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Coronavirus envelope protein activates TMED10-mediated unconventional secretion of inflammatory factors

Author

Listed:
  • Lei Liu

    (Tsinghua University
    Tsinghua University)

  • Lijingyao Zhang

    (Tsinghua University
    Tsinghua University)

  • Xinyan Hao

    (Tsinghua University
    Tsinghua University)

  • Yang Wang

    (Tsinghua University
    Tsinghua University)

  • Xiaochun Zhang

    (Tsinghua University)

  • Liang Ge

    (Tsinghua University
    Tsinghua University)

  • Peihui Wang

    (Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University)

  • Boxue Tian

    (Tsinghua University)

  • Min Zhang

    (Tsinghua University
    Tsinghua University)

Abstract

The precise cellular mechanisms underlying heightened proinflammatory cytokine production during coronavirus infection remain incompletely understood. Here we identify the envelope (E) protein in severe coronaviruses (SARS-CoV-2, SARS, or MERS) as a potent inducer of interleukin-1 release, intensifying lung inflammation through the activation of TMED10-mediated unconventional protein secretion (UcPS). In contrast, the E protein of mild coronaviruses (229E, HKU1, or OC43) demonstrates a less pronounced effect. The E protein of severe coronaviruses contains an SS/DS motif, which is not present in milder strains and facilitates interaction with TMED10. This interaction enhances TMED10-oligomerization, facilitating UcPS cargo translocation into the ER-Golgi intermediate compartment (ERGIC)—a pivotal step in interleukin-1 UcPS. Progesterone analogues were identified as compounds inhibiting E-enhanced release of proinflammatory factors and lung inflammation in a Mouse Hepatitis Virus (MHV) infection model. These findings elucidate a molecular mechanism driving coronavirus-induced hyperinflammation, proposing the E-TMED10 interaction as a potential therapeutic target to counteract the adverse effects of coronavirus-induced inflammation.

Suggested Citation

  • Lei Liu & Lijingyao Zhang & Xinyan Hao & Yang Wang & Xiaochun Zhang & Liang Ge & Peihui Wang & Boxue Tian & Min Zhang, 2024. "Coronavirus envelope protein activates TMED10-mediated unconventional secretion of inflammatory factors," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52818-0
    DOI: 10.1038/s41467-024-52818-0
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    1. Huiping Shuai & Jasper Fuk-Woo Chan & Bingjie Hu & Yue Chai & Terrence Tsz-Tai Yuen & Feifei Yin & Xiner Huang & Chaemin Yoon & Jing-Chu Hu & Huan Liu & Jialu Shi & Yuanchen Liu & Tianrenzheng Zhu & J, 2022. "Attenuated replication and pathogenicity of SARS-CoV-2 B.1.1.529 Omicron," Nature, Nature, vol. 603(7902), pages 693-699, March.
    2. Jin Chai & Yuanheng Cai & Changxu Pang & Liguo Wang & Sean McSweeney & John Shanklin & Qun Liu, 2021. "Structural basis for SARS-CoV-2 envelope protein recognition of human cell junction protein PALS1," Nature Communications, Nature, vol. 12(1), pages 1-6, December.
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