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

  • Nat Commun. 2024 Oct 8;15(1):8708. doi: 10.1038/s41467-024-52818-0.
Lei Liu  #  1  2 ,  Lijingyao Zhang  #  1  3 ,  Xinyan Hao  1  2 ,  Yang Wang  1  3 ,  Xiaochun Zhang  2 ,  Liang Ge  1  3 ,  Peihui Wang  4 ,  Boxue Tian  2 ,  Min Zhang  5  6
Affiliations
  • 1. State Key Laboratory of Membrane Biology, Tsinghua University, Beijing, 100084, China.
  • 2. School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China.
  • 3. Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
  • 4. Key Laboratory for Experimental Teratology of Ministry of Education and Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
  • 5. State Key Laboratory of Membrane Biology, Tsinghua University, Beijing, 100084, China. [email protected].
  • 6. School of Pharmaceutical Sciences, Tsinghua University, Beijing, 100084, China. [email protected].
  • # Contributed equally.
PMID: 39379362 DOI: 10.1038/s41467-024-52818-0
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.

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