Proteoglycans: a common portal for SARS-CoV-2 and extracellular vesicle uptake

As structural components of the glycocalyx, heparan sulfate proteoglycans (HSPGs) are involved in multiple pathophysiological processes at the apex of cell signaling cascades, and as endocytosis receptors for particle structures, such as lipoproteins, extracellular vesicles, and enveloped viruses, including SARS-CoV-2. Given their diversity and complex biogenesis regulation, HSPGs remain understudied. Here we compile some of the latest studies focusing on HSPGs as internalizing receptors of extracellular vesicles (endogenous virus) and SARS-CoV-2 lipid-enclosed particles and highlight similarities in their biophysical and structural characteristics. Specifically, the similarities in their biogenesis, size, and lipid composition may explain a common dependence on HSPGs for efficient cell-surface attachment and uptake. We further discuss the relative complexity of extracellular vesicle composition and the viral mechanisms that evolve towards increased infectivity that complicate therapeutic strategies addressing blockade of their uptake.

Automated summary

As structural components of the glycocalyx, heparan sulfate proteoglycans (HSPGs) play multiple roles in cell signaling cascades and act as endocytosis receptors for particle structures including lipoproteins, extracellular vesicles, and enveloped viruses like SARS-CoV-2. However, HSPGs are still not extensively studied due to their diversity and complex regulation. Recent studies have focused on HSPGs as receptors for internalizing extracellular vesicles and SARS-CoV-2 particles and have highlighted similarities in their biophysical and structural characteristics. Understanding these similarities, such as their biogenesis, size, and lipid composition, may help explain their reliance on HSPGs for efficient attachment and uptake on the cell surface. Additionally, the complex composition of extracellular vesicles and viral mechanisms that enhance infectivity complicate therapeutic strategies targeting their uptake.