SARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl(-) accumulation in respiratory epithelium #MMPMID35896532
Chen L; Guan WJ; Qiu ZE; Xu JB; Bai X; Hou XC; Sun J; Qu S; Huang ZX; Lei TL; Huang ZY; Zhao J; Zhu YX; Ye KN; Lun ZR; Zhou WL; Zhong NS; Zhang YL
Signal Transduct Target Ther 2022[Jul]; 7 (1): 255 PMID35896532show ga
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.
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Signal+Transduct+Target+Ther 2022 ; 7 (1): 255
