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Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling

Author

Listed:
  • Yibo Zuo

    (Soochow University
    Soochow University)

  • Qian Feng

    (Soochow University
    Soochow University)

  • Lincong Jin

    (Soochow University
    Soochow University)

  • Fan Huang

    (Soochow University
    Soochow University)

  • Ying Miao

    (Soochow University
    Soochow University)

  • Jin Liu

    (Soochow University
    Soochow University)

  • Ying Xu

    (the First Affiliated Hospital of Soochow University, Soochow University)

  • Xiangjie Chen

    (Soochow University
    Soochow University)

  • Hongguang Zhang

    (Soochow University
    Soochow University)

  • Tingting Guo

    (Soochow University
    Soochow University)

  • Yukang Yuan

    (Soochow University
    Soochow University)

  • Liting Zhang

    (Soochow University
    Soochow University)

  • Jun Wang

    (the First Affiliated Hospital of Soochow University, Soochow University)

  • Hui Zheng

    (Soochow University
    Soochow University)

Abstract

Linear ubiquitination is a critical regulator of inflammatory signaling pathways. However, linearly ubiquitinated substrates and the biological significance of linear ubiquitination is incompletely understood. Here, we show that STAT1 has linear ubiquitination at Lys511 and Lys652 residues in intact cells, which inhibits STAT1 binding to the type-I interferon receptor IFNAR2, thereby restricting STAT1 activation and resulting in type-I interferon signaling homeostasis. Linear ubiquitination of STAT1 is removed rapidly by OTULIN upon type-I interferon stimulation, which facilitates activation of interferon-STAT1 signaling. Furthermore, viruses induce HOIP expression through the NF-κB pathway, which in turn increases linear ubiquitination of STAT1 and thereby inhibits interferon antiviral response. Consequently, HOIL-1L heterozygous mice have active STAT1 signaling and enhanced responses to type-I interferons. These findings demonstrate a linear ubiquitination-mediated switch between homeostasis and activation of type-I interferon signaling, and suggest potential strategies for clinical antiviral therapy.

Suggested Citation

  • Yibo Zuo & Qian Feng & Lincong Jin & Fan Huang & Ying Miao & Jin Liu & Ying Xu & Xiangjie Chen & Hongguang Zhang & Tingting Guo & Yukang Yuan & Liting Zhang & Jun Wang & Hui Zheng, 2020. "Regulation of the linear ubiquitination of STAT1 controls antiviral interferon signaling," Nature Communications, Nature, vol. 11(1), pages 1-15, December.
  • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-14948-z
    DOI: 10.1038/s41467-020-14948-z
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    Cited by:

    1. Samira Schiefer & Benjamin G. Hale, 2024. "Proximal protein landscapes of the type I interferon signaling cascade reveal negative regulation by PJA2," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Yesheng Fu & Lei Li & Xin Zhang & Zhikang Deng & Ying Wu & Wenzhe Chen & Yuchen Liu & Shan He & Jian Wang & Yuping Xie & Zhiwei Tu & Yadi Lyu & Yange Wei & Shujie Wang & Chun-Ping Cui & Cui Hua Liu & , 2024. "Systematic HOIP interactome profiling reveals critical roles of linear ubiquitination in tissue homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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