Huang Houda, Li Xiuzhen, Zha Duoduo, Lin Hongru, Yang Lingyi, Wang Yihan, Xu Luyan, Wang Linsiqi, Lei Tianhua, Zhou Zhou, Xiao Yun-Fei, Xin Hong-Bo, Fu Mingui, Qian Yisong
The National Engineering Research Center for Bioengineering Drugs and the Technologies, Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
Department of Clinical Laboratory, The Second Affiliated Hospital of Nanchang University, Nanchang, 330006, China.
Biochem Cell Biol. 2023 Aug 1;101(4):303-312. doi: 10.1139/bcb-2022-0359. Epub 2023 Mar 16.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), an emerging pathogenic coronavirus, has been reported to cause excessive inflammation and dysfunction in multiple cells and organs, but the underlying mechanisms remain largely unknown. Here we showed exogenous addition of SARS-CoV-2 envelop protein (E protein) potently induced cell death in cultured cell lines, including THP-1 monocytic leukemia cells, endothelial cells, and bronchial epithelial cells, in a time- and concentration-dependent manner. SARS-CoV-2 E protein caused pyroptosis-like cell death in THP-1 and led to GSDMD cleavage. In addition, SARS-CoV-2 E protein upregulated the expression of multiple pro-inflammatory cytokines that may be attributed to activation of NF-κB, JNK and p38 signal pathways. Notably, we identified a natural compound, Ruscogenin, effectively reversed E protein-induced THP-1 death via inhibition of NLRP3 activation and GSDMD cleavage. In conclusion, these findings suggested that Ruscogenin may have beneficial effects on preventing SARS-CoV-2 E protein-induced cell death and might be a promising treatment for the complications of COVID-19.
严重急性呼吸综合征冠状病毒2（SARS-CoV-2）是一种新出现的致病性冠状病毒，据报道它会在多个细胞和器官中引发过度炎症和功能障碍，但其潜在机制仍 largely 未知。在这里，我们表明外源添加SARS-CoV-2包膜蛋白（E蛋白）能以时间和浓度依赖性方式在培养的细胞系中有效诱导细胞死亡，这些细胞系包括THP-1单核细胞白血病细胞、内皮细胞和支气管上皮细胞。SARS-CoV-2 E蛋白在THP-1中引起类焦亡细胞死亡并导致GSDMD裂解。此外，SARS-CoV-2 E蛋白上调了多种促炎细胞因子的表达，这可能归因于NF-κB、JNK和p38信号通路的激活。值得注意的是，我们鉴定出一种天然化合物鲁斯可皂苷元，它通过抑制NLRP3激活和GSDMD裂解有效逆转了E蛋白诱导的THP-1死亡。总之，这些发现表明鲁斯可皂苷元可能对预防SARS-CoV-2 E蛋白诱导的细胞死亡具有有益作用，并且可能是治疗COVID-19并发症的一种有前景的药物。
