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Handbook of Experimental Pharmacology 2018The conserved oligomeric Golgi (COG) complex is an evolutionary conserved multi-subunit vesicle tethering complex essential for the majority of Golgi apparatus... (Review)
Review
The conserved oligomeric Golgi (COG) complex is an evolutionary conserved multi-subunit vesicle tethering complex essential for the majority of Golgi apparatus functions: protein and lipid glycosylation and protein sorting. COG is present in neuronal cells, but the repertoire of COG function in different Golgi-like compartments is an enigma. Defects in COG subunits cause alteration of Golgi morphology, protein trafficking, and glycosylation resulting in human congenital disorders of glycosylation (CDG) type II. In this review we summarize and critically analyze recent advances in the function of Golgi and Golgi-like compartments in neuronal cells and functions and dysfunctions of the COG complex and its partner proteins.
Topics: Adaptor Proteins, Vesicular Transport; Animals; Glycosylation; Golgi Apparatus; Humans; Neurons; Protein Transport
PubMed: 29063274
DOI: 10.1007/164_2017_65 -
Cancer Metastasis Reviews Mar 2022Metastasis is considered to be responsible for 90% of cancer-related deaths. Although it is clinically evident that metastatic patterns vary by primary tumor type, the... (Review)
Review
Metastasis is considered to be responsible for 90% of cancer-related deaths. Although it is clinically evident that metastatic patterns vary by primary tumor type, the molecular mechanisms underlying the site-specific nature of metastasis are an area of active investigation. One mechanism that has emerged as an important player in this process is glycosylation, or the addition of sugar moieties onto protein and lipid substrates. Glycosylation is the most common post-translational modification, occurring on more than 50% of translated proteins. Many of those proteins are either secreted or expressed on the cell membrane, thereby making glycosylation an important mediator of cell-cell interactions, including tumor-microenvironment interactions. It has been recently discovered that alteration of glycosylation patterns influences cancer metastasis, both globally and in a site-specific manner. This review will summarize the current knowledge regarding the role of glycosylation in the tropism of cancer cells for several common metastatic sites, including the bone, lung, brain, and lymph nodes.
Topics: Cell Membrane; Glycosylation; Humans; Lung Neoplasms; Neoplasm Metastasis; Tumor Microenvironment
PubMed: 34967926
DOI: 10.1007/s10555-021-10015-1 -
Journal of Proteome Research Jun 2023Glycosylation is one of the most common and important protein modifications, and it regulates the properties and functions of a wide range of proteins. Aberrant... (Review)
Review
Glycosylation is one of the most common and important protein modifications, and it regulates the properties and functions of a wide range of proteins. Aberrant glycosylation is directly related to human diseases. Recently, with the advancement of mass spectrometry (MS) instrumentation and MS-based glycoproteomic methods, global characterization of glycoproteins in complex biological samples has become possible. Using quantitative proteomics, the abundance of glycoproteins in different samples can be quantified, which provides a wealth of information to further our understanding of protein functions, cellular activities, and the molecular mechanisms of diseases. In this review, we discuss quantitative proteomic methods used for comprehensive analysis of protein glycosylation, and cover the applications of quantitative glycoproteomics to unveil the properties and functions of glycoproteins and their association with various diseases. It is expected that quantitative proteomic methods will be extensively applied to explore the role of protein glycosylation in complex biological systems, and to identify glycoproteins as biomarkers for disease detection and as therapeutic targets for disease treatment.
Topics: Humans; Proteomics; Glycoproteins; Glycosylation; Protein Processing, Post-Translational; Mass Spectrometry
PubMed: 37010087
DOI: 10.1021/acs.jproteome.3c00015 -
Frontiers in Cellular and Infection... 2020In recent years, protein glycosylation in pathogenic bacteria has attracted more and more attention, and accumulating evidence indicated that this type of... (Review)
Review
In recent years, protein glycosylation in pathogenic bacteria has attracted more and more attention, and accumulating evidence indicated that this type of posttranslational modification is involved in many physiological processes. The NleB from several enteropathogenic bacteria species as well as SseK from are type III secretion system effectors, which have an atypical N-acetylglucosamine (N-GlcNAc) transferase activity that specifically modified a conserved arginine in TRADD, FADD, and RIPK1. NleB/SseKs GlcNAcylation of death domain proteins abrogates homotypic and heterotypic death receptors/adaptors interactions, thereby blocking an important antimicrobial host response. Interestingly, NleB/SseKs could also GlcNAcylate themselves, and self-GlcNAcylation of NleB, SseK1, and SseK3 are crucial for their biological activity during infection. In addition, EarP (EF-P specific arginine rhamnosyl transferase for Posttranslational activation) catalyzes arginine rhamnosylation of translation elongation factor P (EF-P). Importantly, this kind of N-linked protein glycosylation is not only important for EF-P dependent rescue of polyproline stalled ribosomes but also for pathogenicity in and other clinically relevant bacteria. Glycosylation of arginine is unique because the guanidine group of arginine has a high acid dissociation constant value and representing an extremely poor nucleophile. Recently, the crystal structures of NleB, SseKs, EarP, arginine GlcNAcylated death domain-containing proteins, NleB/FADD-DD, and EarP/EF-P/dTDP-β-L-rhamnose were solved by our group and other groups, revealing the unique catalytic mechanisms. In this review, we provide detailed information about the currently known arginine glycosyltransferases and their potential catalytic mechanisms.
Topics: Arginine; Bacterial Proteins; Catalysis; Fas-Associated Death Domain Protein; Glycosylation; Pseudomonas aeruginosa; Receptor-Interacting Protein Serine-Threonine Kinases; TNF Receptor-Associated Death Domain Protein
PubMed: 32411621
DOI: 10.3389/fcimb.2020.00185 -
Journal of Hematology & Oncology Sep 2016Glycosylation is the most complex post-translational modification of proteins. Altered glycans on the tumor- and host-cell surface and in the tumor microenvironment have... (Review)
Review
Glycosylation is the most complex post-translational modification of proteins. Altered glycans on the tumor- and host-cell surface and in the tumor microenvironment have been identified to mediate critical events in cancer pathogenesis and progression. Tumor-associated glycan changes comprise increased branching of N-glycans, higher density of O-glycans, generation of truncated versions of normal counterparts, and generation of unusual forms of terminal structures arising from sialylation and fucosylation. The functional role of tumor-associated glycans (Tn, sTn, T, and sLe) is dependent on the interaction with lectins. Lectins are expressed on the surface of immune cells and endothelial cells or exist as extracellular matrix proteins and soluble adhesion molecules. Expression of tumor-associated glycans is involved in the dysregulation of glycogenes, which mainly comprise glycosyltransferases and glycosidases. Furthermore, genetic and epigenetic mechanisms on many glycogenes are associated with malignant transformation. With better understanding of all aspects of cancer-cell glycomics, many tumor-associated glycans have been utilized for diagnostic, prognostic, and therapeutic purposes. Glycan-based therapeutics has been applied to cancers from breast, lung, gastrointestinal system, melanomas, and lymphomas but rarely to neuroblastomas (NBs). The success of anti-disialoganglioside (GD2, a glycolipid antigen) antibodies sheds light on glycan-based therapies for NB and also suggests the possibility of protein glycosylation-based therapies for NB. This review summarizes our understanding of cancer glycobiology with a focus of how protein glycosylation and associated glycosyltransferases affect cellular behaviors and treatment outcome of various cancers, especially NB. Finally, we highlight potential applications of glycosylation in drug and cancer vaccine development for NB.
Topics: Glycosylation; Glycosyltransferases; Humans; Neoplasm Proteins; Neoplasms; Neuroblastoma; Polysaccharides
PubMed: 27686492
DOI: 10.1186/s13045-016-0334-6 -
Cell Death & Disease Aug 2022On glucose restriction, epithelial cells can undergo entosis, a cell-in-cell cannibalistic process, to allow considerable withstanding to this metabolic stress. Thus, we...
On glucose restriction, epithelial cells can undergo entosis, a cell-in-cell cannibalistic process, to allow considerable withstanding to this metabolic stress. Thus, we hypothesized that reduced protein glycosylation might participate in the activation of this cell survival pathway. Glucose deprivation promoted entosis in an MCF7 breast carcinoma model, as evaluated by direct inspection under the microscope, or revealed by a shift to apoptosis + necrosis in cells undergoing entosis treated with a Rho-GTPase kinase inhibitor (ROCKi). In this context, curbing protein glycosylation defects with N-acetyl-glucosamine partially rescued entosis, whereas limiting glycosylation in the presence of glucose with tunicamycin or NGI-1, but not with other unrelated ER-stress inducers such as thapsigargin or amino-acid limitation, stimulated entosis. Mitochondrial phosphoenolpyruvate carboxykinase (PEPCK-M; PCK2) is upregulated by glucose deprivation, thereby enhancing cell survival. Therefore, we presumed that PEPCK-M could play a role in this process by offsetting key metabolites into glycosyl moieties using alternative substrates. PEPCK-M inhibition using iPEPCK-2 promoted entosis in the absence of glucose, whereas its overexpression inhibited entosis. PEPCK-M inhibition had a direct role on total protein glycosylation as determined by Concanavalin A binding, and the specific ratio of fully glycosylated LAMP1 or E-cadherin. The content of metabolites, and the fluxes from C-glutamine label into glycolytic intermediates up to glucose-6-phosphate, and ribose- and ribulose-5-phosphate, was dependent on PEPCK-M content as measured by GC/MS. All in all, we demonstrate for the first time that protein glycosylation defects precede and initiate the entosis process and implicates PEPCK-M in this survival program to dampen the consequences of glucose deprivation. These results have broad implications to our understanding of tumor metabolism and treatment strategies.
Topics: Breast Neoplasms; Entosis; Female; Glucose; Glycosylation; Humans; Phosphoenolpyruvate Carboxykinase (ATP)
PubMed: 36002449
DOI: 10.1038/s41419-022-05177-x -
Clinical & Translational Oncology :... Oct 2022Endometrial cancer (EC) is one of the most common tumors in the female reproductive system, which seriously threatens women's health, particularly in developed... (Review)
Review
Endometrial cancer (EC) is one of the most common tumors in the female reproductive system, which seriously threatens women's health, particularly in developed countries. 13% of the patients with EC have a poor prognosis due to recurrence and metastasis. Therefore, identifying good predictive biomarkers and therapeutic targets is critical to enable the early detection of metastasis and improve the prognosis. For decades, extensive studies had focused on glycans and glycoproteins in the progression of cancer. The types of glycans that are covalently attached to the polypeptide backbone, usually via nitrogen or oxygen linkages, are known as N‑glycans or O‑glycans, respectively. The degree of protein glycosylation and the aberrant changes in the carbohydrate structures have been implicated in the extent of tumorigenesis and reported to play a critical role in regulating tumor invasion, metabolism, and immunity. This review summarizes the essential biological role of glycosylation in EC, with a focus on the recent advances in glycomics and glycosylation markers, highlighting their implications in the diagnosis and treatment of EC.
Topics: Biomarkers; Endometrial Neoplasms; Female; Glycomics; Glycoproteins; Glycosylation; Humans; Polysaccharides
PubMed: 35752750
DOI: 10.1007/s12094-022-02858-z -
The Protein Journal Jun 2019The site of protein folding and maturation for the majority of proteins that are secreted, localized to the plasma membrane or targeted to endomembrane compartments is... (Review)
Review
The site of protein folding and maturation for the majority of proteins that are secreted, localized to the plasma membrane or targeted to endomembrane compartments is the endoplasmic reticulum (ER). It is essential that proteins targeted to the ER are properly folded in order to carry out their function, as well as maintain protein homeostasis, as accumulation of misfolded proteins could lead to the formation of cytotoxic aggregates. Because protein folding is an error-prone process, the ER contains protein quality control networks that act to optimize proper folding and trafficking of client proteins. If a protein is unable to reach its native state, it is targeted for ER retention and subsequent degradation. The protein quality control networks of the ER that oversee this evaluation or interrogation process that decides the fate of maturing nascent chains is comprised of three general types of families: the classical chaperones, the carbohydrate-dependent system, and the thiol-dependent system. The cooperative action of these families promotes protein quality control and protein homeostasis in the ER. This review will describe the families of the ER protein quality control network and discuss the functions of individual members.
Topics: Endoplasmic Reticulum; Eukaryotic Cells; Glycosylation; Molecular Chaperones; Protein Folding; Secretory Pathway
PubMed: 31004255
DOI: 10.1007/s10930-019-09831-w -
Clinical Chemistry and Laboratory... Mar 2019Glycosylation is among the most important post-translational modifications for proteins and is of intrinsic complex character compared with DNAs and naked proteins.... (Review)
Review
Glycosylation is among the most important post-translational modifications for proteins and is of intrinsic complex character compared with DNAs and naked proteins. Indeed, over 50%-70% of proteins in circulation are glycosylated, and the "sweet attachments" have versatile structural and functional implications. Both the configuration and composition of the attached glycans affect the biological activities of consensus proteins significantly. Glycosylation is generated by complex biosynthetic pathways comprising hundreds of glycosyltransferases, glycosidases, transcriptional factors, transporters and the protein backbone. In addition, lack of direct genetic templates and glyco-specific antibodies such as those commonly used in DNA amplification and protein capture makes research on glycans and glycoproteins even more difficult, thus resulting in sparse knowledge on the pathophysiological implications of glycosylation. Fortunately, cutting-edge technologies have afforded new opportunities and approaches for investigating cancer-related glycosylation. Thus, glycans as well as aberrantly glycosylated protein-based cancer biomarkers have been increasingly recognized. This mini-review highlights the most recent developments in glyco-biomarker studies in an effort to discover clinically relevant cancer biomarkers using advanced analytical methodologies such as mass spectrometry, high-performance liquid chromatographic/ultra-performance liquid chromatography, capillary electrophoresis, and lectin-based technologies. Recent clinical-centered glycobiological studies focused on determining the regulatory mechanisms and the relation with diagnostics, prognostics and even therapeutics are also summarized. These studies indicate that glycomics is a treasure waiting to be mined where the growth of cancer-related glycomics and glycoproteomics is the next great challenge after genomics and proteomics.
Topics: Biomarkers, Tumor; Glycosylation; Humans; Neoplasms
PubMed: 30138110
DOI: 10.1515/cclm-2018-0379 -
Virulence Dec 2022Glycans are among the most important cell molecular components. However, given their structural diversity, their functions have not been fully explored. Glycosylation is... (Review)
Review
Glycans are among the most important cell molecular components. However, given their structural diversity, their functions have not been fully explored. Glycosylation is a vital post-translational modification for various proteins. Many bacteria and viruses rely on -linked and O-linked glycosylation to perform critical biological functions. The diverse functions of glycosylation on viral proteins during viral infections, including Dengue, Zika, influenza, and human immunodeficiency viruses as well as coronaviruses have been reported. -linked glycosylation is the most common form of protein modification, and it modulates folding, transportation and receptor binding. Compared to -linked glycosylation, the functions of O-linked viral protein glycosylation have not been comprehensively evaluated. In this review, we summarize findings on viral protein glycosylation, with particular attention to studies on N-linked glycosylation in viral life cycles. This review informs the development of virus-specific vaccines or inhibitors.
Topics: Glycosylation; Host Microbial Interactions; Humans; Protein Processing, Post-Translational; Viral Proteins; Virulence; Zika Virus; Zika Virus Infection
PubMed: 35436420
DOI: 10.1080/21505594.2022.2060464