Distinct pathways utilized by METTL3 to regulate antiviral innate immune response

作者：Haojie Hao, Fang Zhang, Zhen Chen, Zhongyuan Tan, Hongyan Zhang, Xumei Feng, Xueyan Zhang, Tao Deng, Guanli Zhan, Ting Luo, Kui Zhang, Shuang Ding, Haibin Liu, Zhenhua Zheng, Yanyi Wang, Fang Huang, Wuxiang Guan · 发表于：iScience · 年份：2024 · DOI：10.1016/j.isci.2024.111071 · 被引用次数：9 · 研究领域：RNA modifications and cancer、interferon and immune responses、Cancer-related molecular mechanisms research

-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.