Hao Haojie, Zhang Fang, Chen Zhen, Tan Zhongyuan, Zhang Hongyan, Feng Xumei, Zhang Xueyan, Deng Tao, Zhan Guanli, Luo Ting, Zhang Kui, Ding Shuang, Liu Haibin, Zheng Zhenhua, Wang Yanyi, Huang Fang, Guan Wuxiang
Center for Emerging Infectious Diseases, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan, Hubei 430071, China.
Hubei JiangXia Laboratory, Wuhan, Hubei 430200, China.
iScience. 2024 Sep 30;27(11):111071. doi: 10.1016/j.isci.2024.111071. eCollection 2024 Nov 15.
Methyltransferase-like 3 (METTL3), the core methyltransferase for -methyladenosine (m6A), plays a crucial role in innate immunity by introducing m6A modifications on viral or host RNAs. Despite its well-established catalytic function in m6A deposition, the broader role of METTL3 in immune regulation remains unclear. Here, we uncovered that EV71 infection enhanced METTL3 expression in interferon (IFN)-deficient Vero and IFN-proficient rhabdomyosarcoma (RD) cells by modulating transcription and post-translational modification, respectively. METTL3 was shown to regulate antiviral immune responses in both m6A-dependent and -independent manners. METTL3's catalytic motif impaired viral RNA recognition by retinoic-acid-inducible gene I (RIG-I) via m6A modification, whereas its non-catalytic motif recruited and stabilized DEAD-box helicase 3X (DDX3X) by preventing DDX3X ubiquitination, which all mediate immune inhibition. This study reveals an m6A-independent pathway through which METTL3 regulates immune responses, highlighting its potential as a target for antiviral therapy.
甲基转移酶样 3（METTL3）是 N6-甲基腺苷（m6A）的核心甲基转移酶，通过在病毒或宿主 RNA 上引入 m6A 修饰，在先天免疫中发挥关键作用。尽管其在 m6A 沉积中具有明确的催化功能，但 METTL3 在免疫调节中的更广泛作用仍不清楚。在这里，我们发现肠道病毒 71 型（EV71）感染分别通过调节转录和翻译后修饰，增强了干扰素（IFN）缺陷的非洲绿猴肾细胞（Vero）和 IFN 充足的横纹肌肉瘤细胞（RD）中 METTL3 的表达。结果表明，METTL3 以 m6A 依赖和非依赖的方式调节抗病毒免疫反应。METTL3 的催化基序通过 m6A 修饰损害视黄酸诱导基因 I（RIG-I）对病毒 RNA 的识别，而其非催化基序通过防止 DEAD 盒解旋酶 3X（DDX3X）泛素化来招募和稳定 DDX3X，所有这些都介导免疫抑制。这项研究揭示了 METTL3 调节免疫反应的一条不依赖 m6A 的途径，突出了其作为抗病毒治疗靶点的潜力。
