UNASSIGNED: Type 1 (T1D) and type 2 (T2D) diabetes lead to an aberrant metabolism of sialoglycoconjugates and elevated free serum sialic acid (FSSA) level. The present study evaluated sialidase and sialyltranferase activities in serum and some organs relevant to diabetes at early and late stages of T1D and T2D.
UNASSIGNED: Sialic acid level with sialidase and sialyltransferase activities were monitored in the serum, liver, pancreas, skeletal muscle and kidney of diabetic animals at early and late stages of the diseases.
UNASSIGNED: The FSSA and activity of sialidase in the serum were significantly increased at late stage of both T1D and T2D while sialic acid level in the liver was significantly decreased in the early and late stages of T1D and T2D, respectively. Furthermore, the activity of sialidase was significantly elevated in most of the diabetes-relevant organs while the activity of sialyltransferase remained largely unchanged. A multiple regression analysis revealed the contribution of the liver to the FSSA while pancreas and kidney contributed to the activity of sialidase in the serum.
UNASSIGNED: We concluded that the release of hepatic sialic acid in addition to pancreatic and renal sialidase might (in)directly contribute to the increased FSSA during both types of diabetes mellitus.

Alzheimer\'s disease (AD) is a prevalent neurodegenerative disorder characterized by abnormal protein deposition. With an alarming 30 million people affected worldwide, AD poses a significant public health concern. While inhibiting key enzymes such as β-site amyloid precursor protein-cleaving enzyme 1 and γ-secretase or enhancing amyloid-β clearance, has been considered the reasonable strategy for AD treatment, their efficacy has been compromised by ineffectiveness. Furthermore, our understanding of AD pathogenesis remains incomplete. Normal aging is associated with a decline in glucose uptake in the brain, a process exacerbated in patients with AD, leading to significant impairment of a critical post-translational modification: glycosylation. Glycosylation, a finely regulated mechanism of intracellular secondary protein processing, plays a pivotal role in regulating essential functions such as synaptogenesis, neurogenesis, axon guidance, as well as learning and memory within the central nervous system. Advanced glycomic analysis has unveiled that abnormal glycosylation of key AD-related proteins closely correlates with the onset and progression of the disease. In this context, we aimed to delve into the intricate role and underlying mechanisms of glycosylation in the etiopathology and pathogenesis of AD. By highlighting the potential of targeting glycosylation as a promising and alternative therapeutic avenue for managing AD, we strive to contribute to the advancement of treatment strategies for this debilitating condition.

Sialic acid is a unique sugar moiety that resides in the distal and most accessible position of the glycans on mammalian cell surface and extracellular glycoproteins and glycolipids. The potential for sialic acid to obscure underlying structures has long been postulated, but the means by which such structural changes directly affect biological processes continues to be elucidated. Here, we appraise the growing body of literature detailing the importance of sialic acid for the generation, differentiation, function and death of haematopoietic cells. We conclude that sialylation is a critical post-translational modification utilized in haematopoiesis to meet the dynamic needs of the organism by enforcing rapid changes in availability of lineage-specific cell types. Though long thought to be generated only cell-autonomously within the intracellular ER-Golgi secretory apparatus, emerging data also demonstrate previously unexpected diversity in the mechanisms of sialylation. Emphasis is afforded to the mechanism of extrinsic sialylation, whereby extracellular enzymes remodel cell surface and extracellular glycans, supported by charged sugar donor molecules from activated platelets.

BACKGROUND: Aberrant glycosylation, catalyzed by the specific glycosyltransferase, is one of the dominant features of cancers. Among the glycosyltransferase subfamilies, sialyltransferases (SiaTs) are an essential part which has close linkages with tumor-associated events, such as tumor growth, metastasis and angiogenesis. Considering the relationship between SiaTs and cancer, the current study attempted to establish an effective prognostic model with SiaTs-related genes (SRGs) to predict patients\' outcome and therapeutic responsiveness of bladder cancer.
METHODS: RNA-seq data, clinical information and genomic mutation data were downloaded (TCGA-BLCA and GSE13507 datasets). The comprehensive landscape of the 20 SiaTs was analyzed, and the differentially expressed SiaTs-related genes were screened with \"DESeq2\" R package. ConsensusClusterPlus was applied for clustering, following with survival analysis with Kaplan-Meier curve. The overall survival related SRGs were determined with univariate Cox proportional hazards regression analysis, and the least absolute shrinkage and selection operator (LASSO) regression analysis was performed to generate a SRGs-related prognostic model. The predictive value was estimated with Kaplan-Meier plot and the receiver operating characteristic (ROC) curve, which was further validated with the constructed nomogram and decision curve.
RESULTS: In bladder cancer tissues, 17 out of the 20 SiaTs were differentially expressed with CNV changes and somatic mutations. Two SiaTs_Clusters were determined based on the expression of the 20 SiaTs, and two gene_Clusters were identified based on the expression of differentially expressed genes between SiaTs_Clusters. The SRGs-related prognostic model was generated with 7 key genes (CD109, TEAD4, FN1, TM4SF1, CDCA7L, ATOH8 and GZMA), and the accuracy for outcome prediction was validated with ROC curve and a constructed nomogram. The SRGs-related prognostic signature could separate patients into high- and low-risk group, where the high-risk group showed poorer outcome, more abundant immune infiltration, and higher expression of immune checkpoint genes. In addition, the risk score derived from the SRGs-related prognostic model could be utilized as a predictor to evaluate the responsiveness of patients to the medical therapies.
CONCLUSIONS: The SRGs-related prognostic signature could potentially aid in the prediction of the survival outcome and therapy response for patients with bladder cancer, contributing to the development of personalized treatment and appropriate medical decisions.

Aberrant glycosylation is a hallmark of a cancer cell. One prevalent alteration is an enrichment in α2,6-linked sialylation of N-glycosylated proteins, a modification directed by the ST6GAL1 sialyltransferase. ST6GAL1 is upregulated in many malignancies including ovarian cancer. Prior studies have shown that the addition of α2,6 sialic acid to the epidermal growth factor receptor (EGFR) activates this receptor, although the mechanism was largely unknown. To investigate the role of ST6GAL1 in EGFR activation, ST6GAL1 was overexpressed in the OV4 ovarian cancer line, which lacks endogenous ST6GAL1, or knocked-down in the OVCAR-3 and OVCAR-5 ovarian cancer lines, which have robust ST6GAL1 expression. Cells with high expression of ST6GAL1 displayed increased activation of EGFR and its downstream signaling targets, AKT and NFκB. Using biochemical and microscopy approaches, including total internal reflection fluorescence microscopy, we determined that the α2,6 sialylation of EGFR promoted its dimerization and higher order oligomerization. Additionally, ST6GAL1 activity was found to modulate EGFR trafficking dynamics following EGF-induced receptor activation. Specifically, EGFR sialylation enhanced receptor recycling to the cell surface following activation while simultaneously inhibiting lysosomal degradation. 3D widefield deconvolution microscopy confirmed that in cells with high ST6GAL1 expression, EGFR exhibited greater colocalization with Rab11 recycling endosomes and reduced colocalization with LAMP1-positive lysosomes. Collectively, our findings highlight a novel mechanism by which α2,6 sialylation promotes EGFR signaling by facilitating receptor oligomerization and recycling.

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Every eukaryotic cell is covered with a thick layer of complex carbohydrates with essential roles in their social life. In Deuterostoma, sialic acids present at the outermost positions of glycans of glycoconjugates are known to be key players in cellular interactions including host-pathogen interactions. Their negative charge and hydrophilic properties enable their roles in various normal and pathological states and their expression is altered in many diseases including cancers. Sialylation of glycoproteins and glycolipids is orchestrated by the regulated expression of twenty sialyltransferases in human tissues with distinct enzymatic characteristics and preferences for substrates and linkages formed. However, still very little is known on the functional organization of sialyltransferases in the Golgi apparatus and how the sialylation machinery is finely regulated to provide the ad hoc sialome to the cell. This review summarizes current knowledge on sialyltransferases, their structure-function relationships, molecular evolution, and their implications in human biology.

Modification by sialylated glycans can affect protein functions, underlying mechanisms that control animal development and physiology. Sialylation relies on a dedicated pathway involving evolutionarily conserved enzymes, including CMP-sialic acid synthetase (CSAS) and sialyltransferase (SiaT) that mediate the activation of sialic acid and its transfer onto glycan termini, respectively. In Drosophila, CSAS and DSiaT genes function in the nervous system, affecting neural transmission and excitability. We found that these genes function in different cells: the function of CSAS is restricted to glia, while DSiaT functions in neurons. This partition of the sialylation pathway allows for regulation of neural functions via a glia-mediated control of neural sialylation. The sialylation genes were shown to be required for tolerance to heat and oxidative stress and for maintenance of the normal level of voltage-gated sodium channels. Our results uncovered a unique bipartite sialylation pathway that mediates glia-neuron coupling and regulates neural excitability and stress tolerance.

It has been clarified that pathogens bind to glycosphingolipid (GSL) receptors in mammals, but there have been very few reports on pathogen-binding GSLs in fish. Vibrios are facultative anaerobic bacteria ubiquitous in marine and brackish environments. They are members of the normal intestinal microflora of healthy fish, but some species can cause a disease called vibriosis in fish and shellfish when the hosts are physiologically or immunologically weakened. The adherence of vibrios to host intestinal tracts is a significant event not only for survival and growth but also in terms of pathogenicity. We show in this mini-review that sialic acid-containing GSLs (gangliosides), GM4 and GM3, are receptors to which vibrios adhere to epithelial cells in the intestinal tract of fish. We also describe the enzymes responsible for synthesizing these Vibrio-binding gangliosides in fish.

GM3 synthase deficiency (GM3SD) is caused by biallelic variants in ST3GAL5. The ganglioside GM3, enriched in neuronal tissues, is a component of lipid rafts and regulates numerous signaling pathways. Affected individuals with GM3SD exhibit global developmental delay, progressive microcephaly, and dyskinetic movements. Hearing loss and altered skin pigmentation are also common. Most of the reported variants in ST3GAL5 are found in motifs conserved across all sialyltransferases within the GT29 family of enzymes. These motifs include motif L and motif S which contain amino acids responsible for substrate binding. These loss-of-function variants cause greatly reduced biosynthesis of GM3 and gangliosides derived from GM3. Here we describe an affected female with typical GM3SD features bearing two novel variants that reside in the other two conserved sialyltransferase motifs (motif 3 and motif VS). These missense alterations occur in amino acid residues that are strictly invariant across the entire GT29 family of sialyltransferases. The functional significance of these variants was confirmed by mass spectrometric analysis of plasma glycolipids, demonstrating a striking loss of GM3 and accumulation of lactosylceramide and Gb3 in the patient. The glycolipid profile changes were accompanied by an increase in ceramide chain length on LacCer. No changes in receptor tyrosine phosphorylation were observed in patient-derived lymphoblasts, indicating that GM3 synthase loss-of-function in this cell type does not impact receptor tyrosine kinase activity. These findings demonstrate the high prevalence of loss-of-function ST3GAL5 variants within highly conserved sialyltransferase motifs in affected individuals with GM3SD.