2. Academic Validation
  3. HSV-1-induced N6-methyladenosine reprogramming via ICP0-mediated suppression of METTL14 potentiates oncolytic activity in glioma

HSV-1-induced N6-methyladenosine reprogramming via ICP0-mediated suppression of METTL14 potentiates oncolytic activity in glioma

  • Cell Rep. 2024 Oct 22;43(10):114756. doi: 10.1016/j.celrep.2024.114756.
Yuling Chen 1,  Shasha Bian 2,  Jiamei Zhang 2,  Yuxuan Luan 1,  Bowen Yin 2,  Weiwei Dai 2,  Hanlin Wang 1,  Xi Chen 1,  Yan Dong 2,  Yiheng Cai 3,  Ruitao Dong 2,  Liubing Yu 2,  Minfeng Shu 4
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 2 Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Key Laboratory of Medical Molecular Virology (Ministry of Education/National Health Commission/ Chinese Academy of Medical Sciences), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China.
  • 3 Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Key Laboratory of Medical Molecular Virology (Ministry of Education/National Health Commission/ Chinese Academy of Medical Sciences), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Interventional Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
  • 4 Department of Pharmacology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Key Laboratory of Medical Molecular Virology (Ministry of Education/National Health Commission/ Chinese Academy of Medical Sciences), Shanghai Frontiers Science Center of Pathogenic Microorganisms and Infection, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Pharmacy, Jinshan Hospital, Fudan University, Shanghai 201508, China. Electronic address: minfeng_shu@fudan.edu.cn.
PMID: 39325621 DOI: 10.1016/j.celrep.2024.114756
Abstract

Upon Infection with herpes simplex virus 1 (HSV-1), the virus deploys multiple strategies to evade the host's innate immune response. However, the mechanisms governing this phenomenon remain elusive. Here, we find that HSV-1 leads to a decrease in overall m6A levels by selectively reducing METTL14 protein during early Infection in glioma cells. Specifically, the HSV-1-encoded immediate-early protein ICP0 interacts with METTL14 within ND10 bodies and serves as an E3 ubiquitin protein Ligase, targeting and ubiquitinating METTL14 at the lysine 156 and 162 sites. Subsequently, METTL14 undergoes proteasomal degradation. Furthermore, METTL14 stabilizes ISG15 mRNA mediated by IGF2BP3 to promote Antiviral effects. Notably, METTL14 suppression significantly enhances the anti-tumor effect of oncolytic HSV-1 (oHSV-1) in mice bearing glioma xenografts. Collectively, these findings establish that ICP0-guided m6A modification controls the Antiviral immune response and suggest that targeting METTL14/ISG15 represents a potential strategy to enhance the oncolytic activity of oHSV-1 in glioma treatment.

Keywords

CP: Cancer; CP: Molecular biology; HSV-1; ICP0; IGF2BP3 METTL14; ISG15; glioma; m6A; oncolytic virus.

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