2. Academic Validation
  3. m6A modification in the 3'‑leader region of EBOV genome antagonizes ISG20 to facilitate viral replication

m6A modification in the 3'‑leader region of EBOV genome antagonizes ISG20 to facilitate viral replication

  • Int J Biol Macromol. 2025 Dec 19;339(Pt 2):149804. doi: 10.1016/j.ijbiomac.2025.149804.
Baoxin Zhao 1,  Zengguo Cao 1,  Kaiyue Zhang 1,  Shuqi Xiao 2,  Xiaofan Shen 1,  Fangxu Li 1,  Yan Wu 1,  Baoyue Zhang 1,  Qianqian Wang 3,  Huajun Zhang 1,  Xia Chuai 4,  Sandra Chiu 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega Science, Chinese Academy of Sciences, Wuhan, Hubei, China.
  • 2 National Biosafety Laboratory, Chinese Academy of Sciences, Wuhan, Hubei, China.
  • 3 Department of Infectious Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, Anhui, China.
  • 4 State Key Laboratory of Virology and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega Science, Chinese Academy of Sciences, Wuhan, Hubei, China. Electronic address: [email protected].
  • 5 Department of Infectious Medicine, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China; Key Laboratory of Anhui Province for Emerging and Reemerging Infectious Diseases, Hefei, Anhui, China. Electronic address: [email protected].
PMID: 41423124 DOI: 10.1016/j.ijbiomac.2025.149804
Abstract

Ebola virus (EBOV), a highly lethal pathogen with significant epidemic potential, has evolved multiple mechanisms to counteract and disrupt the host immune responses, including the interferon (IFN) pathway. Epitranscriptomic regulation, such as N6-methyladenosine (m6A) modification, has been demonstrated to regulate the innate immune response during Infection by various viruses. However, its role in EBOV-host interactions remains unclear. The interferon stimulated exonuclease gene 20 (ISG20) is an RNA exonuclease with a broad spectrum of Antiviral activity against many RNA and DNA viruses. Here, we demonstrate that the EBOV genome contains m6A modifications, which are necessary for EBOV replication. Loss-of-function and mutational analyses demonstrate that the m6A in EBOV genome antagonizes the exonuclease activity of ISG20, thereby facilitating viral replication. Mechanistic studies reveal that the m6A-modified EBOV genome 3'‑leader region recruits the m6A reader protein YTHDF1, which impedes the Antiviral effect of ISG20. Our study reveals an interaction between ISG20 and EBOV, demonstrating that EBOV exploits m6A modification to counteract the innate immune response and enhance viral replication. These findings aid in the clarification of EBOV pathogenesis and imply that m6A modification can be used for the modulation of innate immunity.

Keywords

3′‑Leader region; Ebola virus; ISG20; Innate immunity; N(6)-Methyladenosine.

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