Signal Transduction and Targeted Therapy (Jul 2022)

SARS-CoV-2 nucleocapsid protein triggers hyperinflammation via protein-protein interaction-mediated intracellular Cl− accumulation in respiratory epithelium

  • Lei Chen,
  • Wei-Jie Guan,
  • Zhuo-Er Qiu,
  • Jian-Bang Xu,
  • Xu Bai,
  • Xiao-Chun Hou,
  • Jing Sun,
  • Su Qu,
  • Ze-Xin Huang,
  • Tian-Lun Lei,
  • Zi-Yang Huang,
  • Jincun Zhao,
  • Yun-Xin Zhu,
  • Ke-Nan Ye,
  • Zhao-Rong Lun,
  • Wen-Liang Zhou,
  • Nan-Shan Zhong,
  • Yi-Lin Zhang

DOI
https://doi.org/10.1038/s41392-022-01048-1
Journal volume & issue
Vol. 7, no. 1
pp. 1 – 13

Abstract

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Abstract 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.