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Galectins constitute a family of soluble lectins with unique capacity to induce macroscale rearrangements upon interacting with cell membrane glycoconjugates. Galectin-8 (Gal-8) is acknowledged for its role in facilitating antigen uptake and processing upon engaging with cell surface glycoconjugates on antigen-presenting cells (APCs). Gal-8 consists of two covalently fused N- and C-terminal carbohydrate recognition domains (N- and C-CRD), each exhibiting distinct glycan specificity. In this study, we utilized single N- and C-CRD recombinant proteins to dissect the nature of Gal-8-glycan interactions during antigen internalization enhancement. Single C-CRD was able to replicate the effect of full-length Gal-8 (FLGal-8) on antigen internalization in BMDCs. Antigen uptake enhancement was diminished in the presence of lactose or when N-glycosylation-deficient macrophages served as APCs, underscoring the significance of glycan recognition. Measurement of the elastic modulus using Atomic Force Microscopy unveiled that FLGal-8- and C-CRD-stimulated macrophages exhibited heightened membrane stiffness compared to untreated cells, providing a plausible mechanism for their involvement in endocytosis. C-CRD proved to be as efficient as FLGal-8 in promoting antigen degradation, suggesting its implication in antigen-processing induction. Lastly, C-CRD was able to replicate FLGal-8-induced antigen presentation in the MHC-II context both in vitro and in vivo. Our findings support the notion that Gal-8 binds through its C-CRD to cell surface N-glycans, thereby altering membrane mechanical forces conducive to soluble antigen endocytosis, processing, and presentation to cognate CD4 T-cells. These findings contribute to a deeper comprehension of Gal-8 and its mechanisms of action, paving the way for the development of more efficacious immunotherapies.

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Sporothrix schenckii is one of the etiological agents of sporotrichosis, a cutaneous and subcutaneous infection distributed worldwide. Like other medically relevant fungi, its cell wall is a molecular scaffold to display virulence factors, such as protective pigments, hydrolytic enzymes, and adhesins. Cell wall proteins with adhesive properties have been previously reported, but only a handful of them have been identified and characterized. One of them is Gp70, an abundant cell wall protein mainly found on the surface of yeast-like cells. Since the protein also has a role in the activity of 3-carboxy-cis,cis-muconate cyclase and its abundance is low in highly virulent strains, its role in the Sporothrix-host interaction remains unclear. Here, a set of GP70-silenced strains was generated, and the molecular and phenotypical characterization was performed. The results showed that mutants with high silencing levels showed a significant reduction in the adhesion to laminin and fibrinogen, enzyme activity, and defects in the cell wall composition, which included reduced mannose, rhamnose, and protein content, accompanied by an increment in ß-1,3-glucans levels. The cell wall N-linked glycan content was significantly reduced. These strains induced poor TNFα and IL-6 levels when interacting with human peripheral blood mononuclear cells in a dectin-1-, TLR2-, and TLR4-dependent stimulation. The IL-1ß and IL-10 levels were significantly higher and were stimulated via dectin-1. Phagocytosis and stimulation of neutrophil extracellular traps by human granulocytes were increased in highly GP70-silenced strains. Furthermore, these mutants showed virulence attenuation in the invertebrate model Galleria mellonella. Our results demonstrate that Gp70 is a versatile protein with adhesin properties, is responsible for the activity of 3-carboxy-cis,cis-muconate cyclase, and is relevant for the S. schenckii-host interaction.

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Protein glycosylation is a post-translational modification involving the addition of carbohydrates to proteins and plays a crucial role in protein folding and various biological processes such as cell recognition, differentiation, and immune response. The vast array of natural sugars available allows the generation of plenty of unique glycan structures in proteins, adding complexity to the regulation and biological functions of glycans. The diversity is further increased by enzymatic site preferences and stereochemical conjugation, leading to an immense amount of different glycan structures. Understanding glycosylation heterogeneity is vital for unraveling the impact of glycans on different biological functions. Evaluating site occupancies and structural heterogeneity aids in comprehending glycan-related alterations in biological processes. Several software tools are available for large-scale glycoproteomics studies; however, integrating identification and quantitative data to assess heterogeneity complexity often requires extensive manual data processing. To address this challenge, we present a python script that automates the integration of Byonic and MaxQuant outputs for glycoproteomic data analysis. The script enables the calculation of site occupancy percentages by glycans and facilitates the comparison of glycan structures and site occupancies between two groups. This automated tool offers researchers a means to organize and interpret their high-throughput quantitative glycoproteomic data effectively.

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Cells use glycans to encode information that modulates processes ranging from cell-cell recognition to programmed cell death. This information is encoded within a glycocode, and its decoding is performed by carbohydrate-binding proteins. Among these, lectins stand out due to their specific and reversible interaction with carbohydrates. Changes in glycosylation patterns are observed in several pathologies, including cancer, where abnormal glycans are found on the surfaces of affected tissues. Given the importance of the bioprospection of promising biomolecules, the current work aimed to determine the structural properties and anticancer potential of the mannose-specific lectin from seeds of Canavalia villosa (Cvill). Experimental elucidation of the primary and 3D structures of the lectin, along with glycan array and molecular docking, facilitated the determination of its fine carbohydrate-binding specificity. These structural insights, coupled with the lectin's specificity, have been combined to explain the antiproliferative effect of Cvill against cancer cell lines. This effect is dependent on the carbohydrate-binding activity of Cvill and its uptake in the cells, with concomitant activation of autophagic and apoptotic pathways.

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Sporotrichosis is a cutaneous mycosis that affects humans and animals and has a worldwide distribution. This infection is mainly caused by Sporothrix schenckii, Sporothrix brasiliensis, and Sporothrix globosa. Current research about anti-Sporothrix immunity has been mainly focused on S. schenckii and S. brasiliensis, using different types of human or animal immune cells. Granulocytes are a group of cells relevant for cytokine production, with the capacity for phagocytosis and the generation of neutrophil extracellular traps (NETs). Considering their importance, this study aimed to compare the capacity of human granulocytes to stimulate cytokines, uptake, and form NETs when interacting with different Sporothrix species. We found that conidia, germlings, and yeast-like cells from S. schenckii, S. brasiliensis, and S. globosa play an important role in the interaction with these immune cells, establishing morphology- and species-specific cytokine profiles. S. brasil-iensis tended to stimulate an anti-inflammatory cytokine profile, whilst the other two species had a proinflammatory one. S. globosa cells were the most phagocytosed cells, which occurred through a dectin-1-dependent mechanism, while the uptake of S. brasiliensis mainly occurred via TLR4 and CR3. Cell wall N-linked and O-linked glycans, along with ß-1,3-glucan, played a significant role in the interaction of these Sporothrix species with human granulocytes. Finally, this study indicates that conidia and yeast-like cells are capable of inducing NETs, with the latter being a better stimulant. To the best of our knowledge, this is the first study that reports the cytokine profiles produced by human granulocytes interacting with Sporothrix cells.

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The SARS-CoV-2 entry into host cells is mainly mediated by the interactions between the viral spike protein (S) and the ACE-2 cell receptor, which are highly glycosylated. Therefore, carbohydrate binding agents may represent potential candidates to abrogate virus infection. Here, we evaluated the in vitro anti-SARS-CoV-2 activity of two mannose-binding lectins isolated from the Brazilian plants Canavalia brasiliensis and Dioclea violacea (ConBR and DVL). These lectins inhibited SARS-CoV-2 Wuhan-Hu-1 strain and variants Gamma and Omicron infections, with selectivity indexes (SI) of 7, 1.7, and 6.5, respectively for ConBR; and 25, 16.8, and 22.3, for DVL. ConBR and DVL inhibited over 95% of the early stages of the viral infection, with strong virucidal effect, and also protected cells from infection and presented post-entry inhibition. The presence of mannose resulted in the complete lack of anti-SARS-CoV-2 activity by ConBR and DVL, recovering virus titers. ATR-FTIR, molecular docking, and dynamic simulation between SARS-CoV-2 S and either lectins indicated molecular interactions with predicted binding energies of -85.4 and -72.0 Kcal/Mol, respectively. Our findings show that ConBR and DVL lectins possess strong activities against SARS-CoV-2, potentially by interacting with glycans and blocking virus entry into cells, representing potential candidates for the development of novel antiviral drugs.

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Cell surface glycans play essential roles in diverse physiological and pathological processes and their assessment has important implications in biomedicine and biotechnology. Here we present a rapid, versatile, and single-step multicolor flow cytometry method for evaluation of cell surface glycan signatures using a panel of selected fluorochrome-conjugated lectins. This procedure allows simultaneous detection of cell surface glycans with a 10-fold reduction in the number of cells required compared with traditional multistep lectin staining methods. Interestingly, we used this one-step lectin array coupled with dimension reduction algorithms in a proof-of-concept application for discrimination among different tumor and immune cell populations. Moreover, this procedure was also able to unveil T-, B-, and myeloid cell subclusters exhibiting differential glycophenotypes. Thus, we report a rapid and versatile lectin cytometry method to simultaneously detect a particular repertoire of surface glycans on living cells that can be easily implemented in different laboratories and core facilities.

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Sporotrichosis is a human and animal fungal infection distributed worldwide that is caused by the thermodimorphic species of the Sporothrix pathogenic clade, which includes Sporothrix brasiliensis, Sporothrix schenckii, and Sporothrix globosa. The cell wall composition and the immune response against the Sporothrix species have been studied mainly in S. brasiliensis and S. schenckii, whilst little is known about the S. globosa cell wall and the immune response that its components trigger. Therefore, in this study, we aimed to analyze the cell wall composition of S. globosa in three morphologies (germlings, conidia, and yeast-like cells) and the differences in cytokine production when human peripheral blood mononuclear cells (PBMCs) interact with these morphotypes, using S. schenckii and S. brasiliensis as a comparison. We found that S. globosa conidia and yeast-like cells have a higher cell wall chitin content, while all three morphologies have a higher ß-1,3-glucan content, which was found most exposed at the cell surface when compared to S. schenckii and S. brasiliensis. In addition, S. globosa has lower levels of mannose- and rhamnose-based glycoconjugates, as well as of N- and O-linked glycans, indicating that this fungal cell wall has species-specific proportions and organization of its components. When interacting with PBMCs, S. brasiliensis and S. globosa showed a similar cytokine stimulation profile, but with a higher stimulation of IL-10 by S. globosa. Additionally, when the inner cell wall components of S. globosa were exposed at the surface or N- and O-glycans were removed, the cytokine production profile of this species in its three morphotypes did not significantly change, contrasting with the S. schenckii and S. brasiliensis species that showed different cytokine profiles depending on the treatment applied to the walls. In addition, it was found that the anti-inflammatory response stimulated by S. globosa was dependent on the activation of dectin-1, mannose receptor, and TLR2, but not TLR4. All of these results indicate that the cell wall composition and structure of the three Sporothrix species in the three morphologies are different, affecting their interaction with human PBMCs and generating species-specific cytokine profiles.

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BACKGROUND: Although immunostaining of galectins is associated with cartilage damage, the serum levels of these lectins in osteoarthritis (OA) are not fully understood. OBJECTIVE: Therefore, we evaluate the concentrations of galectins-1, 3, 4, and 7 in patients with osteoarthritis and correlate them with clinical parameters. METHODS: This cross-sectional study involved 60 osteoarthritis patients and 43 healthy volunteers, who had serum samples collected for galectins titration by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: Our finds showed that the median values of gal-1 and 4 serum levels in patients were statistically higher (13,990 and 969.1 pg/mL, respectively) than in healthy controls (1,798 and 519.5 pg/mL) with p < 0.001. Further, gal-1 expressed higher levels in patients who had joint edema at the time of collection with a median value of 14,970 pg/mL. CONCLUSION: Surprisingly, galectin-4 appears to be involved in the osteoarthritis inflammation process as the well-known galectin-1.

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BACKGROUND: Post-translational modifications are key factors in the modulation of nuclear protein functions controlling cell physiology and an individual's health. OBJECTIVES: This study examined the influence of protein restriction during the perinatal period on the nuclear O-N-acetylgalactosamine (O-GalNAc) glycosylation of cells from the liver and parts of the brain in the rat. METHODS: Pregnant Wistar rats were divided into 2 groups on day 14 of pregnancy and fed ad libitum 1 of 2 isocaloric diets containing 24% (well-fed) or 8% (protein-restricted diet) casein until the end of the experiment. Male pups were studied after weaning at 30 d of life. Animals and their organ/tissues (liver, cerebral cortex, cerebellum and hippocampus) were weighed. Cell nuclei were purified, and the presence in nucleus and cytoplasm of all factors required for the initiation of O-GalNAc glycan biosynthesis, i.e., the sugar donor (UDP-GalNAc), enzyme activity (ppGalNAc-transferase) and the glycosylation product (O-GalNAc glycans), were evaluated by western blotting, fluorescent microscopy, enzyme activity, enzyme-lectin sorbent assay and mass spectrometry. RESULTS: The perinatal protein deficit reduced progeny weight, as well as the cerebral cortex and cerebellum weight. UDP-GalNAc levels in the cytoplasm and nuclei of the liver, the cerebral cortex, cerebellum, or hippocampus were not affected by the perinatal dietary protein deficits. However, this deficiency affected the ppGalNAc-transferase activity localized in the cerebral cortex and hippocampus cytoplasm as well as in the liver nucleus, thus reducing the "writing" ppGalNAc-transferase activity of O-GalNAc glycans. In addition, liver nucleoplasm from protein-restricted offspring revealed a significant reduction in the expression of O-GalNAc glycans on important nuclear proteins. CONCLUSIONS: Our results report an association between the consumption of a protein-restricted diet by the dam and her progeny with the modulation in the offspring' liver nuclei O-GalNAc glycosylation, which may ultimately regulate nuclear protein functions.

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BACKGROUND: Changes in protein glycosylation are widely observed in tumor cells. N-glycan branching through adding ß1,6-linked N-acetylglucosamine (ß1,6-GlcNAc) to an α1,6-linked mannose, which is catalyzed by the N-acetylglucosaminyltransferase V (MGAT5 or GnT-V), is one of the most frequently observed tumor-associated glycan structure formed. Increased levels of this branching structure play a pro-tumoral role in various ways, for example, through the stabilization of growth factor receptors, the destabilization of intercellular adhesion, or the acquisition of a migratory phenotype. CONCLUSION: In this review, we provide an updated and comprehensive summary of the physiological and pathophysiological roles of MGAT5 and ß1,6-GlcNAc branched N-glycans, including their regulatory mechanisms. Specific emphasis is given to the role of MGAT5 and ß1,6-GlcNAc branched N-glycans in cellular mechanisms that contribute to the development and progression of solid tumors. We also provide insight into possible future clinical implications, such as the use of MGAT5 as a prognostic biomarker.

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Glycosylation is a post-translational modification that affects the stability, structure, antigenicity and charge of proteins. In the immune system, glycosylation is involved in the regulation of ligand-receptor interactions, such as in B-cell and T-cell activating receptors. Alterations in glycosylation have been described in several autoimmune diseases, such as systemic lupus erythematosus (SLE), in which alterations have been found mainly in the glycosylation of B lymphocytes, T lymphocytes and immunoglobulins. In immunoglobulin G of lupus patients, a decrease in galactosylation, sialylation, and nucleotide fucose, as well as an increase in the N-acetylglucosamine bisector, are observed. These changes in glycoisolation affect the interactions of immunoglobulins with Fc receptors and are associated with pericarditis, proteinuria, nephritis, and the presence of antinuclear antibodies. In T cells, alterations have been described in the glycosylation of receptors involved in activation, such as the T cell receptor; these changes affect the affinity with their ligands and modulate the binding to endogenous lectins such as galectins. In T cells from lupus patients, a decrease in galectin 1 binding is observed, which could favor activation and reduce apoptosis. Furthermore, these alterations in glycosylation correlate with disease activity and clinical manifestations, and thus have potential use as biomarkers. In this review, we summarize findings on glycosylation alterations in SLE and how they relate to immune system defects and their clinical manifestations.

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Galectins are an evolutionarily ancient family of lectins characterized by their affinity for ß-galactosides and a conserved binding site in the carbohydrate recognition domain (CRD). These lectins are involved in multiple physiological functions, including the recognition of glycans on the surface of viruses and bacteria. This feature supports their role in innate immune responses in marine mollusks. Here, we identified and characterized a galectin, from the mollusk Haliotis rufescens (named HrGal), with four CRDs that belong to the tandem-repeat type. HrGal was purified by affinity chromatography in a galactose-agarose resin and exhibited a molecular mass of 64.11 kDa determined by MALDI-TOF mass spectrometry. The identity of HrGal was verified by sequencing, confirming that it is a 555 amino acid protein with a mass of 63.86 kDa. This protein corresponds to a galectin reported in GenBank with accession number AHX26603. HrGal is stable in the presence of urea, reducing agents, and ions such as Cu2+ and Zn2+. The recombinant galectin (rHrGal) was purified from inclusion bodies in the presence of these ions. A theoretical model obtained with the AlphaFold server exhibits four non-identical CRDs, with a ß sandwich folding and the representative motifs for binding ß-galactosides. This allows us to classify HrGal within the tandem repeat galectin family. On the basis of a phylogenetic analysis, we found that the mollusk sequences form a monophyletic group of tetradomain galectins unrelated to vertebrate galectins. HrGal showed specificity for galactosides and glucosides but only the sulfated sugars heparin and ι-carrageenan inhibited its hemagglutinating activity with a minimum inhibitory concentration of 4 mM and 6.25 X 10-5% respectively. The position of the sulfate groups seemed crucial for binding, both by carrageenans and heparin.

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Sporothrix schenckii is a member of the Sporothrix pathogenic clade and one of the most common etiological agents of sporotrichosis, a subcutaneous fungal infection that affects both animal and human beings. Like other fungal pathogens, the Sporothrix cell wall is composed of structural polysaccharides and glycoproteins that are covalently modified with both N-linked and O-linked glycans. Thus far, little is known about the N-linked glycosylation pathway in this organism or its contribution to cell wall composition and interaction with the host. Here, we silenced ROT2, which encodes the catalytic subunit of the endoplasmic reticulum α-glucosidase II, a processing enzyme key for the N-linked glycan core processing. Silencing of ROT2 led to the accumulation of the Glc2Man9GlcNAC2 glycan core at the cell wall and a reduction in the total content of N-linked glycans found in the wall. However, the highly silenced mutants showed a compensatory mechanism with increased content of cell wall O-linked glycans. The phenotype of mutants with intermediate levels of ROT2 silencing was more informative, as they showed changes in the cell wall composition and exposure of ß-1.3-glucans and chitin at the cell surface. Furthermore, the ability to stimulate cytokine production by human mononuclear cells was affected, along with the phagocytosis by human monocyte-derived macrophages, in a mannose receptor-, complement receptor 3-, and TLR4-dependent stimulation. In an insect model of experimental sporotrichosis, these mutant cells showed virulence attenuation. In conclusion, S. schenckii ROT2 is required for proper N-linked glycosylation, cell wall organization and composition, and interaction with the host.

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Polypeptide N-acetylgalactosamine transferase 3 (ppGalNAc-T3) is an enzyme involved in the initiation of O-GalNAc glycan biosynthesis. Acting as a writer of frequent post-translational modification (PTM) on human proteins, ppGalNAc-T3 has key functions in the homeostasis of human cells and tissues. We review the relevant roles of this molecule in the biosynthesis of O-GalNAc glycans, as well as in biological functions related to human physiological and pathological conditions. With main emphasis in ppGalNAc-T3, we draw attention to the different ways involved in the modulation of ppGalNAc-Ts enzymatic activity. In addition, we take notice on recent reports of ppGalNAc-T3 having different subcellular localizations, highlight critical intrinsic and extrinsic functions in cellular physiology that are exerted by ppGalNAc-T3-synthesized PTMs, and provide an update on several human pathologies associated with dysfunctional ppGalNAc-T3. Finally, we propose biotechnological tools as new therapeutic options for the treatment of pathologies related to altered ppGalNAc-T3. KEY MESSAGES: ppGalNAc-T3 is a key enzyme in the human O-GalNAc glycans biosynthesis. enzyme activity is regulated by PTMs, lectin domain and protein-protein interactions. ppGalNAc-T3 is located in human Golgi apparatus and cell nucleus. ppGalNAc-T3 has a central role in cell physiology as well as in several pathologies. Biotechnological tools for pathological management are proposed.

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Molecular Dynamics (MD) is a method used to calculate the movement of atoms and molecules broadly applied to several aspects of science. It involves computational simulation, which makes it, at first glance, not easily accessible. The rise of several automated tools to perform molecular simulations has allowed researchers to navigate through the various steps of MD. This enables to elucidate structural properties of proteins that could not be analyzed otherwise, such as the impact of glycosylation. Glycosylation dictates the physicochemical and biological properties of a protein modulating its solubility, stability, resistance to proteolysis, interaction partners, enzymatic activity, binding and recognition. Given the high conformational and compositional diversity of the glycan chains, assessing their influence on the protein structure is challenging using conventional analytical techniques. In this manuscript, we present a step-by-step workflow to build and perform MD analysis of glycoproteins focusing on the SPIKE glycoprotein of SARS-CoV-2 to appraise the impact of glycans in structure stabilization and antibody occlusion.

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The fungal cell wall is an attractive structure to look for new antifungal drug targets and for understanding the host-fungus interaction. Sporothrix schenckii is one of the main causative agents of both human and animal sporotrichosis and currently is the species most studied of the Sporothrix genus. The cell wall of this organism has been previously analyzed, and rhamnoconjugates are signature molecules found on the surface of both mycelia and yeast-like cells. Similar to other reactions where sugars are covalently linked to other sugars, lipids, or proteins, the rhamnosylation process in this organism is expected to involve glycosyltransferases with the ability to transfer rhamnose from a sugar donor to the acceptor molecule, i.e., rhamnosyltransferases. However, no obvious rhamnosyltransferase has thus far been identified within the S. schenckii proteome or genome. Here, using a Hidden Markov Model profile strategy, we found within the S. schenckii genome five putative genes encoding for rhamnosyltransferases. Expression analyses indicated that only two of them, named RHT1 and RHT2, were significantly expressed in yeast-like cells and during interaction with the host. These two genes were heterologously expressed in Escherichia coli, and the purified recombinant proteins showed rhamnosyltransferase activity, dependent on the presence of UDP-rhamnose as a sugar donor. To the best of our knowledge, this is the first report about rhamnosyltransferases in S. schenckii.

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Aberrant glycosylation in tumour progression is currently a topic of main interest. Tumour-associated carbohydrate antigens (TACAs) are expressed in a wide variety of epithelial cancers, being both a diagnostic tool and a potential treatment target, as they have impact on patient outcome and disease progression. Glycans affect both tumour-cell biology properties as well as the antitumor immune response. It has been ascertained that TACAs affect cell migration, invasion and metastatic properties both when expressed by cancer cells or by their extracellular vesicles. On the other hand, tumour-associated glycans recognized by C-type lectin receptors in immune cells possess immunomodulatory properties which enable tumour growth and immune response evasion. Yet, much remains unknown, concerning mechanisms involved in deregulation of glycan synthesis and how this affects cell biology on a major level. This review summarises the main findings to date concerning how aberrant glycans influence tumour growth and immunity, their application in cancer treatment and spotlights of unanswered challenges remaining to be solved.

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Diabetes Mellitus (DM) is both, correlated and a known risk factor for colorectal cancer (CRC). Besides favoring the incidence of CRC, DM also accelerates its progression, worsening its prognosis. Previously, hyperglycemia, the DM hallmark, has been shown to lead to aberrant glycosylation of CRC cells, heightening their malignancy both in vivo and in vitro. Here we use mass spectrometry to elucidate the composition and putative structures of N-glycans expressed by MC38 cultured in normoglycemic (LG) and hyperglycemic-like conditions (HG). N-glycans, 67, were identified in MC38 cells cultured in LG and HG. The cells grown in HG showed a greater abundance of N-glycans when compared to LNG cells, without changes in the proportion of sialylated, fucosylated and mannosylated N-glycans. Among the identified N-glycans, 16 were differentially expressed, mostly mannosylated and fucosylated, with a minority of them being sialylated. Metabolomics analysis indicates that the alterations observed in the N-glycosylation may be mostly due to increase of the activated monosaccharides pool, through an increased glucose entrance into the cells. The alterations found here corroborate data from the literature regarding the progression of CRC, advocating for development or repositioning of effective treatments against CRC in diabetic patients.

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