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<p>Viral infection induces robust reprogramming of metabolic pathways in host cells. However, whether host metabolic enzymes detect viral components remains unknown. Our group and others previously identified <i>O</i>-GlcNAc transferase (OGT), an important glucose metabolic enzyme, as a crucial mediator of the antiviral immune responses. Here, by studying a mouse model with a catalytically impaired OGT, we discover a catalytic activity-independent function of OGT in restraining influenza A virus (IAV) infection in addition to its catalytic activity-dependent effect on MAVS-mediated antiviral immunity. Biochemical studies reveal a critical antiviral effect based on OGT interacting with IAV genomic RNA that requires its N-terminal tetracopeptide repeat-4 motif. This interaction causes the translocation of nuclear OGT to cytosolic lipid droplets (LDs) to destabilize LDs-coating perilipin 2, thereby limiting LDs accumulation and in turn virus replication. In sum, our findings reveal OGT as a multifaceted metabolic sensor that integrates MAVS signaling and lipid metabolism to combat viral infection.</p>

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O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月19日

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  • Hong Dong,
  • Chenxi Liang,
  • Junjie Zhang,
  • Weidong Wu,
  • Nitesh Kumar,
  • Zihao Liu,
  • Yajun Sun,
  • Zhiwei Liao,
  • Xiaolin Cheng,
  • Yanbao Yu,
  • Yong Zhang,
  • Michael J. Holtzman,
  • Jianrong Li,
  • Kymberly M. Gowdy,
  • Paul G. Thomas,
  • Jovica D. Badjic,
  • Anjun Ma,
  • Qin Ma,
  • Jacob S. Yount,
  • Shan-Lu Liu,
  • Haitao Wen

摘要

Viral infection induces robust reprogramming of metabolic pathways in host cells. However, whether host metabolic enzymes detect viral components remains unknown. Our group and others previously identified O-GlcNAc transferase (OGT), an important glucose metabolic enzyme, as a crucial mediator of the antiviral immune responses. Here, by studying a mouse model with a catalytically impaired OGT, we discover a catalytic activity-independent function of OGT in restraining influenza A virus (IAV) infection in addition to its catalytic activity-dependent effect on MAVS-mediated antiviral immunity. Biochemical studies reveal a critical antiviral effect based on OGT interacting with IAV genomic RNA that requires its N-terminal tetracopeptide repeat-4 motif. This interaction causes the translocation of nuclear OGT to cytosolic lipid droplets (LDs) to destabilize LDs-coating perilipin 2, thereby limiting LDs accumulation and in turn virus replication. In sum, our findings reveal OGT as a multifaceted metabolic sensor that integrates MAVS signaling and lipid metabolism to combat viral infection.