RNA N-glycosylation enables immune evasion and homeostatic efferocytosis

• 成果类型: Article
• 署名作者: Graziano, Vincent R.; Porat, Jennifer; Ah Kioon, Marie Dominique; Mejdrova, Ivana; Matz, Alyssa J.; Lebedenko, Charlotta G.; Chai, Peiyuan; Pluvinage, John V.; Ricci-Azevedo, Rafael; Harrison, Andrew G.; Wright, Skylar S.; Wang, Xinzheng; Strine, Madison S.; Wang, Penghua; Wilson, Michael R.; Vanaja, Sivapriya Kailasan; Zhou, Beiyan; Barrat, Franck J.; Carell, Thomas; Flynn, Ryan A.; Rathinam, Vijay A.
• 署名单位: Harvard University; Harvard University Medical Affiliates; Boston Children's Hospital; University of Munich; University of California System; University of California San Francisco; University of California System; University of California San Francisco; Yale University; University of Connecticut; Cornell University; Weill Cornell Medicine; Harvard University; Harvard University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1745
• DOI: 10.1038/s41586-025-09310-6
• 发表日期: 2025-09-18
• 关键词: double-stranded-rna; RECOGNITION; cells; transcriptome; activation; surface

摘要

Glycosylation is central to the localization and function of biomolecules1. We recently discovered that small RNAs undergo N-glycosylation2 at the modified RNA base 3-(3-amino-3-carboxypropyl) uridine (acp3U)3. However, the functional significance of N-glycosylation of RNAs is unknown. Here we show that the N-glycans on glycoRNAs prevent innate immune sensing of endogenous small RNAs. We found that de-N-glycosylation of cell-culture-derived and circulating human and mouse glycoRNA elicited potent inflammatory responses including the production of type I interferons in a Toll-like receptor 3- and Toll-like receptor 7-dependent manner. Furthermore, we show that N-glycans on cell surface RNAs prevent apoptotic cells from triggering endosomal RNA sensors in efferocytes, thus facilitating the non-inflammatory clearance of dead cells. Mechanistically, N-glycans conceal the hypermodified uracil base acp3U, which we identified as immunostimulatory when exposed in RNA. Consistent with this, genetic deletion of an enzyme (DTWD2) that synthesizes acp3U abrogated innate immune activation by de-N-glycosylated small RNAs and apoptotic cells. Furthermore, synthetic acp3U-containing RNAs are sufficient to trigger innate immune responses. Thus, our study has uncovered a natural mechanism by which N-glycans block RNAs from inducing acp3U-dependent innate immune activation, demonstrating how glycoRNAs exist on the cell surface and in the endosomal network without inducing autoinflammatory responses.