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Nuclear membrane protein SUN2 promotes replication of flaviviruses through modulating cytoskeleton reorganization mediated by NS1

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  • Yanxia Huang

    (Ministry of Education
    Zhongshan School of Medicine, Sun Yat-sen University
    First Affiliated Hospital of Sun Yat-sen University)

  • Qinyu Peng

    (Ministry of Education
    Zhongshan School of Medicine, Sun Yat-sen University)

  • Xu Tian

    (Ministry of Education
    Zhongshan School of Medicine, Sun Yat-sen University)

  • Cancan Chen

    (First Affiliated Hospital of Sun Yat-sen University)

  • Xuanfeng Zhu

    (Ministry of Education
    Zhongshan School of Medicine, Sun Yat-sen University)

  • Changbai Huang

    (Ministry of Education
    Zhongshan School of Medicine, Sun Yat-sen University)

  • Zhiting Huo

    (Ministry of Education
    Zhongshan School of Medicine, Sun Yat-sen University)

  • Yang Liu

    (Li Ka Shing Faculty of Medicine, The University of Hong Kong)

  • Chao Yang

    (First Affiliated Hospital of Sun Yat-sen University
    Guangxi Hospital Division of The First Affiliated Hospital, Sun Yat-sen University)

  • Chao Liu

    (Ministry of Education
    Zhongshan School of Medicine, Sun Yat-sen University)

  • Ping Zhang

    (Ministry of Education
    Zhongshan School of Medicine, Sun Yat-sen University)

Abstract

Cytoskeleton is extensively recruited by flaviviruses for their infection. In this study, we uncovered an essential role of a nuclear membrane protein, SAD1/UNC84 domain protein 2 (SUN2) linking cytoskeleton and nucleoskeleton in the flavivirus replication. CRISPR/Cas9-mediated knockout of SUN2, but not SUN1, significantly reduces the replication of Zika virus (ZIKV), dengue virus (DENV), and Japanese encephalitis virus (JEV). In contrast, SUN2 does not affect the infection of non-flaviviridae RNA viruses. All three regions of SUN2 are required for its proviral effect. Mechanistically, SUN2 facilitates rearrangement of cytoskeleton and formation of replication organelles induced by viral infection, and hence promotes viral RNA synthesis. SUN2 is required for the interaction between cytoskeleton actin and ZIKV nonstructural protein 1 (NS1). Expression of dominant negative Nesprin-1 and Nesprin-2, which connect SUN2 to cytoskeleton proteins, alleviates the interaction between actin and NS1 and reduces viral replication levels. In a neonatal mouse infection model, SUN2 knockout dramatically alleviates the in vivo ZIKV replication and development of neuropathology. This work elucidates that recruitment of cytoskeleton proteins by flavivirus is coordinated by nuclear membrane proteins SUN2 and Nesprins, providing evidence for a link between nuclear membrane proteins and flavivirus infection.

Suggested Citation

  • Yanxia Huang & Qinyu Peng & Xu Tian & Cancan Chen & Xuanfeng Zhu & Changbai Huang & Zhiting Huo & Yang Liu & Chao Yang & Chao Liu & Ping Zhang, 2024. "Nuclear membrane protein SUN2 promotes replication of flaviviruses through modulating cytoskeleton reorganization mediated by NS1," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-023-44580-6
    DOI: 10.1038/s41467-023-44580-6
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    References listed on IDEAS

    as
    1. Ranen Aviner & Kathy H. Li & Judith Frydman & Raul Andino, 2021. "Cotranslational prolyl hydroxylation is essential for flavivirus biogenesis," Nature, Nature, vol. 596(7873), pages 558-564, August.
    2. Theodore C. Pierson & Michael S. Diamond, 2018. "The emergence of Zika virus and its new clinical syndromes," Nature, Nature, vol. 560(7720), pages 573-581, August.
    3. Ranen Aviner & Kathy H. Li & Judith Frydman & Raul Andino, 2021. "Author Correction: Cotranslational prolyl hydroxylation is essential for flavivirus biogenesis," Nature, Nature, vol. 599(7885), pages 3-3, November.
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