Sialyl-Tn (STn) is a disaccharide expressed by several solid tumours and is frequently reported as tumour-specific. This incomplete O-glycan arises from the dysregulation of glycosyltransferase activity, such as the sialyltransferase ST6GalNAc-I, favouring premature sialylation. Here, we aimed to review the literature for the prognostic value of STn across various cancers, as it remains unclear. Of the 25 selected studies reporting patient survival according to STn expression, STn was associated with worse survival in 14 studies, mostly in gastric, bladder, breast and sinonasal cancers. No impact was reported in 10 studies and the impact was uncertain in 2. We also inspected the STn protein carriers reported according to cancer type. Interestingly, while O-glycosylation is present in many cell surface proteins, only a few are described as STn carriers, with MUC1 mucin identified across several cancers. Yet the list of known STn carriers is likely increasing due to technology improvements. We also identified a striking diversity of antibodies used to identify STn, often with little information on their exact specificity, which may explain study divergences. The current review highlights the tumour-specific character of STn and its potential as a target for novel immunotherapies. However, challenges remain due to STn heterogeneous presentation and the need for standardization methods for its detection.
Glycans cover the surface of essentially all cells, giving rise to the so-called glycocalyx. Glycans, and particularly N-glycans are key players in defining the fate and the nature of the immune response, participating in both pro-inflammatory and anti-inflammatory pathways occurring in inflammation, autoimmunity and cancer. Glycans and glycan-binding proteins (GBPs) are instrumental molecules that integrate the immunological landscape in homeostasis, being involved in how the host immune system perceives the self and non-self. Perturbations in these immune regulatory circuits created by glycans and GBPs may result in the loss of immune tolerance associated with autoimmunity and inflammatory conditions, but also in malignant transformation. This chapter will discuss the regulatory role played by N-glycans as fundamental immune-checkpoints in the interplay between the immune cells and their surrounding microenvironment associated with homeostasis and disease. Furthermore, we will also explore how N-glycans can act as promising diagnostic and prognostic biomarkers in disease, as well as appealing targets for new therapeutic approaches in inflammation, autoimmunity and cancer.
The genus Mycobacterium comprises numerous species, including major human pathogens responsible for two diseases – tuberculosis and leprosy – that have afflicted humanity for millennia. Other Mycobacterium species are known to cause chronic lung infections, some of which spread through modern water distribution systems that they can colonize. Mycobacteria have a distinctive cell envelope that comprises a complex matrix of lipids, sugars, and lipoglycans, and which forms a formidable barrier against environmental stress and host immune responses, contributing to their resilience. They also possess two types of intracellular polymethylated polysaccharides, 6-O-methylglucose lipopolysaccharide (MGLP) and 3-O-methylmannose polysaccharide (MMP), which influence the synthesis of fatty acid precursors of envelope components. While in vitro studies have demonstrated their interactions with fatty acids and regulatory effects on fatty acid synthase activity, the precise in vivo functions remain elusive. MGLP has been implicated in heat stress adaptation, whereas MMP may play a role in cold stress responses. Although MGLP biosynthetic genes are conserved across mycobacterial genomes, a MMP biosynthetic gene cluster is absent in the important pathogens M. tuberculosis, M. leprae, and M. abscessus. MGLP biosynthesis follows a de novo pathway beginning with the glycoside glucosylglycerate (GG) and involving various gene clusters, whereas MMP biosynthesis seems to be governed by a single gene cluster encoding an MMP hydrolase that facilitates a self-recycling mechanism, generating oligomannoside primers for synthesis of new MMP. Despite gaps in our understanding of their physiological roles, particularly their impact on fatty acid metabolism and envelope integrity, and their restricted distribution, the enzymes in these pathways may represent promising targets for novel therapeutic interventions against mycobacterial infections, which remain pressing global health challenges.
The main hallmarks of Parkinson’s disease (PD) are the degeneration of nigral dopaminergic neurons and increased number of intracellular inclusions of aggregated α-synuclein called Lewy bodies. Mitochondrial dysfunction, oxidative stress, impaired proteostasis and neuroinflammation are strongly implicated in the pathogenesis of PD. Paralleled with the emergence of novel analytical methods and more sensitive tools, there has been increasing evidence revealing an association of aberrant glycosylation with PD. Here, we provide an overview of the most important cellular mechanisms implicated in the pathology of PD and explore aspects of dysfunctional or aberrant glycosylation establishing a link with the described pathological mechanisms for neurodegeneration. Some of the glycosylation pattern alterations described here have already been directly associated with pathological mechanisms of PD, while others are more generally associated with neurodegenerative diseases and could potentially have an impact on PD. Not intending to be an exhaustive review of all putative glycosylation modifications associated with PD, we selected classical proteins and pathways involved in different steps of the pathogenic process. The identification of these mechanisms will be crucial for the discovery of new therapeutic targets and pharmacological strategies based on glycans to afford neuroprotection in PD.
The LytR-CpsA-Psr (LCP) family of proteins plays a critical role in bacterial cell wall biosynthesis, specifically in the attachment of wall teichoic acids (WTAs) and other cell wall glycopolymers (CWGPs) to peptidoglycan. These CWGPs are essential components of the Gram-positive bacterial cell wall, contributing to its structural integrity, ion homeostasis, and resistance to environmental stress. By catalysing the covalent attachment of these polymers to the peptidoglycan layer, LCP proteins ensure the stability and function of the bacterial cell wall, which is critical for bacterial survival. This study presents a comprehensive structural analysis of experimentally determined LCP structures available and deposited in the Protein Data Bank (PDB) as well as AlphaFold2 models, revealing both conserved and variable features within the family. Our analysis focused on specific regions important for binding and activity on peptidoglycan substrates, such as the Mg²⁺ coordination site, active site, the hydrophobic pocket, and the peptidoglycan-binding groove. Despite low sequence identity, the analysis revealed high structural similarity among the proteins, particularly in the substrate binding sites and catalytic residues. This analysis provides a detailed understanding of the molecular determinants governing LCP protein function and their essential role in bacterial cell wall assembly, with potential implications for the development of novel antibacterial therapies.
