an increase in H3K9ac, SP1, and MGMT levels, underscoring the potential role of H3K9ac in tumor relapse following TMZ therapy. Conclusions The increase in H3K9ac appears to enhance the recruitment of the transcription factor SP1 to its binding sites within the MGMT locus, consequently upregulating MGMT expression and driving TMZ resistance in GBM. The acetylation of histone H3 at lysine 9 leads to an open chromatin structure at the MGMT gene locus, facilitating the binding of transcription factors SP1 to the promoter and enhancer regions, resulting in increased transcription of MGMT, thereby contributing to the TMZ resistance in GBM cells.

Key Points O -GlcNAcylation is a nutrient- and stress-responsive post-translational modification (PTM) that involves the attachment of O -linked N -acetylglucosamine moieties to Ser and Thr residues of cytoplasmic, nuclear and mitochondrial proteins. A single pair of enzymes — O -GlcNAc transferase (OGT) and O -GlcNAcase (OGA) — controls the dynamic cycling of this PTM. Potential mechanisms that enable a single OGT enzyme to recognize hundreds of protein substrates include substrate-specific interactions with the tetratricopeptide repeat (TPR) domain of OGT and context-dependent recruitment of OGT to its substrates by a hierarchy of conserved adaptor proteins. Furthermore, in response to cellular stress, O -GlcNAcylation may occur nonspecifically in unstructured regions of unfolded proteins in order to block their aggregation and degradation and facilitate their refolding. O -GlcNAcylation is involved in the spatiotemporal regulation of diverse cellular processes, which include transcription, epigenetic modifications and cell signalling dynamics. O -GlcNAcylation is highly dynamic and often transient, but the mechanisms underlying the temporal control of O -GlcNAc signalling are largely unknown. Nutrient availability regulates cellular O -GlcNAcylation levels not only by determining the abundance of the donor substrate uridine diphosphate GlcNAc (UDP-GlcNAc) but also by modulating the levels of OGT, OGA and their respective adaptor proteins and substrates. Hormones such as insulin, glucagon and ghrelin are secreted in response to systemic metabolic changes and modulate O -GlcNAc signalling in specific cell types and tissues to regulate key response pathways that help maintain metabolic homeostasis. Cellular O -GlcNAcylation levels may be maintained within an 'optimal zone' by a 'buffering system' that is generated by mutual regulation of OGT and OGA at the transcriptional and post-translational levels. Maintenance of O -GlcNAc homeostasis is essential for optimal cellular function, and disruption of the cellular O -GlcNAcylation 'buffer' may contribute to the pathogenesis of various human diseases. O -GlcNAcylation can be viewed as the essential 'grease and glue' of the cell: it acts as a 'grease' by coating target proteins (folded or unfolded, mature or nascent) and preventing unwanted protein aggregation or modification; it also acts as a 'glue' by modulating protein–protein interactions in time and space in response to internal and external cues, thereby affecting the functions of various proteins in the cell. Many cellular proteins are reversibly modified by O -linked N -acetylglucosamine ( O -GlcNAc) moieties on Ser and Thr residues. Studies on the mechanisms and functions of O -GlcNAcylation and its links to metabolism reveal the importance of this modification in the maintenance of cellular and organismal homeostasis. O -GlcNAcylation — the attachment of O -linked N -acetylglucosamine ( O -GlcNAc) moieties to cytoplasmic, nuclear and mitochondrial proteins — is a post-translational modification that regulates fundamental cellular processes in metazoans. A single pair of enzymes — O -GlcNAc transferase (OGT) and O -GlcNAcase (OGA) — controls the dynamic cycling of this protein modification in a nutrient- and stress-responsive manner. Recent years have seen remarkable advances in our understanding of O -GlcNAcylation at levels that range from structural and molecular biology to cell signalling and gene regulation to physiology and disease. New mechanisms and functions of O -GlcNAcylation that are emerging from these recent developments enable us to begin constructing a unified conceptual framework through which the significance of this modification in cellular and organismal physiology can be understood.

Nε-lysine acetylation was discovered more than half a century ago as a post-translational modification of histones and has been extensively studied in the context of transcription regulation. In the past decade, proteomic analyses have revealed that non-histone proteins are frequently acetylated and constitute a major portion of the acetylome in mammalian cells. Indeed, non-histone protein acetylation is involved in key cellular processes relevant to physiology and disease, such as gene transcription, DNA damage repair, cell division, signal transduction, protein folding, autophagy and metabolism. Acetylation affects protein functions through diverse mechanisms, including by regulating protein stability, enzymatic activity, subcellular localization and crosstalk with other post-translational modifications and by controlling protein–protein and protein–DNA interactions. In this Review, we discuss recent progress in our understanding of the scope, functional diversity and mechanisms of non-histone protein acetylation.

Post‐translational modifications are key in the regulation of activity, structure, localization, and stability of most proteins in eukaryotes. Phosphorylation is potentially the most studied post‐translational modification, also due to its reversibility and thereby the regulatory role this modification often plays. While most research attention was focused on kinases in the past, phosphatases remain understudied, most probably because the addition and presence of the modification is more easily studied than its removal and absence. Here, we report the identification of an uncharacterized protein tyrosine phosphatase PPH‐7 in C. elegans, a member of the evolutionary conserved PTPN family of phosphatases. Lack of PPH‐7 function led to reduction of fertility and embryonic lethality at elevated temperatures. Proteomics revealed changes in the regulation of targets of the von Hippel–Lindau (VHL) E3 ligase, suggesting a potential role for PPH‐7 in the regulation of VHL. Using long‐read sequencing, we identify the genetic lesion in a temperature‐sensitive C. elegans mutant. We find that a previously uncharacterized tyrosine phosphatase (PPH‐7) is required for spermatogenesis and embryonic development at elevated temperatures. Analysis of the proteome revealed that multiple known targets of the Von Hippel–Lindau tumor suppressor are downregulated in PPH‐7 deficient mutants.

Background End-stage renal disease (ESRD) is a condition that is characterized by the loss of kidney function. ESRD patients suffer from various endothelial dysfunctions, inflammation, and immune system defects. Lysine malonylation (Kmal) is a recently discovered post-translational modification (PTM). Although Kmal has the ability to regulate a wide range of biological processes in various organisms, its specific role in ESRD is limited. Methods In this study, the affinity enrichment and liquid chromatography-tandem mass spectrometry (LC-MS/MS) techniques have been used to create the first global proteome and malonyl proteome (malonylome) profiles of peripheral blood mononuclear cells (PBMCs) from twenty patients with ESRD and eighty-one controls. Results On analysis, 793 differentially expressed proteins (DEPs) and 12 differentially malonylated proteins (DMPs) with 16 Kmal sites were identified. The Rap1 signaling pathway and platelet activation pathway were found to be important in the development of chronic kidney disease (CKD), as were DMPs TLN1 and ACTB, as well as one malonylated site. One conserved Kmal motif was also discovered. Conclusions These findings provided the first report on the Kmal profile in ESRD, which could be useful in understanding the potential role of lysine malonylation modification in the development of ESRD.