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<p>Japanese encephalitis virus (JEV), a neurotropic flavivirus, poses a significant public health threat, yet the molecular mechanisms underlying its interaction with host immunity remain poorly understood. This study reveals that zinc finger protein ZNF33B promotes JEV replication by subverting the RLR-mediated innate immune response through orchestrating m⁶A RNA modification. ZNF33B directly binds to antiviral transcripts <i>Ifih1</i> (encoding MDA5), <i>Mavs</i>, and <i>Irf3</i>, recruiting the m⁶A methyltransferase METTL14 to enhance their m⁶A methylation. Concurrently, ZNF33B interacts with the nuclear m⁶A reader YTHDC1 to facilitate the export of these methylated transcripts from the nucleus to the cytoplasm. In the cytoplasm, the m⁶A-modified transcripts are recognized by the cytoplasmic reader YTHDF2, leading to accelerated RNA decay. This process downregulates MDA5 and IRF3 protein levels, suppressing type I interferon production and downstream antiviral responses, thereby creating a permissive environment for JEV replication. Our findings establish a regulatory axis where ZNF33B integrates m⁶A modification and RNA metabolism to evade host immunity, highlighting the potential of targeting epitranscriptomic pathways for antiviral therapy.</p>

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Zinc finger protein ZNF33B facilitates Japanese encephalitis virus replication by regulating m6A modification on Ifih1 and Irf3 transcripts to antagonize antiviral response

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月4日

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  • Jian Du,
  • Chunwei Li,
  • Jinyan Zhang,
  • Jiyuan Luo,
  • Huizhi Zhang,
  • Huanchun Chen,
  • Xiangmin Li,
  • Ping Qian

摘要

Japanese encephalitis virus (JEV), a neurotropic flavivirus, poses a significant public health threat, yet the molecular mechanisms underlying its interaction with host immunity remain poorly understood. This study reveals that zinc finger protein ZNF33B promotes JEV replication by subverting the RLR-mediated innate immune response through orchestrating m⁶A RNA modification. ZNF33B directly binds to antiviral transcripts Ifih1 (encoding MDA5), Mavs, and Irf3, recruiting the m⁶A methyltransferase METTL14 to enhance their m⁶A methylation. Concurrently, ZNF33B interacts with the nuclear m⁶A reader YTHDC1 to facilitate the export of these methylated transcripts from the nucleus to the cytoplasm. In the cytoplasm, the m⁶A-modified transcripts are recognized by the cytoplasmic reader YTHDF2, leading to accelerated RNA decay. This process downregulates MDA5 and IRF3 protein levels, suppressing type I interferon production and downstream antiviral responses, thereby creating a permissive environment for JEV replication. Our findings establish a regulatory axis where ZNF33B integrates m⁶A modification and RNA metabolism to evade host immunity, highlighting the potential of targeting epitranscriptomic pathways for antiviral therapy.