Department of Stem Cells and Regenerative Medicine, College of Basic Medical Science, China Medical University, Shenyang, People's Republic of China.
Department of Anesthesiology, the First Hospital of China Medical University, Shenyang, People's Republic of China.
Am J Physiol Lung Cell Mol Physiol. 2022 Nov 1;323(5):L569-L577. doi: 10.1152/ajplung.00152.2022. Epub 2022 Oct 4.
Cleavage of the furin site in SARS-CoV-2 spike (S) protein accounts for increased transmissibility of COVID-19 by promoting the entry of virus into host cells through specific angiotensin-converting enzyme 2 (ACE2) receptors. Plasmin, a key serine protease of fibrinolysis system, cleaves the furin site of γ subunit of human epithelial sodium channels (ENaCs). Sharing the plasmin cleavage by viral S and host ENaC proteins may competitively inter-regulate SARS-CoV-2 transmissibility and edema resolution via the ENaC pathway. To address this possibility, we analyzed single-cell RNA sequence (scRNA-seq) data sets and found that (encoding urokinase plasminogen activator), (γENaC), and (SARS-CoV-2 receptor) were co-expressed in airway/alveolar epithelial cells. The expression levels of and were significantly higher compared with in healthy group. This difference was further amplified in both epithelial and immune cells in patients with moderate/severe COVID-19 and SARS-CoV-2 infected airway/alveolar epithelial cell lines. Of note, plasmin cleaved the S protein and facilitated the entry of pseudovirus in HEK293 cells. Conclusively, SARS-CoV-2 may expedite infusion by competing the fibrinolytic protease network with ENaC.
SARS-CoV-2 刺突（S）蛋白中弗林蛋白酶裂解位点的存在通过促进病毒通过特定的血管紧张素转化酶 2（ACE2）受体进入宿主细胞，从而导致 COVID-19 的传染性增加。纤溶系统的关键丝氨酸蛋白酶——纤溶酶，可裂解人上皮钠离子通道（ENaC）γ亚基的弗林蛋白酶裂解位点。病毒 S 蛋白和宿主 ENaC 蛋白通过纤溶酶切割可能会通过 ENaC 途径竞争调节 SARS-CoV-2 的传染性和水肿消退。为了验证这一假设，我们分析了单细胞 RNA 测序（scRNA-seq）数据集，发现 （编码尿激酶纤溶酶原激活物）、 （γENaC）和 （SARS-CoV-2 受体）在气道/肺泡上皮细胞中共同表达。与健康组相比， 和 的表达水平明显更高。在 COVID-19 中度/重度患者的上皮细胞和免疫细胞中，这种差异进一步放大，SARS-CoV-2 感染的气道/肺泡上皮细胞系也是如此。值得注意的是，纤溶酶可切割 S 蛋白并促进假病毒在 HEK293 细胞中的进入。总而言之，SARS-CoV-2 可能通过与 ENaC 竞争纤溶蛋白酶网络来加速融合。
