A new study published in Nature provides mechanistic evidence for how N-glycosylation of RNA helps prevent immune activation, offering fresh context for innate immune tolerance to self-RNA. The work, led by Ryan Flynn at Boston Children’s Hospital and Vijay Rathinam at UConn Health, shows that glycosylated RNAs evade detection by innate immune sensors by chemically concealing a specific immunostimulatory RNA modification.
In previous research, Flynn’s group identified that small RNAs are modified with sialic acid-containing N-linked glycans, forming glycoRNAs that appear on the cell surface without triggering immune responses. This study aimed to clarify the functional consequence of this glycosylation.
“We wanted to better understand the significance of glycoRNAs,” said Flynn. “Why does RNA undergo glycosylation in the first place and what prevents glycoRNAs from activating an immune response?”
The team found that these N-glycans physically shield the RNA base acp³U (3-(3-amino-3-carboxypropyl)uridine), a hypermodified form of uracil that activates innate immune signaling when exposed. By chemically "caging" acp³U, N-glycans suppress its immunostimulatory potential, allowing glycoRNAs to circulate without triggering pattern recognition receptors such as TLRs or RIG-I-like receptors.
Interestingly, the Flynn Lab had previously identified acp³U as the specific site of N-glycosylation in RNA. This study builds on that finding by showing how this single post-transcriptional modification can influence immune recognition pathways.
Given that dysregulated RNA sensing contributes to autoimmune conditions like lupus, the findings raise new possibilities for understanding how changes in RNA glycosylation might contribute to autoimmunity. While further studies are needed to explore these links, the identification of glycan-masked acp³U as a natural immune evasion strategy deepens our molecular understanding of RNA immunogenicity.
Publication Details
Graziano, V.R., Porat, J., Ah Kioon, M.D. et al. RNA N-glycosylation enables immune evasion and homeostatic efferocytosis. Nature (2025). https://doi.org/10.1038/s41586-025-09310-6
In previous research, Flynn’s group identified that small RNAs are modified with sialic acid-containing N-linked glycans, forming glycoRNAs that appear on the cell surface without triggering immune responses. This study aimed to clarify the functional consequence of this glycosylation.
“We wanted to better understand the significance of glycoRNAs,” said Flynn. “Why does RNA undergo glycosylation in the first place and what prevents glycoRNAs from activating an immune response?”
The team found that these N-glycans physically shield the RNA base acp³U (3-(3-amino-3-carboxypropyl)uridine), a hypermodified form of uracil that activates innate immune signaling when exposed. By chemically "caging" acp³U, N-glycans suppress its immunostimulatory potential, allowing glycoRNAs to circulate without triggering pattern recognition receptors such as TLRs or RIG-I-like receptors.
Interestingly, the Flynn Lab had previously identified acp³U as the specific site of N-glycosylation in RNA. This study builds on that finding by showing how this single post-transcriptional modification can influence immune recognition pathways.
Given that dysregulated RNA sensing contributes to autoimmune conditions like lupus, the findings raise new possibilities for understanding how changes in RNA glycosylation might contribute to autoimmunity. While further studies are needed to explore these links, the identification of glycan-masked acp³U as a natural immune evasion strategy deepens our molecular understanding of RNA immunogenicity.
Publication Details
Graziano, V.R., Porat, J., Ah Kioon, M.D. et al. RNA N-glycosylation enables immune evasion and homeostatic efferocytosis. Nature (2025). https://doi.org/10.1038/s41586-025-09310-6