Functional Inclusion of RNA Biology in the Tethered Extracellular Matrix

RNA biology is traditionally confined to the cytosolic and nuclear spaces, where it plays critical roles across nearly all biochemical processes. Our recent observation of spatiotemporal regulation of cell surface ribonucleoproteins, consisting of glycoRNA and RNA-binding proteins, by heparan sulfate expands this knowledge to the extracellular matrix (ECM). We identified VEGF-A as a new noncanonical cell surface RNA-binding protein through the arginine residues within the heparan sulfate binding domain. The interaction between VEGF-A and cell surface RNA as a polyanion in the ECM provides an expanded example of the cell surface RNA interactome. Here, we review the common features of the heparan sulfate-binding domain and RNA-binding domain to provide a logical and testable path toward understanding the regulation and function of cell surface glycoRNAs.