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Linear ubiquitination regulates the KSHV replication and transcription activator protein to control infection

Author

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  • Yi Luan

    (The First Affiliated Hospital of Zhengzhou University
    Henan Academy of Innovations in Medical Science
    the First Affiliated Hospital of Zhengzhou University
    the First Affiliated Hospital of Zhengzhou University)

  • Wenying Long

    (Zhejiang University)

  • Lisi Dai

    (Zhejiang University School of Medicine
    Zhejiang University School of Medicine
    Zhejiang University)

  • Panfeng Tao

    (Zhejiang University)

  • Zhifen Deng

    (The First Affiliated Hospital of Zhengzhou University
    Henan Academy of Innovations in Medical Science
    the First Affiliated Hospital of Zhengzhou University
    the First Affiliated Hospital of Zhengzhou University)

  • Zongping Xia

    (The First Affiliated Hospital of Zhengzhou University
    Henan Academy of Innovations in Medical Science
    the First Affiliated Hospital of Zhengzhou University
    the First Affiliated Hospital of Zhengzhou University)

Abstract

Like many other viruses, KSHV has two life cycle modes: the latent phase and the lytic phase. The RTA protein from KSHV is essential for lytic reactivation, but how this protein’s activity is regulated is not fully understood. Here, we report that linear ubiquitination regulates the activity of RTA during KSHV lytic reactivation and de novo infection. Overexpressing OTULIN inhibits KSHV lytic reactivation, whereas knocking down OTULIN or overexpressing HOIP enhances it. Intriguingly, we found that RTA is linearly polyubiquitinated by HOIP at K516 and K518, and these modifications control the RTA’s nuclear localization. OTULIN removes linear polyubiquitin chains from cytoplasmic RTA, preventing its nuclear import. The RTA orthologs encoded by the EB and MHV68 viruses are also linearly polyubiquitinated and regulated by OTULIN. Our study establishes that linear polyubiquitination plays a critically regulatory role in herpesvirus infection, adding virus infection to the list of biological processes known to be controlled by linear polyubiquitination.

Suggested Citation

  • Yi Luan & Wenying Long & Lisi Dai & Panfeng Tao & Zhifen Deng & Zongping Xia, 2024. "Linear ubiquitination regulates the KSHV replication and transcription activator protein to control infection," Nature Communications, Nature, vol. 15(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-49887-6
    DOI: 10.1038/s41467-024-49887-6
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    1. Fumiyo Ikeda & Yonathan Lissanu Deribe & Sigrid S. Skånland & Benjamin Stieglitz & Caroline Grabbe & Mirita Franz-Wachtel & Sjoerd J. L. van Wijk & Panchali Goswami & Vanja Nagy & Janos Terzic & Fumin, 2011. "SHARPIN forms a linear ubiquitin ligase complex regulating NF-κB activity and apoptosis," Nature, Nature, vol. 471(7340), pages 637-641, March.
    2. Elena Rivkin & Stephanie M. Almeida & Derek F. Ceccarelli & Yu-Chi Juang & Teresa A. MacLean & Tharan Srikumar & Hao Huang & Wade H. Dunham & Ryutaro Fukumura & Gang Xie & Yoichi Gondo & Brian Raught , 2013. "The linear ubiquitin-specific deubiquitinase gumby regulates angiogenesis," Nature, Nature, vol. 498(7454), pages 318-324, June.
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