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

Author

Listed:
  • Hong Dong

    (The Ohio State University)

  • Chenxi Liang

    (The Ohio State University)

  • Junjie Zhang

    (The Ohio State University)

  • Weidong Wu

    (The Ohio State University)

  • Nitesh Kumar

    (The Ohio State University)

  • Zihao Liu

    (The Ohio State University)

  • Yajun Sun

    (The Ohio State University)

  • Zhiwei Liao

    (The Ohio State University)

  • Xiaolin Cheng

    (The Ohio State University
    The Ohio State University)

  • Yanbao Yu

    (University of Delaware)

  • Yong Zhang

    (Washington University School of Medicine)

  • Michael J. Holtzman

    (Washington University School of Medicine)

  • Jianrong Li

    (The Ohio State University)

  • Kymberly M. Gowdy

    (The Ohio State University)

  • Paul G. Thomas

    (St. Jude Children’s Research Hospital)

  • Jovica D. Badjic

    (The Ohio State University)

  • Anjun Ma

    (The Ohio State University
    The Ohio State University)

  • Qin Ma

    (The Ohio State University
    The Ohio State University)

  • Jacob S. Yount

    (The Ohio State University)

  • Shan-Lu Liu

    (The Ohio State University
    The Ohio State University)

  • Haitao Wen

    (The Ohio State University
    The Ohio State University)

Abstract

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.

Suggested Citation

  • 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. Gow, 2025. "O-GlcNAc transferase plays dual antiviral roles by integrating innate immunity and lipid metabolism," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-63085-y
    DOI: 10.1038/s41467-025-63085-y
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    References listed on IDEAS

    as
    1. Yazan M. Abbas & Andreas Pichlmair & Maria W. Górna & Giulio Superti-Furga & Bhushan Nagar, 2013. "Structural basis for viral 5′-PPP-RNA recognition by human IFIT proteins," Nature, Nature, vol. 494(7435), pages 60-64, February.
    2. Shuofeng Yuan & Hin Chu & Jasper Fuk-Woo Chan & Zi-Wei Ye & Lei Wen & Bingpeng Yan & Pok-Man Lai & Kah-Meng Tee & Jingjing Huang & Dongdong Chen & Cun Li & Xiaoyu Zhao & Dong Yang & Man Chun Chiu & Cy, 2019. "SREBP-dependent lipidomic reprogramming as a broad-spectrum antiviral target," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    3. Michael B. Lazarus & Yunsun Nam & Jiaoyang Jiang & Piotr Sliz & Suzanne Walker, 2011. "Structure of human O-GlcNAc transferase and its complex with a peptide substrate," Nature, Nature, vol. 469(7331), pages 564-567, January.
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