PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism

Metabolic reprogramming is a hallmark of cancer, including lung cancer. However, the exact underlying mechanism and therapeutic potential are largely unknown. Here we report that protein arginine methyltransferase 6 (PRMT6) is highly expressed in lung cancer and is required for cell metabolism, tumorigenicity, and cisplatin response of lung cancer. PRMT6 regulated the oxidative pentose phosphate pathway (PPP) flux and glycolysis pathway in human lung cancer by increasing the activity of 6-phospho-gluconate dehydrogenase (6PGD) and α-enolase (ENO1). Furthermore, PRMT6 methylated R324 of 6PGD to enhancing its activity; while methylation at R9 and R372 of ENO1 promotes formation of active ENO1 dimers and 2-phosphoglycerate (2-PG) binding to ENO1, respectively. Lastly, targeting PRMT6 blocked the oxidative PPP flux, glycolysis pathway, and tumor growth, as well as enhanced the anti-tumor effects of cisplatin in lung cancer. Together, this study demonstrates that PRMT6 acts as a post-translational modification (PTM) regulator of glucose metabolism, which leads to the pathogenesis of lung cancer. It was proven that the PRMT6-6PGD/ENO1 regulatory axis is an important determinant of carcinogenesis and may become a promising cancer therapeutic strategy.

Research progress on targeted SUMOylation inhibitors and their antitumor activity / 药学学报

SUMOylation is an important post-translational modification of proteins. Similar to ubiquitylation, SUMOylation is the process that the small ubiquitin-like modifier (SUMO) proteins are specifically and covalently binding to lysine residues of substrate proteins. Through SUMOylation, the physiological functions and pathological processes of cells are well controlled and balanced, and its abnormal activation has been reported in various tumors. Therefore, SUMOylation has been a potential target for anti-tumor drug development. In this review, we summarize recent advances on development of inhibitors targeting SUMOylation pathway and their antitumor properties.

Genetic incorporation of unnatural amino acids into proteins and its translational application in biomedicine / 中国药科大学学报

@#Proteins in the human body are usually made of 20 natural amino acids.Through different amino acid combinations and isomerization, proteins of diverse functions are built.An emerging genetic code expansion technology can introduce unnatural amino acids into specific sites of target protein, endowing the protein with new biological characteristics including covalently binding with proximal proteins, carrying fluorescence, and mimicking specific protein post-translational modifications.In this paper, based on the structure and function of unnatural amino acids, the applications of different types of unnatural amino acids in regulating protein''s stability, studying protein''s conformation, expression level, and localization, and uncovering heretofore unknown protein-protein interactions were reviewed.Besides, genetic code expansion of unnatural amino acids is anticipated to find broad utilities in biomedicine by bringing new ideas and methods to the design and optimization of biologics.

Role of acetylation modification of host proteins in tuberculosis / 中华微生物学和免疫学杂志

Post-translational modification of host proteins induced by pathogenic microorganism plays a critical role in the development, treatment and prevention of diseases. Mycobacterium tuberculosis ( Mtb) is an intracellular pathogen that causes tuberculosis. The post-translational modification induced by Mtb infection is essential in the development and progression of tuberculosis. In recent years, it has been found that Mtb-induced host protein acetylation plays an important role in the regulation of host immunity against tuberculosis, which significantly affects the development of tuberculosis. This review focused on the role and mechanism of Mtb in regulating host protein acetylation, aiming to provide reference for future investigation on potential immunotherapy for tuberculosis.

Effects of human albumin products on human stem cell culture / 中国输血杂志

【Objective】 To compare the effects of human albumin products from different domestic manufacturers on human stem cell culture. 【Methods】 Human CD34+ cells were cultured by supplementing human albumin from different manufacturers to serum-free medium, and the expansion ratios of cells within 15 days were counted. Post translational modifications of human albumin products were studied by LC-MS. 【Results】 Supplementing plasma-derived human albumin(pd-alb) to serum-free medium, the expansion ratios of cells could reach up to 20.6±5.7, while the recombinant human albumin(rhAlb) resulted in no significant expansion within 15 days. LC-MS showed significant differences in post-translational modifications from different human albumin products. 【Conclusion】 Different human albumin products showed significantly different effects in the expansion of stem cells due to different sources, processes and stabilizers. Pd-alb products were better for stem cell culture than rhAlb products. There are significant differences between pd-albs and rhAlbs in post-translational modification, but whether these differences are related to stem cell expansion remains to be studied.

Mining histone methyltransferases and demethylases from whole genome sequence

Epigenetic regulation through post-translational modification of histones, especially methylation, is wellconserved in evolution. Although there are several insect genomes sequenced, an analysis with a focus on theirepigenetic repertoire is limited. We have utilized a novel work-flow to identify one or more domains as highpriority domain (HPD), if present in at least 50% of the genes of a given functional class in the referencegenome, namely, that of Drosophila melanogaster. Based on this approach, we have mined histone methyltransferases and demethylases from the whole genome sequence of Aedes aegypti (Diptera), the pea aphidAcyrthosiphon pisum, the triatomid bug Rhodnius prolixus (Hemiptera), the honeybee Apis mellifera (Hymenoptera), the silkworm Bombyx mori (Lepidoptera) and the red flour beetle Tribolium castaneum(Coleoptera). We identified 38 clusters consisting of arginine methyltransferases, lysine methyltransferases anddemethylases using OrthoFinder, and the presence of HPD was queried in these sequences using InterProScan.This approach led us to identify putative novel members and currently inaccurate ones. Other than the highpriority domains, these proteins contain shared and unique domains that can mediate protein–protein interaction. Phylogenetic analysis indicates that there is different extent of protein sequence similarity; averagesimilarity between histone lysine methyltransferases varies from 41% (for active mark) to 48% (for repressivemark), arginine methyltransferases is 51%, and demethylases is 52%. The method utilized here facilitatesreliable identification of desired functional class in newly sequenced genomes

Characterization of Lysine Monomethylome and Methyltransferase in Model Cyanobacterium Synechocystis sp. PCC 6803 / 基因组蛋白质组与生物信息学报·英文版

Protein lysine methylation is a prevalent post-translational modification (PTM) and plays critical roles in all domains of life. However, its extent and function in photosynthetic organisms are still largely unknown. Cyanobacteria are a large group of prokaryotes that carry out oxygenic photosynthesis and are applied extensively in studies of photosynthetic mechanisms and environmental adaptation. Here we integrated propionylation of monomethylated proteins, enrichment of the modified peptides, and mass spectrometry (MS) analysis to identify monomethylated proteins in Synechocystis sp. PCC 6803 (Synechocystis). Overall, we identified 376 monomethylation sites in 270 proteins, with numerous monomethylated proteins participating in photosynthesis and carbon metabolism. We subsequently demonstrated that CpcM, a previously identified asparagine methyltransferase in Synechocystis, could catalyze lysine monomethylation of the potential aspartate aminotransferase Sll0480 both in vivo and in vitro and regulate the enzyme activity of Sll0480. The loss of CpcM led to decreases in the maximum quantum yield in primary photosystem II (PSII) and the efficiency of energy transfer during the photosynthetic reaction in Synechocystis. We report the first lysine monomethylome in a photosynthetic organism and present a critical database for functional analyses of monomethylation in cyanobacteria. The large number of monomethylated proteins and the identification of CpcM as the lysine methyltransferase in cyanobacteria suggest that reversible methylation may influence the metabolic process and photosynthesis in both cyanobacteria and plants.

Advances in salivary protein glycosylation and its relationship with systemic and oral diseases / 华西口腔医学杂志

Protein glycosylation is one of the most important protein post-translational modifications that can affect life activities by endowing the protein with various structural and functional features. Saliva is an easy-to-obtain, noninvasive body fluid that contains components originating from serum, gingival crevicular fluid, and oropharyngeal mucosae. In recent years, understanding of saliva has been constantly updated with the developments in related research. Studies have shown that salivary proteins can be used as diagnostic markers for certain diseases, and changes of protein glycosylation in saliva are generally considered to be related to many diseases. In this review, salivary protein glycosylation and its relationship with systemic and oral diseases were discussed.

Advances on the effect of post-translational modification on HMGB1 localization / 医学研究生学报

High mobility group box 1 (HMGB1) is a highly conserved and evolutionarily non-histone chromosomal protein that is modified by different PTMs,such as acetylation,glycosylation,phosphorylation,ADP-ribosylation,methylation and oxidation,which induces HMGB1 translocation to the cytosol or releases to the extracellular secretion following various stimuli,and its biological function also changes with the location change.This review aims to summarize the structure,the effect of PTMs on HMGB1 location and function.

Potential coordination role between O-GlcNAcylation and epigenetics

Dynamic changes of the post-translational O-GlcNAc modification (O-GlcNAcylation) are controlled by O-linked β-N-acetylglucosamine (O-GlcNAc) transferase (OGT) and the glycoside hydrolase O-GlcNAcase (OGA) in cells. O-GlcNAcylation often occurs on serine (Ser) and threonine (Thr) residues of the specific substrate proteins via the addition of O-GlcNAc group by OGT. It has been known that O-GlcNAcylation is not only involved in many fundamental cellular processes, but also plays an important role in cancer development through various mechanisms. Recently, accumulating data reveal that O-GlcNAcylation at histones or non-histone proteins can lead to the start of the subsequent biological processes, suggesting that O-GlcNAcylation as 'protein code' or 'histone code' may provide recognition platforms or executive instructions for subsequent recruitment of proteins to carry out the specific functions. In this review, we summarize the interaction of O-GlcNAcylation and epigenetic changes, introduce recent research findings that link crosstalk between O-GlcNAcylation and epigenetic changes, and speculate on the potential coordination role of O-GlcNAcylation with epigenetic changes in intracellular biological processes.

Interdependence of laforin and malin proteins for their stability and functions could underlie the molecular basis of locus heterogeneity in Lafora disease.

Lafora disease (LD), an autosomal recessive and fatal form of neurodegenerative disorder, is characterized by the presence of polyglucosan inclusions in the affected tissues including the brain. LD can be caused by defects either in the EPM2A gene coding for the laforin protein phosphatase or the NHLRC1 gene coding for the malin ubiquitin ligase. Since the clinical symptoms of LD patients representing the two genetic groups are very similar and since malin is known to interact with laforin, we were curious to examine the possibility that the two proteins regulate each other’s function. Using cell biological assays we demonstrate here that (i) malin promotes its own degradation via autoubiquitination, (ii) laforin prevents the auto-degradation of malin by presenting itself as a substrate and (iii) malin preferentially degrades the phosphatase-inactive laforin monomer. Our results that laforin and malin regulate each other’s stability and activity offers a novel and attractive model to explain the molecular basis of locus heterogeneity observed in LD.

Molecular differences between recombinant coagulation factors and plasma-derived coagulation factors, and their effects on pharmacology and efficacy / 国际药学研究杂志

Since their successful launch, the recombinant coagulation factors have been effective in the treatment and prophylaxis of respective deficiencies, and started to replace plasma-derived coagulation factors. However, immunogenicity and induction of inhibitors associated with the uses of these recombinant products have drawn certain attention. This manuscript reviews the structural differences between several major recombinant coagulation factors and their plasma-derived counteiparts, including sequences and many forms of post-translational modifications, and discusses the possible effects of these structural differences on the pharmacology, efficacy and pharmacokinetics of the products. The demonstration of structural differences and underlying mechanisms helps to improve the production yield and quality of recombinant coagulation factors, which is of significant clinical importance.

Role of transcription factor acetylation in the regulation of metabolic homeostasis

Post-translational modifications (PTMs) of transcription factors play a crucial role in regulating metabolic homeostasis. These modifications include phosphorylation, methylation, acetylation, ubiquitination, SUMOylation, and O-GlcNAcylation. Recent studies have shed light on the importance of lysine acetylation at nonhistone proteins including transcription factors. Acetylation of transcription factors affects subcellular distribution, DNA affinity, stability, transcriptional activity, and current investigations are aiming to further expand our understanding of the role of lysine acetylation of transcription factors. In this review, we summarize recent studies that provide new insights into the role of protein lysine-acetylation in the transcriptional regulation of metabolic homeostasis.

Molecular differences between recombinant coagulation factors and plasma-derived coagulation factors, and their effects on pharmacology and efficacy / 国际药学研究杂志

Since their successful launch, the recombinant coagulation factors have been effective in the treatment and prophylaxis of respective deficiencies, and started to replace plasma-derived coagulation factors. However, immunogenicity and induction of inhibitors associated with the uses of these recombinant products have drawn certain attention. This manuscript reviews the structural differences between several major recombinant coagulation factors and their plasma-derived counterparts, including sequences and many forms of post-translational modifications, and discusses the possible effects of these structural differences on the pharmacology, efficacy and pharmacokinetics of the products. The demonstration of structural differences and underlying mechanisms helps to improve the production yield and quality of recombinant coagulation factors, which is of significant clinical importance.

Indentification of several kinds of post-translational modifications in recombinant protein pharmaceuticals using MS/MS / 中国药学杂志

OBJECTIVE: To identify several kinds of post-translational modifications in recombinant protein pharmaceuticals by MS/MS. METHODS: Firstly the proteins were digested with enzymes, and the obtained peptides were analyzed by UPLC-MS. By MS analysis, peptides with post-translational modifications could be detected, then it was then identified by MS/MS. RESULTS: Using MS/MS, the disulfide bonds, peptides with similar molecular mass, O-glycosylation site and the type of N-linked oligosaccharides were identified. CONCLUSION: MS/MS analvsis can make up for the deficiency of enzyme digestion in some extent, and provide more sufficient evidence for the identification of post-translational modifications.

The Expression of HDAC2 In PeripheraI BIood MononucIear CeIIs from Patients with Sudden SensorineuraI Hearing Loss / 听力学及言语疾病杂志

Objective To evaluate expression of HDAC2 in peripheral blood mononuclear cells(PBMCs)from glucocorticoid-resistant versus glucocorticoid-sensitive patients with sudden sensorineural hearing loss and identi-ty the relationship between the level of HDAC2 and glucocorticoid insensitivity.Methods PBMCs were collected from10 patients with deviation of nasal septum (control group)and 20 sudden sensorineural hearing loss patients be-fore and after intratympanic methylprednisolone for 10 days.We divided the SSNHL patients into 2 groups (GC sensitive group and GC insensitive group)according to their hearing recovery.Real time PCR and HDAC2 Assay Kit were used to detect the expression level of HDAC2 mRNA and HDAC2 activity in PBMCs.The data were analyzed with SPSS 17.0 software.ResuIts Before intratympanic methylprednisolone,the level of HDAC2 activity were sig-nificantly depressed in SSNHL patients,while the HDAC2 mRNA expressing much higher than the control group. The expression level of HDAC2 mRNA increased significantly after intratympanic methylprednisolone.The HDAC2 activity in GC sensitive group increased significantly.ConcIusion Knockdown of HDAC2 expression induces corti-costeroid in-sensitivity.Glucocorticoids can increase the expression of HDAC2 mRNA.HDAC2 activity can be down-regulated by post-translational modifications.

Research progress on racemization of crystallins and pathogenesis of cataract / 中华实验眼科杂志

Racemization is probably the most abundant post-translational modification (PTM) in aged lens.According to previous studies,L-amino acid in α,β and γ crystallins are tend to transfer into D-amino acid with aging,leading to a series of age-related changes in the structure,metabolism and function of lens.Aggregated highmolecular-weight proteins gradually accumulate in both nuclear and cortex region,which will have a negative effect on the function of crystallins and finally lead to capacity of lens.Moreover,it is likely that racemization of crystallins eventually leads to cataract formation and development as well.The material effect and mechanism of racemization changes in human age-related lens still requires further research.

Post-Translational Modification of Proteins in Toxicological Research: Focus on Lysine Acylation

Toxicoproteomics integrates the proteomic knowledge into toxicology by enabling protein quantification in biofluids and tissues, thus taking toxicological research to the next level. Post-translational modification (PTM) alters the three-dimensional (3D) structure of proteins by covalently binding small molecules to them and therefore represents a major protein function diversification mechanism. Because of the crucial roles PTM plays in biological systems, the identification of novel PTMs and study of the role of PTMs are gaining much attention in proteomics research. Of the 300 known PTMs, protein acylation, including lysine formylation, acetylation, propionylation, butyrylation, malonylation, succinylation, and crotonylation, regulates the crucial functions of many eukaryotic proteins involved in cellular metabolism, cell cycle, aging, growth, angiogenesis, and cancer. Here, I reviewed recent studies regarding novel types of lysine acylation, their biological functions, and their applicationsin toxicoproteomics research.

Stathmin: a potential tumor biomarker / 肿瘤

Stathmin, a ubiquitously expressed cytosolic protein(Mr=19×10~3), is also called oncogene protein 18 (Op18). Stathmin is involved in the assembly of microtubule (MT) and spindle by binding the tubulin protein. It plays a key role in cell proliferation, differentiation, regeneration, and migration and has regulatory effects on the signal transduction. Recently, it is reported that stathmin is overexpressed in a variety of human malignancies. It induces tumor cell migration and invasion by regulating MT depolymeri-zation. Its post-translational modification influences the interaction with p53 protein and is involved in the initiation and progression of malignant tumor. Stathmin alone or in combination with chemotherapeutics has been used for tumor therapy. The internal association of stathmin with cancer etiology is still unknown. So, further studies are needed to determine the role of stathmin as potential tumor biomarker and a drug target in tumor therapy.

Influence of oxidative stress on p53 post-translational modifications / 上海交通大学学报（医学版）

Protein post-translational modifications are important ways to regulate protein function and cell behavior, and oxidative stress directly influences protein post-translational modifications. P53 protein has various post-translational modifications, which can be quickly regulated under stress conditions to activate a series of downstream target genes and facilitate the p53 function diversity. The effects of oxidative stress on p53 post-translational modifications of phosphorylation, ubiquitination, sumoylation, acetylation and methylation are introduced in this paper.