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Frontiers in Immunology 2022Cancer immunotherapy, including the inhibition of immune checkpoints, improves the tumor immune microenvironment and is an effective tool for cancer therapy. More... (Review)
Review
Cancer immunotherapy, including the inhibition of immune checkpoints, improves the tumor immune microenvironment and is an effective tool for cancer therapy. More effective and alternative inhibitory targets are critical for successful immune checkpoint blockade therapy. The interaction of the immunomodulatory ligand B7 family with corresponding receptors induces or inhibits T cell responses by sending co-stimulatory and co-inhibitory signals respectively. Blocking the glycosylation of the B7 family members PD-L1, PD-L2, B7-H3, and B7-H4 inhibited the self-stability and receptor binding of these immune checkpoint proteins, leading to immunosuppression and rapid tumor progression. Therefore, regulation of glycosylation may be the "golden key" to relieve tumor immunosuppression. The exploration of a more precise glycosylation regulation mechanism and glycan structure of B7 family proteins is conducive to the discovery and clinical application of antibodies and small molecule inhibitors.
Topics: Humans; Glycosylation; Neoplasms; Immunotherapy; T-Lymphocytes; Immunomodulation; Tumor Microenvironment
PubMed: 36561746
DOI: 10.3389/fimmu.2022.1088560 -
Ageing Research Reviews Aug 2023Glycosylation is a common post-translational modification of brain proteins including cell surface adhesion molecules, synaptic proteins, receptors and channels, as well... (Review)
Review
Glycosylation is a common post-translational modification of brain proteins including cell surface adhesion molecules, synaptic proteins, receptors and channels, as well as intracellular proteins, with implications in brain development and functions. Using advanced state-of-the-art glycomics and glycoproteomics technologies in conjunction with glycoinformatics resources, characteristic glycosylation profiles in brain tissues are increasingly reported in the literature and growing evidence shows deregulation of glycosylation in central nervous system disorders, including aging associated neurodegenerative diseases. Glycan signatures characteristic of brain tissue are also frequently described in cerebrospinal fluid due to its enrichment in brain-derived molecules. A detailed structural analysis of brain and cerebrospinal fluid glycans collected in publications in healthy and neurodegenerative conditions was undertaken and data was compiled to create a browsable dedicated set in the GlyConnect database of glycoproteins (https://glyconnect.expasy.org/brain). The shared molecular composition of cerebrospinal fluid with brain enhances the likelihood of novel glycobiomarker discovery for neurodegeneration, which may aid in unveiling disease mechanisms, therefore, providing with novel therapeutic targets as well as diagnostic and progression monitoring tools.
Topics: Humans; Glycosylation; Neurodegenerative Diseases; Glycoproteins; Protein Processing, Post-Translational; Glycomics; Polysaccharides; Biomarkers
PubMed: 37348818
DOI: 10.1016/j.arr.2023.101991 -
Glycoconjugate Journal Jun 2016Glycosylation is the most abundant and complex protein modification, and can have a profound structural and functional effect on the conjugate. The oligosaccharide... (Review)
Review
Glycosylation is the most abundant and complex protein modification, and can have a profound structural and functional effect on the conjugate. The oligosaccharide fraction is recognized to be involved in multiple biological processes, and to affect proteins physical properties, and has consequentially been labeled a critical quality attribute of biopharmaceuticals. Additionally, due to recent advances in analytical methods and analysis software, glycosylation is targeted in the search for disease biomarkers for early diagnosis and patient stratification. Biofluids such as saliva, serum or plasma are of great use in this regard, as they are easily accessible and can provide relevant glycosylation information. Thus, as the assessment of protein glycosylation is becoming a major element in clinical and biopharmaceutical research, this review aims to convey the current state of knowledge on the N-glycosylation of the major plasma glycoproteins alpha-1-acid glycoprotein, alpha-1-antitrypsin, alpha-1B-glycoprotein, alpha-2-HS-glycoprotein, alpha-2-macroglobulin, antithrombin-III, apolipoprotein B-100, apolipoprotein D, apolipoprotein F, beta-2-glycoprotein 1, ceruloplasmin, fibrinogen, immunoglobulin (Ig) A, IgG, IgM, haptoglobin, hemopexin, histidine-rich glycoprotein, kininogen-1, serotransferrin, vitronectin, and zinc-alpha-2-glycoprotein. In addition, the less abundant immunoglobulins D and E are included because of their major relevance in immunology and biopharmaceutical research. Where available, the glycosylation is described in a site-specific manner. In the discussion, we put the glycosylation of individual proteins into perspective and speculate how the individual proteins may contribute to a total plasma N-glycosylation profile determined at the released glycan level.
Topics: Blood Proteins; Glycoproteins; Glycosylation; Humans; Protein Processing, Post-Translational
PubMed: 26555091
DOI: 10.1007/s10719-015-9626-2 -
Current Opinion in Structural Biology Jun 2021O-GalNAc type glycosylation is an abundant and complex protein modification. Recent developments in mass spectrometry resulted in significant success in quantitative... (Review)
Review
O-GalNAc type glycosylation is an abundant and complex protein modification. Recent developments in mass spectrometry resulted in significant success in quantitative analysis of O-GalNAc glycosylation. The analysis of released O-GalNAc type glycans expanded our horizons of understanding the glycome of various biological models. The site-specific analysis of glycosylation micro-heterogeneity of purified proteins opened perspectives for the improved design of glycoprotein therapeutics. Advanced gene editing and chemical technologies applied to O-glycoproteomics enabled to identify O-GalNAc glycosylation at unprecedented depth. Progress in the analysis of intact glycoproteins under native and reduced conditions enabled the monitoring of glycosylation proteoform variants. Despite of the astonishing results in quantitative O-GalNAc glycoproteomics, site-specific mapping of the full O-GalNAc structural repertoire in complex samples is yet a long way off. Here, we summarize the most common quantitative strategies in O-GalNAc glycoproteomics, review recent progress and discuss benefits and limitations of the various approaches in the field.
Topics: Glycoproteins; Glycosylation; Mass Spectrometry; Polysaccharides; Protein Processing, Post-Translational
PubMed: 33508547
DOI: 10.1016/j.sbi.2020.12.010 -
Biotechnology Advances Oct 2023Over recent decades, therapeutic proteins have had widespread success in treating a myriad of diseases. Glycosylation, a near universal feature of this class of drugs,... (Review)
Review
Over recent decades, therapeutic proteins have had widespread success in treating a myriad of diseases. Glycosylation, a near universal feature of this class of drugs, is a critical quality attribute that significantly influences the physical properties, safety profile and biological activity of therapeutic proteins. Optimizing protein glycosylation, therefore, offers an important avenue to developing more efficacious therapies. In this review, we discuss specific examples of how variations in glycan structure and glycoengineering impacts the stability, safety, and clinical efficacy of protein-based drugs that are already in the market as well as those that are still in preclinical development. We also highlight the impact of glycosylation on next generation biologics such as T cell-based cancer therapy and gene therapy.
Topics: Humans; Glycosylation; Antibodies, Monoclonal; Polysaccharides; Neoplasms; Cell- and Tissue-Based Therapy
PubMed: 37354999
DOI: 10.1016/j.biotechadv.2023.108206 -
Nature Communications Jun 2023Recent interest in targeted therapies has been sparked by the study of MHC-associated peptides (MAPs) that undergo post-translational modifications (PTMs), particularly...
Recent interest in targeted therapies has been sparked by the study of MHC-associated peptides (MAPs) that undergo post-translational modifications (PTMs), particularly glycosylation. In this study, we introduce a fast computational workflow that merges the MSFragger-Glyco search algorithm with a false discovery rate control for glycopeptide analysis from mass spectrometry-based immunopeptidome data. By analyzing eight large-scale publicly available studies, we find that glycosylated MAPs are predominantly presented by MHC class II. Here, we present HLA-Glyco, a comprehensive resource containing over 3,400 human leukocyte antigen (HLA) class II N-glycopeptides from 1,049 distinct protein glycosylation sites. This resource provides valuable insights, including high levels of truncated glycans, conserved HLA-binding cores, and differences in glycosylation positional specificity between HLA allele groups. We integrate the workflow within the FragPipe computational platform and provide HLA-Glyco as a free web resource. Overall, our work provides a valuable tool and resource to aid the nascent field of glyco-immunopeptidomics.
Topics: Humans; Glycosylation; Protein Processing, Post-Translational; Algorithms; Genes, MHC Class II; Glycopeptides
PubMed: 37308510
DOI: 10.1038/s41467-023-39270-2 -
Oncogene Jun 2023Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Understanding the cancer mechanisms provides novel diagnostic, prognostic, and... (Review)
Review
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. Understanding the cancer mechanisms provides novel diagnostic, prognostic, and therapeutic markers for the management of HCC disease. In addition to genomic and epigenomic regulation, post-translational modification exerts a profound influence on protein functions and plays a critical role in regulating various biological processes. Protein glycosylation is one of the most common and complex post-translational modifications of newly synthesized proteins and acts as an important regulatory mechanism that is implicated in fundamental molecular and cell biology processes. Recent studies in glycobiology suggest that aberrant protein glycosylation in hepatocytes contributes to the malignant transformation to HCC by modulating a wide range of pro-tumorigenic signaling pathways. The dysregulated protein glycosylation regulates cancer growth, metastasis, stemness, immune evasion, and therapy resistance, and is regarded as a hallmark of HCC. Changes in protein glycosylation could serve as potential diagnostic, prognostic, and therapeutic factors in HCC. In this review, we summarize the functional importance, molecular mechanism, and clinical application of protein glycosylation alterations in HCC.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Glycosylation; Protein Processing, Post-Translational; Carcinogenesis; Proteins
PubMed: 37193819
DOI: 10.1038/s41388-023-02702-w -
Advances in Experimental Medicine and... 2021Diabetes mellitus is a group of metabolic disorders characterized by the presence of hyperglycaemia. Due to its high prevalence and substantial heterogeneity, many...
Diabetes mellitus is a group of metabolic disorders characterized by the presence of hyperglycaemia. Due to its high prevalence and substantial heterogeneity, many studies have been investigating markers that could identify predisposition for the disease development, differentiate between the various subtypes, establish early diagnosis, predict complications or represent novel therapeutic targets. N-glycans, complex oligosaccharide molecules covalently linked to proteins, emerged as potential markers and functional effectors of various diabetes subtypes, appearing to have the capacity to meet these requirements. For instance, it has been shown that N-glycome changes in patients with type 2 diabetes and that N-glycans can even identify individuals with an increased risk for its development. Moreover, genome-wide association studies identified glycosyltransferase genes as candidate causal genes for both type 1 and type 2 diabetes. N-glycans have also been suggested to have a major role in preventing the impairment of glucose-stimulated insulin secretion by modulating cell surface expression of glucose transporters. In this chapter we aimed to describe four major diabetes subtypes: type 1, type 2, gestational and monogenic diabetes, giving an overview of suggested role for N-glycosylation in their development, diagnosis and management.
Topics: Biomarkers; Diabetes Mellitus, Type 2; Genome-Wide Association Study; Glycosylation; Humans; Hyperglycemia; Polysaccharides
PubMed: 34495541
DOI: 10.1007/978-3-030-70115-4_14 -
Pharmacological Research May 2023Acute ischemic stroke (AIS) is a serious and life-threatening disease worldwide. Despite thrombolysis or endovascular thrombectomy, a sizeable fraction of patients with... (Review)
Review
Acute ischemic stroke (AIS) is a serious and life-threatening disease worldwide. Despite thrombolysis or endovascular thrombectomy, a sizeable fraction of patients with AIS have adverse clinical outcomes. In addition, existing secondary prevention strategies with antiplatelet and anticoagulant drugs therapy are not able to adequately decrease the risk of ischemic stroke recurrence. Thus, exploring novel mechanisms for doing so represents an urgent need for the prevention and treatment of AIS. Recent studies have discovered that protein glycosylation plays a critical role in the occurrence and outcome of AIS. As a common co- and post-translational modification, protein glycosylation participates in a wide variety of physiological and pathological processes by regulating the activity and function of proteins or enzymes. Protein glycosylation is involved in two causes of cerebral emboli in ischemic stroke: atherosclerosis and atrial fibrillation. Following ischemic stroke, the level of brain protein glycosylation becomes dynamically regulated, which significantly affects stroke outcome through influencing inflammatory response, excitotoxicity, neuronal apoptosis, and blood-brain barrier disruption. Drugs targeting glycosylation in the occurrence and progression of stroke may represent a novel therapeutic idea. In this review, we focus on possible perspectives about how glycosylation affects the occurrence and outcome of AIS. We then propose the potential of glycosylation as a therapeutic drug target and prognostic marker for AIS patients in the future.
Topics: Humans; Brain Ischemia; Glycosylation; Ischemic Stroke; Stroke; Treatment Outcome
PubMed: 36907285
DOI: 10.1016/j.phrs.2023.106726 -
Bioscience Reports Oct 2022Protein glycosylation is ubiquitous throughout biology. From bacteria to humans, this post translational modification with sophisticated carbohydrate structures plays a... (Review)
Review
Protein glycosylation is ubiquitous throughout biology. From bacteria to humans, this post translational modification with sophisticated carbohydrate structures plays a profound role in the interaction of proteins with cells and changes the physiochemical properties of the proteins that carry them. When the glycans are linked to Ser or Thr residues, they are known as O-linked glycans, as the glycosidic linkage is through oxygen. O-glycans are perhaps best known as part of the mucin proteins, however many soluble proteins carry these types of glycans, and that their roles in biology are still being discovered. Many of the soluble proteins that carry O-glycans have a role as therapeutic proteins, and in the 21st century, the application of synthetic biology is starting to be applied to improving these proteins through manipulation of the glycans. This review will explore the role of these O-linked glycans in proteins with pharmaceutical significance, as well as recent advancements in recombinant glycoprotein therapeutics.
Topics: Humans; Glycosylation; Polysaccharides; Mucins; Protein Processing, Post-Translational; Recombinant Proteins
PubMed: 36214107
DOI: 10.1042/BSR20220094