Abstract
Heparan sulfate proteoglycans (HSPGs) encompass a group of glycoproteins composed of unbranched negatively charged heparan sulfate (HS) chains covalently attached to a core protein. The complex HSPG biosynthetic machinery generates an extraordinary structural variety of HS chains that enable them to bind a plethora of ligands, including growth factors, morphogens, cytokines, chemokines, enzymes, matrix proteins, and bacterial and viral pathogens. These interactions translate into key regulatory activity of HSPGs on a wide range of cellular processes such as receptor activation and signaling, cytoskeleton assembly, extracellular matrix remodeling, endocytosis, cell-cell crosstalk, and others. Due to their ubiquitous expression within tissues and their large functional repertoire, HSPGs are involved in many physiopathological processes; thus, they have emerged as valuable targets for the therapy of many human diseases. Among their functions, HSPGs assist many viruses in invading host cells at various steps of their life cycle. Viruses utilize HSPGs for the attachment to the host cell, internalization, intracellular trafficking, egress, and spread. Recently, HSPG involvement in the pathogenesis of SARS-CoV-2 infection has been established. Here, we summarize the current knowledge on the molecular mechanisms underlying HSPG/SARS-CoV-2 interaction and downstream effects, and we provide an overview of the HSPG-based therapeutic strategies that could be used to combat such a fearsome virus.
Highlights
Heparan sulfate proteoglycans (HSPGs) encompass a group of glycoproteins composed of unbranched negatively charged heparan sulfate (HS) chains covalently attached to a core protein
Protein binding to HS for ACE interaction, and the prominent role of HSPGs in the structure and function of the vascular endothelial glycocalyx, it follows that the extraordinary structural variety of HSPGs generated by synthetic and post-synthetic modifying enzymes as well as the key regulatory functions exerted by HSPGs in different cell types and tissues—which depend on the sex and age of individuals [170,171]—might strongly contribute to the tissue tropism [141,142,143,144,145,146], as well as the different susceptibility of distinct patient populations to SARS-CoV-2 infection [158,161,172,173]
A consistent amount of data supports the dependence of SARS-CoV-2 on HSPGs for an efficient infection
Summary
Proteoglycans (PGs) consist of a core protein bearing one or more carbohydrate chain of glycosaminoglycans (GAGs) [1,2]. Syndecan-1 shedding by heparanase is an essential step in the dengue virus (DENV) infection; this action leads to hyperpermeability of human endothelial cells in vitro and systemic vascular leakage in vivo [102,103] These effects are mediated by the secreted DENV non-structural protein 1 (NS1), which disrupts the endothelial glycocalyx layer through the activation of sialic acid degradation and HSPG shedding. The proposed mechanisms to explain heparanase involvement in the severe forms and worsened outcomes of COVID-19 include its well-established roles in the degradation of the endothelial glycocalyx and the activation of inflammatory responses [110] These findings and other evidence suggest that biosynthetic and/or posttranslational modifying enzymes are important for the interaction of viruses with host cells and the infection process. Further structure–function analyses of modified-HS chains in different tissues and organs might provide more insights into the pathogenesis of viral diseases and could be useful for developing novel potential diagnostic tools and therapeutic interventions
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