Unveiling the Role of GlycoRNAs
Written by Oindree Bal
Keywords: glycans; ribonucleic acids; glycosylation; Siglec receptors; glycoRNAs
Ribonucleic acid (RNA) is a group of multifunctional nucleic acids that utilize DNA templates during transcription and translation processes to produce proteins. We are well aware that the central dogma of life helps people see DNA’s role as a carrier of genetic information and that RNA is necessary to express genes. For instance, in certain viruses like the human immunodeficiency virus (HIV) and influenza, RNA functions as a genome and is still independently active.
The intricate folding properties of RNA drive the multifunctionality of RNA, which enables it to interface with numerous biological molecules to interact with other RNA molecules, DNA, and proteins. RNA-related interactions are involved in multiple cellular processes, including cell growth and differentiation as well as apoptosis (cell death).
What are glycoRNAs?
GlycoRNAs, which stand for glycosylated RNAs, are a group of RNA molecules that are modulated through a post-translational modification, namely the attachment of glycans (sugar molecules) to existing RNA molecules. This glycosylation phenomenon is displayed in more or less all RNA types.
Our cell membrane proteins have surface sugars named glycans that are vital and play major roles in the body. These carbohydrates have certain distinctive patterns that may be recognized by cellular receptors. Glycans play a notable role in doing so by attaching to proteins and fats as well as influencing the formation of proteins, or, in turn, by controlling the transmission of signals between cells.
Path of discovery:
In 2021, Ryan Flynn at Harvard and Dr. Carolyn Bertozzi at Stanford experimented with the metabolic tagging technique that was intended to label the precursor sugars for the glycans. Through this endeavor, the presence of glycoRNAs on the cell surface was ascertained, which resembles the appearance of the proteins and lipids.
In their research, they scrutinized the possibility of a link between glycoRNAs and Siglecs, which are immunoproteins with sialic acid-binding characteristics found to be predominantly on immune cells as a friend of the I-lectin family. In theory, naturally, the interactions belonging to the Siglec receptor family at the surface of a cell were believed to be between glycolipids or glycoproteins. Nevertheless, Flynn showed that two of the Siglec family members (-14 and -11) are known to be sensitive to RNase treatment, pointing to their exceptional capability to activate RNA-glycan engagements. During the sialylation process, which mainly involves the binding of sialic acid, cells foster galectin-1-dependent anoikis resistance in tumor cells. This happens with the association of a glycan receptor, which is a protein, and following that, the receptor’s signaling path would be deactivated.
The principal result of the experiment is the novel discovery that glycoRNAs can interact with one another directly, which suggests that the cell surface RNAs might play a major role and have more functions than previously assumed. The research procedure also showed that glycoRNAs reside on the cell membrane, and they use the secretory pathway to transit the molecules to the cell surface. Finally, these glycoRNA
molecules occupy this specific spot to display their functionality as ligands for the receptors or chemical moieties on adjacent cells. Such findings will have pathophysiological implications. Therefore, glycoRNA on the plasma membrane could be significantly involved in processes that might affect the immune system and deploy anti-dsRNA antibodies.
Future Directions of the Discovery :
As in the case of glycoRNAs and their clinical impact, the goal of research now is to identify their contribution to the achievements in immunotherapy. With the advent of glycoRNAs, autoimmune serum markers are on the brink of a promising future. Interestingly, RNA modifications that are achieved through glycosylation have been reported to be a response to immunotherapeutic interventions, and thus glycoRNA could serve as a good target for therapeutic use. The modifications of glycans within glycoRNAs might provide a factor in the epigenetic components concerned with the development of plaques in disorders like systemic lupus erythematosus. Moreover, glycoRNAs could act as receptors for immune responses to chemotherapeutic drugs, complementary to the role of enzymatic receptors.
The emerging glyoRNAs have led to the discovery of non-coding RNAs (ncRNAs) due to the involvement of glycoRNA, which is explained, by the direct connection between N-glycans and ncRNAs, which bridges the gap between RNA biology and glycobiology. The difference between glycosylation processes related to RNA and glycoRNA itself is in their role — the former participates in glycosylation, but the latter is defined as RNA itself subjected to glycosylation. From a scientific point of view, glycoRNAs are both very important, but, especially considering implementing new diagnostic and therapeutic strategies, they might become the most effective ones for autoimmune diseases in the near future. While glycoRNAs’ place in cell biology is still under certain constraints within mammalian cells, this discovery gives us new ways of linking glycoRNA data with how traditional RNA biology, glycosylation processes, glycobiology, the newest trends in glycomics, and other areas of cell and molecular biology function.
References :
Flynn, R.A., Pedram, K., Malaker, S.A., Batista, P.J., Smith, B.A.H., Johnson, A.G., George,
B.M., Majzoub, K., Villalta, P.W., Carette, J.E., et al. (2021). Small RNAs are modified with N-glycans and displayed on the surface of living cells.
https://doi.org/10.1016/j.cell.2021.04.023
Disney, M.D, 2021. A glimpse at the glycoRNA world.
https://doi.org/10.1016/j.cell.2021.05.025
Wilcox, C, 2021. Newly Discovered Glycosylated RNA Is All Over Cells: Study. https://www.the-scientist.com/newly-discovered-glycosylated-rna-is-all-over-cell s-study-68773
Manzano,J.A.H., Maningas, M.B.B. (2023). The Much-Awaited Bridge: Connecting the Worlds of RNA Biology and Glycobiology through the Discovery of GlycoRNAs https://doi.org/10.53603/actamanil.71.2023.slha3330
