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<p>Host factors that directly target viral immune antagonists are crucial for antiviral defense. In this study, we identify NPRL2 as a novel host restriction factor that directly interacts with the porcine reproductive and respiratory syndrome virus (PRRSV) protein Nsp1α, a key viral virulence factor. This interaction is mediated by the C-terminal domain of NPRL2 and the PCPα domain of Nsp1α. Functional studies demonstrated that NPRL2 overexpression inhibits PRRSV replication, while its knockdown enhanced viral propagation. Mechanistically, NPRL2 acts as a bridge, mediating K63-linked ubiquitination of Nsp1α at lysine 150 and subsequently recruiting the autophagic machinery for its degradation. This process was confirmed by monitoring LC3-II conversion and autophagic flux. Our findings reveal a precise mechanism by which NPRL2 antagonizes PRRSV by targeting a critical viral protein for autophagic degradation, highlighting the therapeutic potential of harnessing the host’s ubiquitin–autophagy pathway to combat viral infections.</p>

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NPRL2 restricts porcine reproductive and respiratory syndrome virus replication by targeting viral Nsp1α for autophagic degradation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月25日

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  • Heyou Yi,
  • Shaojun Wang,
  • Qiumei Wang,
  • Lechen Lu,
  • Ermin Xie,
  • Ruirui Ye,
  • Heng Wang,
  • Guihong Zhang

摘要

Host factors that directly target viral immune antagonists are crucial for antiviral defense. In this study, we identify NPRL2 as a novel host restriction factor that directly interacts with the porcine reproductive and respiratory syndrome virus (PRRSV) protein Nsp1α, a key viral virulence factor. This interaction is mediated by the C-terminal domain of NPRL2 and the PCPα domain of Nsp1α. Functional studies demonstrated that NPRL2 overexpression inhibits PRRSV replication, while its knockdown enhanced viral propagation. Mechanistically, NPRL2 acts as a bridge, mediating K63-linked ubiquitination of Nsp1α at lysine 150 and subsequently recruiting the autophagic machinery for its degradation. This process was confirmed by monitoring LC3-II conversion and autophagic flux. Our findings reveal a precise mechanism by which NPRL2 antagonizes PRRSV by targeting a critical viral protein for autophagic degradation, highlighting the therapeutic potential of harnessing the host’s ubiquitin–autophagy pathway to combat viral infections.