-
Experimental Hematology Sep 2021Posttranslational protein modification through addition of the O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) moiety to serine or threonine residues, termed... (Review)
Review
Posttranslational protein modification through addition of the O-linked β-N-acetyl-D-glucosamine (O-GlcNAc) moiety to serine or threonine residues, termed O-GlcNAcylation, is a highly dynamic process conserved throughout eukaryotes. O-GlcNAcylation is reversibly catalyzed by a single pair of enzymes, O-GlcNAc transferase and O-GlcNAcase, and it acts as a fundamental regulator for a wide variety of biological processes including gene expression, cell cycle regulation, metabolism, stress response, cellular signaling, epigenetics, and proteostasis. O-GlcNAcylation is regulated by various intracellular or extracellular cues such as metabolic status, nutrient availability, and stress. Studies over decades have unveiled the profound biological significance of this unique protein modification in normal physiology and pathologic processes of diverse cell types or tissues. In hematopoiesis, recent studies have indicated the essential and pleiotropic roles of O-GlcNAcylation in differentiation, proliferation, and function of hematopoietic cells including T cells, B cells, myeloid progenitors, and hematopoietic stem and progenitor cells. Moreover, aberrant O-GlcNAcylation is implicated in the development of hematologic malignancies with dysregulated epigenetics, metabolism, and gene transcription. Thus, it is now recognized that O-GlcNAcylation is one of the key regulators of normal and malignant hematopoiesis.
Topics: Acetylglucosamine; Animals; Epigenesis, Genetic; Hematologic Neoplasms; Hematopoiesis; Hematopoietic Stem Cells; Humans; Protein Processing, Post-Translational
PubMed: 34302904
DOI: 10.1016/j.exphem.2021.07.003 -
Nature Sep 2022Bacterial cell wall components provide various unique molecular structures that are detected by pattern recognition receptors (PRRs) of the innate immune system as...
Bacterial cell wall components provide various unique molecular structures that are detected by pattern recognition receptors (PRRs) of the innate immune system as non-self. Most bacterial species form a cell wall that consists of peptidoglycan (PGN), a polymeric structure comprising alternating amino sugars that form strands cross-linked by short peptides. Muramyl dipeptide (MDP) has been well documented as a minimal immunogenic component of peptidoglycan. MDP is sensed by the cytosolic nucleotide-binding oligomerization domain-containing protein 2 (NOD2). Upon engagement, it triggers pro-inflammatory gene expression, and this functionality is of critical importance in maintaining a healthy intestinal barrier function. Here, using a forward genetic screen to identify factors required for MDP detection, we identified N-acetylglucosamine kinase (NAGK) as being essential for the immunostimulatory activity of MDP. NAGK is broadly expressed in immune cells and has previously been described to contribute to the hexosamine biosynthetic salvage pathway. Mechanistically, NAGK functions upstream of NOD2 by directly phosphorylating the N-acetylmuramic acid moiety of MDP at the hydroxyl group of its C6 position, yielding 6-O-phospho-MDP. NAGK-phosphorylated MDP-but not unmodified MDP-constitutes an agonist for NOD2. Macrophages from mice deficient in NAGK are completely deficient in MDP sensing. These results reveal a link between amino sugar metabolism and innate immunity to bacterial cell walls.
Topics: Acetylmuramyl-Alanyl-Isoglutamine; Animals; Bacteria; Cell Wall; Hexosamines; Immunity, Innate; Macrophages; Mice; Nod2 Signaling Adaptor Protein; Peptidoglycan; Phosphorylation; Phosphotransferases (Alcohol Group Acceptor)
PubMed: 36002575
DOI: 10.1038/s41586-022-05125-x -
Nutrients Jul 2023The causal effects of chondroitin, glucosamine, and vitamin/mineral supplement intake on kidney function remain unknown, despite being commonly used. We conducted a...
The causal effects of chondroitin, glucosamine, and vitamin/mineral supplement intake on kidney function remain unknown, despite being commonly used. We conducted a two-sample summary-level Mendelian randomization (MR) analysis to test for causal associations between regular dietary supplement intake and kidney function. Genetic instruments for chondroitin, glucosamine, and vitamin/mineral supplement intake were obtained from a genome-wide association study of European ancestry. Summary statistics for the log-transformed estimated glomerular filtration rate (log-eGFR) were provided by the CKDGen consortium. The multiplicative random-effects inverse-variance weighted method showed that genetically predicted chondroitin and glucosamine intake was causally associated with a lower eGFR (chondroitin, eGFR change beta = -0.113%, standard error (SE) = 0.03%, -value = 2 × 10; glucosamine, eGFR change beta = -0.240%, SE = 0.035%, -value = 6 × 10). However, a genetically predicted vitamin/mineral supplement intake was associated with a higher eGFR (eGFR change beta = 1.426%, SE = 0.136%, -value = 1 × 10). Validation analyses and pleiotropy-robust MR results for chondroitin and vitamin/mineral supplement intake supported the main results. Our MR study suggests a potential causal effect of chondroitin and glucosamine intake on kidney function. Therefore, clinicians should carefully monitor their long-term effects.
Topics: Vitamins; Glucosamine; Mendelian Randomization Analysis; Genome-Wide Association Study; Chondroitin; Polymorphism, Single Nucleotide; Kidney; Minerals
PubMed: 37571255
DOI: 10.3390/nu15153318 -
Current Oncology Reports Jan 2023This study aims to review state-of-the-art advances in Siglec-9-directed antibodies and to highlight specific aspects of Siglec-9 antibodies that are suitable to mount... (Review)
Review
PURPOSE OF REVIEW
This study aims to review state-of-the-art advances in Siglec-9-directed antibodies and to highlight specific aspects of Siglec-9 antibodies that are suitable to mount anti-tumor immunity.
RECENT FINDINGS
Controversies surrounding studies on Siglec-9 antibodies can confound future studies. In this review, we have highlighted some controversies, explained the distinction between Siglec-9 agonistic and antagonistic (endocytic) antibodies, and discussed their suitability in sustaining anti-tumor immunity. Siglec-9 is an immune checkpoint target and an immunoinhibitory receptor that can engage either sialic acid ligands or agonistic antibodies. Through Siglec-9 sialic acid interactions, activated immunoreceptor tyrosine-based inhibitory signaling of the immune cells can lead to unfavorable immunosuppression. To overcome tumor-related immunosuppression, different types of Siglec-9 antibody blockade need to be developed. However, whether a Siglec-9-directed antibody is agonistic or antagonistic is probably affinity-dependent and not epitope-dependent. Additionally, unlike immune-modulatory antibodies such as agonistic antibodies (OX40, CD28, ICOS, and 4-1BB) or Fc-inert antibodies (PD1 and PD-L1) directed against cancer cells, the nature of antagonistic Siglec-9 antibodies is more suitable to enhance anti-tumor immunity and will be discussed.
Topics: Humans; N-Acetylneuraminic Acid; Neoplasms; Sialic Acid Binding Immunoglobulin-like Lectins; Antibodies; Signal Transduction
PubMed: 36445569
DOI: 10.1007/s11912-022-01347-4 -
International Journal of Molecular... Mar 2023Temporomandibular disorders (TMDs) occur frequently within the general population and are the most common non-dental cause of orofacial pain. Temporomandibular joint... (Review)
Review
Temporomandibular disorders (TMDs) occur frequently within the general population and are the most common non-dental cause of orofacial pain. Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative joint disease (DJD). There have been several different methods of treatment of TMJ OA listed, including pharmacotherapy among others. Due to its anti-aging, antioxidative, bacteriostatic, anti-inflammatory, immuno-stimulating, pro-anabolic and anti-catabolic properties, oral glucosamine seems to be a potentially very effective agent in the treatment of TMJ OA. The aim of this review was to critically assess the efficacy of oral glucosamine in the treatment of TMJ OA on the basis of the literature. PubMed and Scopus databases were analyzed with the keywords: (temporomandibular joints) AND ((disorders) OR (osteoarthritis)) AND (treatment) AND (glucosamine). After the screening of 50 results, eight studies have been included in this review. Oral glucosamine is one of the symptomatic slow-acting drugs for osteoarthritis. There is not enough scientific evidence to unambiguously confirm the clinical effectiveness of glucosamine supplements in the treatment of TMJ OA on the basis of the literature. The most important aspect affecting the clinical efficacy of oral glucosamine in the treatment of TMJ OA was the total administration time. Administration of oral glucosamine for a longer period of time, i.e., 3 months, led to a significant reduction in TMJ pain and a significant increase in maximum mouth opening. It also resulted in long-term anti-inflammatory effects within the TMJs. Further long-term, randomized, double-blind studies, with a unified methodology, ought to be performed to draw the general recommendations for the use of oral glucosamine in the treatment of TMJ OA.
Topics: Humans; Glucosamine; Osteoarthritis; Temporomandibular Joint; Anti-Inflammatory Agents; Facial Pain; Randomized Controlled Trials as Topic
PubMed: 36902359
DOI: 10.3390/ijms24054925 -
Cellular and Molecular Life Sciences :... May 2023Tumors create an immunosuppressive tumor microenvironment by altering protein expression, but also by changing their glycosylation status, like altered expression of...
Tumors create an immunosuppressive tumor microenvironment by altering protein expression, but also by changing their glycosylation status, like altered expression of sialoglycans. Sialoglycans are capped with sialic acid sugar residues and are recognized by Siglec immune receptors. Siglec-7 is an inhibitory immune receptor similar to PD-1, and is emerging as glycoimmune checkpoint exploited by cancer cells to evade the immune system. However, the exact cellular and molecular conditions required for Siglec-7-mediated immune cell inhibition remain largely unknown. Here, we report on the development of a chimeric Siglec-7 cell system that enables dissection of Siglec-7 signaling, rather than Siglec-7 binding. Antibody-induced clustering, sialic acid-containing polymers, and highly sialylated erythrocytes effectively induced Siglec-7 signaling, thereby validating functionality of this reporter system. Moreover, the system reveals tumor cell-dependent Siglec-7 signaling. Tumor-associated conditions important for Siglec-7 signaling were defined, such as Siglec-7 ligand expression levels, presence of the known Siglec-7 ligand CD43, and sialic acid availability for sialylation of glycans. Importantly, therapeutic targeting of the Siglec-7/sialic acid axis using a sialyltransferase inhibitor resulted in strong reduction of Siglec-7 signaling. In conclusion, using a newly established cellular tool, we defined a set of tumor-associated conditions that influence Siglec-7 signaling. Moreover, the system allows to assess the efficacy of novel cancer drugs interfering with the Siglec-7/sialic acid axis as immunotherapy to treat cancer.
Topics: Humans; N-Acetylneuraminic Acid; Tumor Microenvironment; Ligands; Neoplasms; Sialic Acid Binding Immunoglobulin-like Lectins
PubMed: 37253806
DOI: 10.1007/s00018-023-04816-6 -
Science Advances Jun 2023Deleterious variants in acetylneuraminate pyruvate lyase (NPL) cause skeletal myopathy and cardiac edema in humans and zebrafish, but its physiological role remains...
Deleterious variants in acetylneuraminate pyruvate lyase (NPL) cause skeletal myopathy and cardiac edema in humans and zebrafish, but its physiological role remains unknown. We report generation of mouse models of the disease: , carrying the human p.Arg63Cys variant, and with a 116-bp exonic deletion. In both strains, NPL deficiency causes drastic increase in free sialic acid levels, reduction of skeletal muscle force and endurance, slower healing and smaller size of newly formed myofibers after cardiotoxin-induced muscle injury, increased glycolysis, partially impaired mitochondrial function, and aberrant sialylation of dystroglycan and mitochondrial LRP130 protein. NPL-catalyzed degradation of sialic acid in the muscle increases after fasting and injury and in human patient and mouse models with genetic muscle dystrophy, demonstrating that NPL is essential for muscle function and regeneration and serves as a general marker of muscle damage. Oral administration of acetylmannosamine rescues skeletal myopathy, as well as mitochondrial and structural abnormalities in mice, suggesting a potential treatment for human patients.
Topics: Animals; Humans; Mice; Disease Models, Animal; Glycoproteins; Muscle, Skeletal; N-Acetylneuraminic Acid; Pyruvates; Regeneration; Zebrafish
PubMed: 37390204
DOI: 10.1126/sciadv.ade6308 -
BMC Biology Jul 2019Altered metabolism and deregulated cellular energetics are now considered a hallmark of all cancers. Glucose, glutamine, fatty acids, and amino acids are the primary... (Review)
Review
Altered metabolism and deregulated cellular energetics are now considered a hallmark of all cancers. Glucose, glutamine, fatty acids, and amino acids are the primary drivers of tumor growth and act as substrates for the hexosamine biosynthetic pathway (HBP). The HBP culminates in the production of an amino sugar uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) that, along with other charged nucleotide sugars, serves as the basis for biosynthesis of glycoproteins and other glycoconjugates. These nutrient-driven post-translational modifications are highly altered in cancer and regulate protein functions in various cancer-associated processes. In this review, we discuss recent progress in understanding the mechanistic relationship between the HBP and cancer.
Topics: Biosynthetic Pathways; Hexosamines; Neoplasms; Protein Processing, Post-Translational; Proteins
PubMed: 31272438
DOI: 10.1186/s12915-019-0671-3 -
Neuro-oncology Nov 2023In glioblastoma (GBM), the effects of altered glycocalyx are largely unexplored. The terminal moiety of cell coating glycans, sialic acid, is of paramount importance for...
BACKGROUND
In glioblastoma (GBM), the effects of altered glycocalyx are largely unexplored. The terminal moiety of cell coating glycans, sialic acid, is of paramount importance for cell-cell contacts. However, sialic acid turnover in gliomas and its impact on tumor networks remain unknown.
METHODS
We streamlined an experimental setup using organotypic human brain slice cultures as a framework for exploring brain glycobiology, including metabolic labeling of sialic acid moieties and quantification of glycocalyx changes. By live, 2-photon and high-resolution microscopy we have examined morphological and functional effects of altered sialic acid metabolism in GBM. By calcium imaging we investigated the effects of the altered glycocalyx on a functional level of GBM networks.
RESULTS
The visualization and quantitative analysis of newly synthesized sialic acids revealed a high rate of de novo sialylation in GBM cells. Sialyltrasferases and sialidases were highly expressed in GBM, indicating that significant turnover of sialic acids is involved in GBM pathology. Inhibition of either sialic acid biosynthesis or desialylation affected the pattern of tumor growth and lead to the alterations in the connectivity of glioblastoma cells network.
CONCLUSIONS
Our results indicate that sialic acid is essential for the establishment of GBM tumor and its cellular network. They highlight the importance of sialic acid for glioblastoma pathology and suggest that dynamics of sialylation have the potential to be targeted therapeutically.
Topics: Humans; Glioblastoma; N-Acetylneuraminic Acid; Sialic Acids; Signal Transduction; Brain Neoplasms; Cell Line, Tumor
PubMed: 37288604
DOI: 10.1093/neuonc/noad101 -
Immunology Nov 2020Mounting an effective immune response is crucial for the host to protect itself against invading pathogens. It is now well appreciated that reprogramming of core... (Review)
Review
Mounting an effective immune response is crucial for the host to protect itself against invading pathogens. It is now well appreciated that reprogramming of core metabolic pathways in immune cells is a key requirement for their activation and function during infections. The role of several ancillary metabolic pathways in shaping immune cell function is less well understood. One such pathway, for which interest has recently been growing, is the hexosamine biosynthesis pathway (HBP) that generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the donor substrate for a specific form of glycosylation termed O-GlcNAcylation. O-GlcNAc is an intracellular post-translational modification that alters the functional properties of the modified proteins, in particular transcription factors and epigenetic regulators. An increasing number of studies suggest a central role for the HBP and O-GlcNAcylation in dictating immune cell function, including the response to different pathogens. We here discuss the most recent insights regarding O-GlcNAcylation and immunity, and explore whether targeting of O-GlcNAcylation could hold promise as a therapeutic approach to modulate immune responses to infections.
Topics: Animals; Epigenesis, Genetic; Glucosamine; Glycosylation; Hexosamines; Humans; Immunity; Immunomodulation; Infections; beta-N-Acetylhexosaminidases
PubMed: 32740921
DOI: 10.1111/imm.13245