SARS-CoV-2 envelope protein impairs airway epithelial barrier function and exacerbates airway inflammation via increased intracellular Cl- concentration
© 2024. The Author(s)..
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts the epithelial barrier and triggers airway inflammation. The envelope (E) protein, a core virulence structural component of coronaviruses, may play a role in this process. Pathogens could interfere with transepithelial Cl- transport via impairment of the cystic fibrosis transmembrane conductance regulator (CFTR), which modulates nuclear factor κB (NF-κB) signaling. However, the pathological effects of SARS-CoV-2 E protein on airway epithelial barrier function, Cl- transport and the robust inflammatory response remain to be elucidated. Here, we have demonstrated that E protein down-regulated the expression of tight junctional proteins, leading to the disruption of the airway epithelial barrier. In addition, E protein triggered the activation of Toll-like receptor (TLR) 2/4 and downstream c-Jun N-terminal kinase (JNK) signaling, resulting in an increased intracellular Cl- concentration ([Cl-]i) via up-regulating phosphodiesterase 4D (PDE4D) expression in airway epithelial cells. This elevated [Cl-]i contributed to the heightened airway inflammation through promoting the phosphorylation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, blockade of SGK1 or PDE4 alleviated the robust inflammatory response induced by E protein. Overall, these findings provide novel insights into the pathogenic role of SARS-CoV-2 E protein in airway epithelial damage and the ongoing airway inflammation during SARS-CoV-2 infection.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Signal transduction and targeted therapy - 9(2024), 1 vom: 25. März, Seite 74 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Xu, Jian-Bang [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 27.03.2024 Date Revised 28.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1038/s41392-024-01753-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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NLM370175751 |
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| 520 | |a Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection disrupts the epithelial barrier and triggers airway inflammation. The envelope (E) protein, a core virulence structural component of coronaviruses, may play a role in this process. Pathogens could interfere with transepithelial Cl- transport via impairment of the cystic fibrosis transmembrane conductance regulator (CFTR), which modulates nuclear factor κB (NF-κB) signaling. However, the pathological effects of SARS-CoV-2 E protein on airway epithelial barrier function, Cl- transport and the robust inflammatory response remain to be elucidated. Here, we have demonstrated that E protein down-regulated the expression of tight junctional proteins, leading to the disruption of the airway epithelial barrier. In addition, E protein triggered the activation of Toll-like receptor (TLR) 2/4 and downstream c-Jun N-terminal kinase (JNK) signaling, resulting in an increased intracellular Cl- concentration ([Cl-]i) via up-regulating phosphodiesterase 4D (PDE4D) expression in airway epithelial cells. This elevated [Cl-]i contributed to the heightened airway inflammation through promoting the phosphorylation of serum/glucocorticoid regulated kinase 1 (SGK1). Moreover, blockade of SGK1 or PDE4 alleviated the robust inflammatory response induced by E protein. Overall, these findings provide novel insights into the pathogenic role of SARS-CoV-2 E protein in airway epithelial damage and the ongoing airway inflammation during SARS-CoV-2 infection | ||
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| 700 | 1 | |a Qiu, Zhuo-Er |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Lei |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Xiao-Chun |e verfasserin |4 aut | |
| 700 | 1 | |a Yue, Junqing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Yu-Yun |e verfasserin |4 aut | |
| 700 | 1 | |a Sheng, Jie |e verfasserin |4 aut | |
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| 700 | 1 | |a Zhu, Yun-Xin |e verfasserin |4 aut | |
| 700 | 1 | |a Sun, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jincun |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Wen-Liang |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Nan-Shan |e verfasserin |4 aut | |
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