SARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl - accumulation in respiratory epithelium.
Lei ChenWei-Jie GuanZhuo-Er QiuJian-Bang XuXu BaiXiao-Chun HouJing SunSu QuZe-Xin HuangTian-Lun LeiZi-Yang HuangJin-Cun ZhaoYun-Xin ZhuKe-Nan YeZhao-Rong LunWen-Liang ZhouNan-Shan ZhongYi-Lin ZhangPublished in: Signal transduction and targeted therapy (2022)
SARS-CoV-2, the culprit pathogen of COVID-19, elicits prominent immune responses and cytokine storms. Intracellular Cl - is a crucial regulator of host defense, whereas the role of Cl - signaling pathway in modulating pulmonary inflammation associated with SARS-CoV-2 infection remains unclear. By using human respiratory epithelial cell lines, primary cultured human airway epithelial cells, and murine models of viral structural protein stimulation and SARS-CoV-2 direct challenge, we demonstrated that SARS-CoV-2 nucleocapsid (N) protein could interact with Smad3, which downregulated cystic fibrosis transmembrane conductance regulator (CFTR) expression via microRNA-145. The intracellular Cl - concentration ([Cl - ] i ) was raised, resulting in phosphorylation of serum glucocorticoid regulated kinase 1 (SGK1) and robust inflammatory responses. Inhibition or knockout of SGK1 abrogated the N protein-elicited airway inflammation. Moreover, N protein promoted a sustained elevation of [Cl - ] i by depleting intracellular cAMP via upregulation of phosphodiesterase 4 (PDE4). Rolipram, a selective PDE4 inhibitor, countered airway inflammation by reducing [Cl - ] i . Our findings suggested that Cl - acted as the crucial pathological second messenger mediating the inflammatory responses after SARS-CoV-2 infection. Targeting the Cl - signaling pathway might be a novel therapeutic strategy for COVID-19.
Keyphrases
- sars cov
- respiratory syndrome coronavirus
- protein protein
- signaling pathway
- cystic fibrosis
- endothelial cells
- coronavirus disease
- binding protein
- small molecule
- immune response
- amino acid
- epithelial mesenchymal transition
- transcription factor
- reactive oxygen species
- oxidative stress
- pseudomonas aeruginosa
- pi k akt
- pulmonary hypertension
- lung function
- drug delivery
- cell proliferation
- induced pluripotent stem cells
- transforming growth factor
- dendritic cells
- air pollution
- endoplasmic reticulum stress
- candida albicans
- innate immune