Certain RNA modifications could contribute to the development of autoimmune disorders

New research published today in Nature from Ryan Flynn, MD, PhD, in collaboration with Vijay Rathinam, DVM, PhD, and his graduate student Vincent Graziano at UConn Health and other colleagues at Boston Children’s Hospital and UConn Health has uncovered powerful evidence that may explain why a new chemical modification of RNA is made in cells. The findings could provide new concepts for understanding the development of autoimmunity and how bacterial pathogens are detected — and ultimately help identify new therapeutic targets.

RNA sensing is a crucial function of our innate immune system that protects our bodies from invading pathogens. Because RNA itself not a pathogen-specific molecular pattern, our bodies deploy a multitude of mechanisms to prevent immune sensing of self-RNA, including RNA modifications.

One such RNA modification is N-glycosylation, which was recently discovered by Flynn and his mentor, Nobel laureate Carolyn Bertozzi. They found that small RNAs are modified with sialic acid-containing N-linked glycans (glycoRNAs) which are guided to and deployed on the cell surface without stimulating immune sensors. But the function of the glycan on RNAs has remained unclear.

“We wanted to better understand the significance of glycoRNAs,” says Flynn. “Why does RNA undergo glycosylation in the first place and what prevents glycoRNAs from activating an immune response?”

In this work, Flynn, Rathinam, and his colleagues show that the N-glycans on glycoRNAs prevent innate immune sensing of endogenous small RNAs. The N-glycans chemically “cage” or conceal the hypermodified RNA base known as uracil base acp³U, which they identified as immunostimulatory when exposed in RNA. Interestingly, the Flynn Lab had previously discovered that acp3U is the endogenous site for N-glycosylation in RNA (PMID: 39173631)

This study uncovers a natural mechanism by which N-glycans block RNAs from inducing innate immune activation, demonstrating how glycoRNAs exist on the cell surface and in the endosomal network without inducing autoinflammatory responses. Because the innate immune sensors that detect RNA are important in diverse autoimmune disorders such as lupus, these  findings raise the question of whether changes in the N-glycosylation of RNA could be related to the development of autoimmunity.