tetano
Editor, Senior Moderator
Signal Transduct Target Ther
. 2024 Mar 25;9(1):74.
doi: 10.1038/s41392-024-01753-z. SARS-CoV-2 envelope protein impairs airway epithelial barrier function and exacerbates airway inflammation via increased intracellular Cl[SUP]-[/SUP] concentration
Jian-Bang Xu[SUP] #[/SUP][SUP] 1 [/SUP], Wei-Jie Guan[SUP] #[/SUP][SUP] 2 3 4 [/SUP], Yi-Lin Zhang[SUP] #[/SUP][SUP] 5 6 [/SUP], Zhuo-Er Qiu[SUP] 5 [/SUP], Lei Chen[SUP] 5 [/SUP], Xiao-Chun Hou[SUP] 5 [/SUP], Junqing Yue[SUP] 1 7 [/SUP], Yu-Yun Zhou[SUP] 5 [/SUP], Jie Sheng[SUP] 5 [/SUP], Lei Zhao[SUP] 1 8 [/SUP], Yun-Xin Zhu[SUP] 5 [/SUP], Jing Sun[SUP] 1 7 [/SUP], Jincun Zhao[SUP] 1 7 [/SUP], Wen-Liang Zhou[SUP] 9 [/SUP], Nan-Shan Zhong[SUP] 10 11 [/SUP]
Affiliations
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[SUP]-[/SUP] 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[SUP]-[/SUP] 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[SUP]-[/SUP] concentration ([Cl[SUP]-[/SUP]][SUB]i[/SUB]) via up-regulating phosphodiesterase 4D (PDE4D) expression in airway epithelial cells. This elevated [Cl[SUP]-[/SUP]][SUB]i[/SUB] 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.
. 2024 Mar 25;9(1):74.
doi: 10.1038/s41392-024-01753-z. SARS-CoV-2 envelope protein impairs airway epithelial barrier function and exacerbates airway inflammation via increased intracellular Cl[SUP]-[/SUP] concentration
Jian-Bang Xu[SUP] #[/SUP][SUP] 1 [/SUP], Wei-Jie Guan[SUP] #[/SUP][SUP] 2 3 4 [/SUP], Yi-Lin Zhang[SUP] #[/SUP][SUP] 5 6 [/SUP], Zhuo-Er Qiu[SUP] 5 [/SUP], Lei Chen[SUP] 5 [/SUP], Xiao-Chun Hou[SUP] 5 [/SUP], Junqing Yue[SUP] 1 7 [/SUP], Yu-Yun Zhou[SUP] 5 [/SUP], Jie Sheng[SUP] 5 [/SUP], Lei Zhao[SUP] 1 8 [/SUP], Yun-Xin Zhu[SUP] 5 [/SUP], Jing Sun[SUP] 1 7 [/SUP], Jincun Zhao[SUP] 1 7 [/SUP], Wen-Liang Zhou[SUP] 9 [/SUP], Nan-Shan Zhong[SUP] 10 11 [/SUP]
Affiliations
- PMID: 38528022
- PMCID: PMC10963779
- DOI: 10.1038/s41392-024-01753-z
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[SUP]-[/SUP] 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[SUP]-[/SUP] 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[SUP]-[/SUP] concentration ([Cl[SUP]-[/SUP]][SUB]i[/SUB]) via up-regulating phosphodiesterase 4D (PDE4D) expression in airway epithelial cells. This elevated [Cl[SUP]-[/SUP]][SUB]i[/SUB] 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.