美国康涅狄格大学Vijay A. Rathinam研究团队发现了RNA N-糖基化使免疫逃避和稳态有效细胞作用成为可能。该研究于2025年8月6日发表于国际一流学术期刊《自然》杂志上。

研究团队最近发现小RNA在修饰的RNA碱基3-（3-氨基-3-羧基丙基）尿苷（acp³U）上进行N-糖基化。

然而，RNA N-糖基化的功能意义尚不清楚。

在这里，该研究组表明糖RNA上的N-聚糖阻止内源性小RNA的先天免疫感应。课题组发现细胞培养来源的和循环的人类和小鼠glycoRNA的去N-糖基化引发了强有力的炎症反应，包括以Toll样受体3和Toll样受体7依赖的方式产生I型干扰素。

此外，课题组发现细胞表面RNA上的N-聚糖可以阻止凋亡细胞触发胚胎细胞内体RNA传感器，从而促进死细胞的非炎性清除。从机制上讲，N-聚糖隐藏了超修饰的尿嘧啶碱基acp³U，小组发现当暴露在RNA中时，它具有免疫刺激作用。与此一致的是，一种合成acp³U的酶（DTWD2）的基因缺失可以消除去N-糖基化小RNA和凋亡细胞的先天免疫激活。

此外，合成含有acp³u的RNA足以触发先天免疫反应。他们的研究揭示了N-聚糖阻断RNA诱导acp³U依赖性先天免疫激活的自然机制，证明了糖RNA如何存在于细胞表面和内体网络中而不诱导自身炎症反应。

据悉，糖基化对生物分子的定位和功能至关重要。

附：英文原文

Title: RNA N-glycosylation enables immune evasion and homeostatic efferocytosis

Author: Graziano, Vincent R., Porat, Jennifer, Ah Kioon, Marie Dominique, Mejdrov, 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.

Issue&Volume: 2025-08-06

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.

DOI: 10.1038/s41586-025-09310-6

Source: https://www.nature.com/articles/s41586-025-09310-6