Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06519, USA.
Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
Mol Cell. 2019 Oct 3;76(1):96-109.e9. doi: 10.1016/j.molcel.2019.07.016. Epub 2019 Aug 29.
Circular RNAs (circRNAs) are prevalent in eukaryotic cells and viral genomes. Mammalian cells possess innate immunity to detect foreign circRNAs, but the molecular basis of self versus foreign identity in circRNA immunity is unknown. Here, we show that N6-methyladenosine (mA) RNA modification on human circRNAs inhibits innate immunity. Foreign circRNAs are potent adjuvants to induce antigen-specific T cell activation, antibody production, and anti-tumor immunity in vivo, and mA modification abrogates immune gene activation and adjuvant activity. mA reader YTHDF2 sequesters mA-circRNA and is essential for suppression of innate immunity. Unmodified circRNA, but not mA-modified circRNA, directly activates RNA pattern recognition receptor RIG-I in the presence of lysine-63-linked polyubiquitin chain to cause filamentation of the adaptor protein MAVS and activation of the downstream transcription factor IRF3. CircRNA immunity has considerable parallel to prokaryotic DNA restriction modification system that transforms nucleic acid chemical modification into organismal innate immunity.
环状 RNA（circRNAs）在真核细胞和病毒基因组中普遍存在。哺乳动物细胞具有先天免疫能力来检测外来的 circRNAs，但 circRNA 免疫中自身与非自身身份的分子基础尚不清楚。在这里，我们表明人类 circRNAs 上的 N6-甲基腺苷（mA）RNA 修饰抑制先天免疫。外源性 circRNAs 是强有力的佐剂，可在体内诱导抗原特异性 T 细胞激活、抗体产生和抗肿瘤免疫，而 mA 修饰会阻断免疫基因激活和佐剂活性。mA 阅读器 YTHDF2 隔离 mA-circRNA，是抑制先天免疫所必需的。未修饰的 circRNA，但不是 mA 修饰的 circRNA，在存在赖氨酸 63 连接多泛素链的情况下直接激活 RNA 模式识别受体 RIG-I，导致衔接蛋白 MAVS 的丝化和下游转录因子 IRF3 的激活。circRNA 免疫与原核 DNA 限制修饰系统具有相当大的平行性，后者将核酸化学修饰转化为机体先天免疫。
