Wuhan Institute of Biomedical Sciences, School of Medicine, Jianghan University, Wuhan, China.
State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, China.
Front Immunol. 2021 Nov 10;12:750969. doi: 10.3389/fimmu.2021.750969. eCollection 2021.
The COVID-19 is an infectious disease caused by SARS-CoV-2 infection. A large number of clinical studies found high-level expression of pro-inflammatory cytokines in patients infected with SARS-CoV-2, which fuels the rapid development of the disease. However, the specific molecular mechanism is still unclear. In this study, we found that SARS-CoV-2 Nsp5 can induce the expression of cytokines IL-1β, IL-6, TNF-α, and IL-2 in Calu-3 and THP1 cells. Further research found that Nsp5 enhances cytokine expression through activating the NF-κB signaling pathway. Subsequently, we investigated the upstream effectors of the NF-κB signal pathway on Nsp5 overexpression and discovered that Nsp5 increases the protein level of MAVS. Moreover, Nsp5 can promote the SUMOylation of MAVS to increase its stability and lead to increasing levels of MAVS protein, finally triggering activation of NF-κB signaling. The knockdown of MAVS and the inhibitor of SUMOylation treatment can attenuate Nsp5-mediated NF-κB activation and cytokine induction. We identified a novel role of SARS-CoV-2 Nsp5 to enhance cytokine production by activating the NF-κB signaling pathway.
新型冠状病毒病（COVID-19）是由严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）感染引起的传染病。大量临床研究发现，感染 SARS-CoV-2 的患者体内促炎细胞因子呈高水平表达，这推动了疾病的快速发展。然而，其具体的分子机制尚不清楚。在本研究中，我们发现 SARS-CoV-2 Nsp5 可诱导 Calu-3 和 THP1 细胞中细胞因子白细胞介素 1β（IL-1β）、白细胞介素 6（IL-6）、肿瘤坏死因子-α（TNF-α）和白细胞介素 2（IL-2）的表达。进一步的研究发现，Nsp5 通过激活核因子 κB（NF-κB）信号通路增强细胞因子的表达。随后，我们研究了 NF-κB 信号通路中 Nsp5 过表达的上游效应物，发现 Nsp5 增加了线粒体抗病毒信号蛋白（MAVS）的蛋白水平。此外，Nsp5 可以促进 MAVS 的 SUMO 化，从而增加其稳定性，导致 MAVS 蛋白水平增加，最终引发 NF-κB 信号的激活。MAVS 的敲低和 SUMO 化抑制剂处理可以减弱 Nsp5 介导的 NF-κB 激活和细胞因子诱导。我们鉴定出 SARS-CoV-2 Nsp5 通过激活 NF-κB 信号通路增强细胞因子产生的新作用。
