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Frontiers in Oncology 2024The oncogenesis and development of glioblastoma multiforme have been linked to glycosylation modifications, which are common post-translational protein modifications....
The oncogenesis and development of glioblastoma multiforme have been linked to glycosylation modifications, which are common post-translational protein modifications. Abnormal glycosyltransferase development leads to irregular glycosylation patterns, which hold clinical significance for GB prognosis. By utilizing both single-cell and bulk data, we developed a scoring system to assess glycosylation levels in GB. Moreover, a glycosylation-based signature was created to predict GB outcomes and therapy responsiveness. The study led to the development of an glyco-model incorporating nine key genes. This risk assessment tool effectively stratified GB patients into two distinct groups. Extensive validation through ROC analysis, RMST, and Kaplan-Meier (KM) survival analysis emphasized the model's robust predictive capabilities. Additionally, a nomogram was constructed to predict survival rates at specific time intervals. The research revealed substantial disparities in immune cell infiltration between low-risk and high-risk groups, characterized by differences in immune cell abundance and elevated immune scores. Notably, the glyco-model predicted diverse responses to immune checkpoint inhibitors and drug therapies, with high-risk groups exhibiting a preference for immune checkpoint inhibitors and demonstrated superior responses to drug treatments. Furthermore, the study identified two potential drug targets and utilized Connectivity Map analysis to pinpoint promising therapeutic agents. Clofarabine and YM155 were identified as potent candidates for the treatment of high-risk GB. Our well-crafted glyco-model effectively discriminates patients by calculating the risk score, accurately predicting GB outcomes, and significantly enhancing prognostic assessment while identifying novel immunotherapeutic and chemotherapeutic strategies for GB treatment.
PubMed: 38841168
DOI: 10.3389/fonc.2024.1288820 -
Frontiers in Immunology 2024Because of the considerable tumor heterogeneity in gastric cancer (GC), only a limited group of patients experiences positive outcomes from immunotherapy. Herein, we aim...
Because of the considerable tumor heterogeneity in gastric cancer (GC), only a limited group of patients experiences positive outcomes from immunotherapy. Herein, we aim to develop predictive models related to glycosylation genes to provide a more comprehensive understanding of immunotherapy for GC. RNA sequencing (RNA-seq) data and corresponding clinical outcomes were obtained from GEO and TCGA databases, and glycosylation-related genes were obtained from GlycoGene DataBase. We identified 48 differentially expressed glycosylation-related genes and established a prognostic model (seven prognosis genes including ) based on these glycosylation-related genes using the results from Cox regression analysis. We found that these glycosylation-related genes revealed a robust correlation with the abundance of Tumor Infiltrating Lymphocytes (TILs), especially the GLT8D2 which is associated with many TILs. Finally, we employed immunohistochemistry and Multiplex Immunohistochemical to discover that GLT8D2 serves as a valuable prognostic biomarker in GC and is closely associated with macrophage-related markers. Collectively, we established a prognostic model based on glycosylation-related genes to provide a more comprehensive understanding of prediction for GC prognosis, and identified that GLT8D2 is closely correlated with adverse prognosis and may underscore its role in regulating immune cell infiltration in GC patients.
Topics: Humans; Stomach Neoplasms; Biomarkers, Tumor; Lymphocytes, Tumor-Infiltrating; Prognosis; Glycosylation; Female; Male; Gene Expression Regulation, Neoplastic; Middle Aged; Tumor Microenvironment
PubMed: 38840920
DOI: 10.3389/fimmu.2024.1370367 -
Kidney Diseases (Basel, Switzerland) Jun 2024IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel...
INTRODUCTION
IgA nephropathy (IgAN) is a leading cause of end-stage renal disease. The exact pathogenesis of IgAN is not well defined, but some genetic studies have led to a novel discovery that the (immuno)proteasome probably plays an important role in IgAN.
METHODS
We firstly analyzed the association of variants in the region with susceptibility to IgAN in 3,495 patients and 9,101 controls, and then analyzed the association between lead variant and clinical phenotypes in 1,803 patients with regular follow-up data. The blood mRNA levels of members of the ubiquitin-proteasome system including were analyzed in peripheral blood mononuclear cells from 53 patients and 28 healthy controls. The associations between and the expression levels of genes involved in Gd-IgA1 production were also explored.
RESULTS
The rs131654 showed the most significant association signal in region (OR: 1.10, 95% CI: 1.04-1.16, = 2.29 × 10), whose genotypes were also associated with the levels of Gd-IgA1 ( = 0.04). The rs131654 was observed to exert eQTL effects on in various tissues and cell types, particularly in immune cell types in multiple databases. The , , and proteasome subunits were highly expressed in patients compared with healthy controls. High expression levels of were not only associated with higher proteinuria ( = 0.34, = 0.01) and lower eGFR ( = -0.28, = 0.04), but also positively correlated with the gene expression of and other proteasome subunits. Additionally, mRNA expression levels of were also positively correlated with IL-6 and , but negatively correlated with the expression levels of the key enzyme in the process of glycosylation including and .
CONCLUSION
In conclusion, by combined genetic association and differed expression analysis of , our data support a role of genetically conferred dysregulation of the (immuno)proteasome in regulating galactose-deficient IgA1 in the development of IgAN.
PubMed: 38835407
DOI: 10.1159/000537987 -
Discover Oncology Jun 2024Colorectal cancer is a leading cause of cancer-related mortality worldwide. Traditionally, colorectal cancer has been recognized as a disease caused by genetic... (Review)
Review
Colorectal cancer is a leading cause of cancer-related mortality worldwide. Traditionally, colorectal cancer has been recognized as a disease caused by genetic mutations. However, recent studies have revealed the significant role of epigenetic alterations in the progression of colorectal cancer. Epithelial-mesenchymal transition, a critical step in cancer cell metastasis, has been found to be closely associated with the tumor microenvironment and immune factors, thereby playing a crucial role in many kinds of biological behaviors of cancers. In this review, we explored the impact of N6-methyladenosine and post-translational modifications (like methylation, acetylation, ubiquitination, SUMOylation, glycosylation, etc.) on the process of epithelial-mesenchymal transition in colorectal cancer and the epigenetic regulation for the transcription factors and pathways correlated to epithelial-mesenchymal transition. Furthermore, we emphasized that the complex regulation of epithelial-mesenchymal transition by epigenetics can provide new strategies for overcoming drug resistance and improving treatment outcomes. This review aims to provide important scientific evidence for the prevention and treatment of colorectal cancer based on epigenetic modifications.
PubMed: 38834851
DOI: 10.1007/s12672-024-01048-3 -
Proceedings of the National Academy of... Jun 2024Microalgae are promising production platforms for the cost-effective production of recombinant proteins. We have recently established that the red alga provides...
Microalgae are promising production platforms for the cost-effective production of recombinant proteins. We have recently established that the red alga provides superior transgene expression properties, due to the episomal maintenance of transformation vectors as multicopy plasmids in the nucleus. Here, we have explored the potential of to synthesize complex pharmaceutical proteins to high levels. Testing expression constructs for a candidate subunit vaccine against the hepatitis C virus (HCV), we show that the soluble HCV E2 glycoprotein can be produced in transgenic algal cultures to high levels. The antigen undergoes faithful posttranslational modification by N-glycosylation and is recognized by conformationally selective antibodies, suggesting that it adopts a proper antigenic conformation in the endoplasmic reticulum of red algal cells. We also report the experimental determination of the structure of the N-glycan moiety that is attached to glycosylated proteins in . Finally, we demonstrate the immunogenicity of the HCV antigen produced in red algae when administered by injection as pure protein or by feeding of algal biomass.
Topics: Porphyridium; Hepacivirus; Glycosylation; Viral Envelope Proteins; Recombinant Proteins; Animals
PubMed: 38833465
DOI: 10.1073/pnas.2400145121 -
Journal of Virology Jun 2024Porcine hemagglutinating encephalomyelitis virus (PHEV), a neurotropic betacoronavirus, is prevalent in natural reservoir pigs and infects mice. This raises concerns...
Porcine hemagglutinating encephalomyelitis virus (PHEV), a neurotropic betacoronavirus, is prevalent in natural reservoir pigs and infects mice. This raises concerns about host jumping or spillover, but little is known about the cause of occurrence. Here, we revealed that dipeptidyl peptidase 4 (DPP4) is a candidate binding target of PHEV spikes and works as a broad barrier to overcome. Investigations of the host breadth of PHEV confirmed that cells derived from pigs and mice are permissive to virus propagation. Both porcine DPP4 and murine DPP4 have high affinity for the viral spike receptor-binding domain (RBD), independent of their catalytic activity. Loss of DPP4 expression results in limited PHEV infection. Structurally, PHEV spike protein binds to the outer surface of blades IV and V of the DPP4 β-propeller domain, and the DPP4 residues N229 and N321 (relative to human DPP4 numbering) participate in RBD binding via its linked carbohydrate entities. Removal of these -glycosylations profoundly enhanced the RBD-DPP4 interaction and viral invasion, suggesting they act as shielding in PHEV infection. Furthermore, we found that glycosylation, rather than structural differences or surface charges, is more responsible for DPP4 recognition and species barrier formation. Overall, our findings shed light on virus-receptor interactions and highlight that PHEV tolerance to DPP4 orthologs is a putative determinant of its cross-species transmission or host range expansion.IMPORTANCEPHEV is a neurotropic betacoronavirus that is circulating worldwide and has raised veterinary and economic concerns. In addition to being a reservoir species of pigs, PHEV can also infect wild-type mice, suggesting a "host jump" event. Understanding cross-species transmission is crucial for disease prevention and control but remains to be addressed. Herein, we show that the multifunctional receptor DPP4 plays a pivotal role in the host tropism of PHEV and identifies the conserved glycosylation sites in DPP4 responsible for this restriction. These findings highlight that the ability of PHEV to utilize DPP4 orthologs potentially affects its natural host expansion.
PubMed: 38829136
DOI: 10.1128/jvi.00753-24 -
Frontiers in Immunology 2024Sialic acids as terminal sugar residues on cell surface or secreted proteins have many functional roles. In particular, the presence or absence of α2,6-linked sialic...
Sialic acids as terminal sugar residues on cell surface or secreted proteins have many functional roles. In particular, the presence or absence of α2,6-linked sialic acid residues at the immunoglobulin G (IgG) Fc fragment can switch IgG effector functions from pro- to anti-inflammatory activity. IgG glycosylation is considered to take place inside the plasma blast/plasma cell while the molecule travels through the endoplasmic reticulum and Golgi apparatus before being secreted. However, more recent studies have suggested that IgG sialylation may occur predominantly post-antibody secretion. To what extent this extracellular IgG sialylation process contributes to overall IgG sialylation remains unclear, however. By generating bone marrow chimeric mice with a B cell-specific deletion of ST6Gal1, the key enzyme required for IgG sialylation, we now show that sialylation of the IgG Fc fragment exclusively occurs within B cells pre-IgG secretion. We further demonstrate that B cells expressing ST6Gal1 have a developmental advantage over B cells lacking ST6Gal1 expression and thus dominate the plasma cell pool and the resulting serum IgG population in mouse models in which both ST6Gal1-sufficient and -deficient B cells are present.
Topics: Animals; Immunoglobulin G; Mice; Sialyltransferases; B-Lymphocytes; Mice, Knockout; Glycosylation; Mice, Inbred C57BL; Immunoglobulin Fc Fragments; beta-D-Galactoside alpha 2-6-Sialyltransferase; Plasma Cells; Antibody Formation
PubMed: 38827747
DOI: 10.3389/fimmu.2024.1402000 -
MLife Mar 2024O-glycosylation is an ancient yet underappreciated protein posttranslational modification, on which many bacteria and viruses heavily rely to perform critical biological... (Review)
Review
O-glycosylation is an ancient yet underappreciated protein posttranslational modification, on which many bacteria and viruses heavily rely to perform critical biological functions involved in numerous infectious diseases or even cancer. But due to the innate complexity of O-glycosylation, research techniques have been limited to study its exact role in viral attachment and entry, assembly and exit, spreading in the host cells, and the innate and adaptive immunity of the host. Recently, the advent of many newly developed methodologies (e.g., mass spectrometry, chemical biology tools, and molecular dynamics simulations) has renewed and rekindled the interest in viral-related O-glycosylation in both viral proteins and host cells, which is further fueled by the COVID-19 pandemic. In this review, we summarize recent advances in viral-related O-glycosylation, with a particular emphasis on the mucin-type O-linked α-N-acetylgalactosamine (O-GalNAc) on viral proteins and the intracellular O-linked β-N-acetylglucosamine (O-GlcNAc) modifications on host proteins. We hope to provide valuable insights into the development of antiviral reagents or vaccines for better prevention or treatment of infectious diseases.
PubMed: 38827513
DOI: 10.1002/mlf2.12105 -
Frontiers in Nutrition 2024Pea protein is one of plant proteins with high nutritional value, but its lower solubility and poor emulsifying properties limit its application in food industry. Based...
Pea protein is one of plant proteins with high nutritional value, but its lower solubility and poor emulsifying properties limit its application in food industry. Based on wet-heating glycosylation of pea protein and inulin, effects of discharge power of atmospheric pressure plasma jet (APPJ) on structure, solubility, and emulsifying ability of pea protein-inulin glycosylation conjugate were explored. Results indicated that the APPJ discharge power did not affect the primary structure of pea protein. However, changes in secondary and spatial structure of pea protein were observed. When APPJ discharge power was 600 W, the solubility of glycosylation conjugate was 75.0% and the emulsifying stability index was 98.9 min, which increased by 14.85 and 21.95% than that of only glycosylation sample, respectively. These findings could provide technical support for APPJ treatment combination with glycosylation to enhance the physicochemical properties of plant-based proteins.
PubMed: 38826578
DOI: 10.3389/fnut.2024.1416753 -
BioRxiv : the Preprint Server For... May 2024The sodium-coupled citrate transporter (NaCT, SLC13A5) mediates citrate uptake across the plasma membrane via an inward Na gradient. Mutations in SLC13A5 cause early...
UNLABELLED
The sodium-coupled citrate transporter (NaCT, SLC13A5) mediates citrate uptake across the plasma membrane via an inward Na gradient. Mutations in SLC13A5 cause early infantile epileptic encephalopathy type-25 (EIEE25, SLC13A5 Epilepsy) due to impaired citrate uptake in neurons. Despite clinical identification of disease-causing mutations, underlying mechanisms and cures remain elusive. We mechanistically classify the molecular phenotypes of six mutations. C50R, T142M, and T227M exhibit impaired citrate transport despite normal expression at the cell surface. G219R, S427L, and L488P are hampered by low protein expression, ER retention, and reduced transport. Mutants' mRNA levels resemble wildtype, suggesting post-translational defects. Class II mutations display immature core-glycosylation and shortened half-lives, indicating protein folding defects. These experiments provide a comprehensive understanding of the mutation's defects in SLC13A5 Epilepsy at the biochemical and molecular level and shed light into the trafficking pathway(s) of NaCT. The two classes of mutations will require fundamentally different treatment approaches to either restore transport function, or enable correction of protein folding defects.
SUMMARY
Loss-of-function mutations in the SLC13A5 causes SLC13A5-Epilepsy, a devastating disease characterized by neonatal epilepsy. Currently no cure is available. We clarify the molecular-level defects to guide future developments for phenotype-specific treatment of disease-causing mutations.
PubMed: 38826402
DOI: 10.1101/2024.05.23.594637