Wang Na, Liu Qiaoling, Wang Bo, Yang Zhuo, Li Siru, Li Ran, Liang Xinyuan, Fan Jiayu, Wang Hui, Sun Zhen, Dong Ling, Hou Yueru, Wang Shengnan, Song Chengli, Wang Yang, Quan Chunshan, Yang Qingkai, Wang Lina
Institute of Cancer Stem Cell, DaLian Medical University, Dalian 116044, China.
Department of General Surgery, The Second Affiliated Hospital of DaLian Medical University, Dalian, China.
Mol Ther. 2024 Dec 4;32(12):4418-4434. doi: 10.1016/j.ymthe.2024.10.027. Epub 2024 Oct 28.
Self-non-self discrimination is fundamental to life, thereby even microbes can apply DNA modifications to recognize non-self DNA. However, mammalian cytosolic DNA sensors indiscriminately bind DNA, necessitating specific mechanism(s) for self-non-self discrimination. Here, we show that mammalian RNA N-methyladenosine (m6A) and incoming DNA N-methyldeoxyadenosine (6mdA) cooperatively elevate the condensation potential of DNA to activate immunosurveillance. RNA m6A modification was found to enhance the activation of cyclic guanosine monophosphate-AMP synthase (cGAS) via increasing DNA phase separation. And 6mdA further increased the phase separation potential of DNA. Consistently, host RNA m6A and incoming DNA 6mdA modifications cooperatively elevated the incoming DNA condensation and cGAS activation. Moreover, we developed a prodrug, QKY-613. QKY-613 promoted a discriminative incorporation of 6mdA into viral DNAs to elevate host immune surveillance, and decreased mortality in virus-infected aged mice. Our results link nucleic acid modification diversity with immune surveillance via phase separation, which might be targeted for therapeutic intervention.
自我与非自我的区分是生命的基础，因此即使是微生物也能通过DNA修饰来识别非自我DNA。然而，哺乳动物胞质DNA传感器会不加区分地结合DNA，这就需要特定的自我与非自我区分机制。在此，我们表明哺乳动物RNA N-甲基腺苷（m6A）和进入的DNA N-甲基脱氧腺苷（6mdA）协同提高DNA的凝聚潜力以激活免疫监视。研究发现RNA m6A修饰通过增加DNA相分离来增强环磷酸鸟苷-腺苷合成酶（cGAS）的激活。而6mdA进一步增加了DNA的相分离潜力。一致地，宿主RNA m6A和进入的DNA 6mdA修饰协同提高了进入DNA的凝聚和cGAS激活。此外，我们开发了一种前药QKY-613。QKY-613促进6mdA特异性掺入病毒DNA以提高宿主免疫监视，并降低病毒感染老龄小鼠的死亡率。我们的结果通过相分离将核酸修饰多样性与免疫监视联系起来，这可能成为治疗干预的靶点。
