biostudies-literatureUnknown7(1)Chen LSARS-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 pSignal transduction and targeted therapy255https://www.ebi.ac.uk/biostudies/studies/S-EPMC9328007biostudies-literatureSARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl^- accumulation in respiratory epithelium.PMC9328007Huang ZXLun ZRHuang ZYYe KNChen LLei TLBai XQu SGuan WJZhong NSZhang YLHou XCXu JBQiu ZEZhu YXZhou WLZhao JSun JfalseSARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl^- accumulation in respiratory epithelium.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 p2022-01-01T00:00:00Z2022 Jul2025-05-31T23:03:29.194Z2022-08-03T07:05:23.275ZS-EPMC93280073589653210.1038/s41392-022-01048-1