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

Lei Liu, Lijingyao Zhang, Xinyan Hao, Yang Wang, Xiaochun Zhang, Liang Ge, Peihui Wang, Boxue Tian and Min Zhang ()
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Lei Liu: Tsinghua University
Lijingyao Zhang: Tsinghua University
Xinyan Hao: Tsinghua University
Yang Wang: Tsinghua University
Xiaochun Zhang: Tsinghua University
Liang Ge: Tsinghua University
Peihui Wang: Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University
Boxue Tian: Tsinghua University
Min Zhang: Tsinghua University

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-52818-0

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