RNA N-glycosylation enables immune evasion and homeostatic efferocytosis

Vincent R. Graziano, Jennifer Porat, Marie Dominique Ah Kioon, Ivana Mejdrová, Alyssa J. Matz, Charlotta G. Lebedenko, Peiyuan Chai, John V. Pluvinage, Rafael Ricci-Azevedo, Andrew G. Harrison, Skylar S. Wright, Xinzheng Wang, Madison S. Strine, Penghua Wang, Michael R. Wilson, Sivapriya Kailasan Vanaja, Beiyan Zhou, Franck J. Barrat, Thomas Carell, Ryan A. Flynn () and Vijay A. Rathinam ()
Additional contact information
Vincent R. Graziano: UConn Health School of Medicine
Jennifer Porat: Boston Children’s Hospital
Marie Dominique Ah Kioon: Hospital for Special Surgery
Ivana Mejdrová: Ludwig-Maximilians-Universität (LMU) München
Alyssa J. Matz: UConn Health School of Medicine
Charlotta G. Lebedenko: Boston Children’s Hospital
Peiyuan Chai: Boston Children’s Hospital
John V. Pluvinage: San Francisco (UCSF)
Rafael Ricci-Azevedo: UConn Health School of Medicine
Andrew G. Harrison: UConn Health School of Medicine
Skylar S. Wright: UConn Health School of Medicine
Xinzheng Wang: UConn Health School of Medicine
Madison S. Strine: Yale School of Medicine
Penghua Wang: UConn Health School of Medicine
Michael R. Wilson: San Francisco (UCSF)
Sivapriya Kailasan Vanaja: UConn Health School of Medicine
Beiyan Zhou: UConn Health School of Medicine
Franck J. Barrat: Hospital for Special Surgery
Thomas Carell: Ludwig-Maximilians-Universität (LMU) München
Ryan A. Flynn: Boston Children’s Hospital
Vijay A. Rathinam: UConn Health School of Medicine

Nature, 2025, vol. 645, issue 8081, 784-792

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-09310-6

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