The recent discovery of glycoRNAs on the cell surface upended the world of cell biology. These glycoRNAs were found to form highly organized clusters with cell surface RNA binding proteins (csRBPs), but their purpose remained unknown. Now, new findings published today in Nature report a distinct function for cell surface RNA, offering a clearer understanding of the mechanisms underlying cell to cell communication involved in processes such as vessel development (angiogenesis).
Heparan sulfate (HS) is present on the surface of all cells, serving as a magnet for growth factors that act as messengers, signaling cells to perform functions like growth, repair, and regeneration. Flynn and his lab found that HS chains play an important role in assembling glycoRNAs and csRBPs into cell surface ribonucleoprotein (csRNP) clusters. These clusters act as scaffolds on the cell-tethered HS chains which forms a new physical method for holding onto the glycoRNAs and csRBPs on the cell surface.
The team also established a new mechanistic pathway for information to be transferred from outside to inside of a cell: through the direct binding and regulation of growth factors (such as VEGF-A which is responsible for angiogenesis) to RNAs including glycoRNAs in csRNPs. They found that changing the amount of RNA on the cell surface controlled VEGF-A mediated activation of ERK signaling, which transfers signals from the cell surface into the nucleus. Disrupting this RNA-interaction enhanced vascular development both in vitro and in vivo.
"Our data establishes a new type of RNA regulation where the abundance or organization of cell surface RNPs can directly modify intracellular signaling cascades through selective interaction with growth factors, impacting cellular decision making," said Ryan Flynn, MD, PhD, from the Stem Cell and Regenerative Biology Program at Boston Children's Hospital. "Understanding the organization of HS-binding proteins, glycoRNAs, and csRBPs could enable better modeling of developmental and homeostatic processes in complex cellular environments."
This work leveraged a collaborative network of experts across Boston Children's, MIT, University of Cambridge, and UC San Diego.
