Distinct pathways utilized by METTL3 to regulate antiviral innate immune response

• Published in: iScience 2024-11, Vol.27 (11), p.111071, Article 111071
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Immunology; Molecular biology; Virology
• ISSN: 2589-0042; 2589-0042
• DOI: 10.1016/j.isci.2024.111071

Methyltransferase-like 3 (METTL3), the core methyltransferase for N6-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. [Display omitted] •METTL3 exhibits distinct expression patterns in IFN-proficient and IFN-deficient cells•METTL3 suppresses immune responses in both m6A-dependent and -independent manners•METTL3 recruits DDX3X via its non-catalytic motif to inhibit immune response•METTL3 enhances DDX3X expression by inhibiting its ubiquitination Immunology; Molecular biology; Virology