N6-Methyladenosine Modification Controls Circular RNA Immunity
N6-Methyladenosine Modification Controls Circular RNA Immunity
复制标题
DOI：
10.1016/j.molcel.2019.07.016
复制
发表时间：
2019-10-03
期刊：
影响因子：
16
通讯作者：
Chang, Howard Y.
中科院分区：
文献类型：
--
作者：
Chen, Y. Grace;Chen, Robert;Chang, Howard Y.
环状RNA（circRNA）普遍存在于真核细胞和病毒基因组中。哺乳动物细胞具有检测外源circRNA的先天免疫，但circRNA免疫中自身与外源身份的分子基础尚不清楚。在这里，我们表明，N6-甲基腺苷（m（6）A）RNA修饰人circRNA抑制先天免疫。外源circRNA是体内诱导抗原特异性T细胞活化、抗体产生和抗肿瘤免疫的有效佐剂，并且m（6）A修饰消除免疫基因活化和佐剂活性。m（6）A reader YTHDF 2隔离m（6）A-circRNA，对于抑制先天免疫至关重要。未修饰的circRNA，而不是m（6）A修饰的circRNA，在赖氨酸-63-连接的多聚泛素链存在下直接激活RNA模式识别受体RIG-I，以引起衔接蛋白MAVS的重复表达和下游转录因子IRF 3的激活。CircRNA免疫与原核DNA限制性内切酶修饰系统具有相当大的相似性，该系统将核酸的化学修饰转化为生物体的先天免疫。
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 (m(6)A) 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 m(6)A modification abrogates immune gene activation and adjuvant activity. m(6)A reader YTHDF2 sequesters m(6)A-circRNA and is essential for suppression of innate immunity. Unmodified circRNA, but not m(6)A-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.