Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, 90095, CA, USA.
Cell Mol Immunol. 2022 Aug;19(8):872-882. doi: 10.1038/s41423-022-00887-w. Epub 2022 Jun 23.
Most deaths from the COVID-19 pandemic are due to acute respiratory distress syndrome (ARDS)-related respiratory failure. Cytokine storms and oxidative stress are the major players in ARDS development during respiratory virus infections. However, it is still unknown how oxidative stress is regulated by viral and host factors in response to SARS-CoV-2 infection. Here, we found that activation of NRF2/HMOX1 significantly suppressed SARS-CoV-2 replication in multiple cell types by producing the metabolite biliverdin, whereas SARS-CoV-2 impaired the NRF2/HMOX1 axis through the action of the nonstructural viral protein NSP14. Mechanistically, NSP14 interacts with the catalytic domain of the NAD-dependent deacetylase Sirtuin 1 (SIRT1) and inhibits its ability to activate the NRF2/HMOX1 pathway. Furthermore, both genetic and pharmaceutical evidence corroborated the novel antiviral activity of SIRT1 against SARS-CoV-2. Therefore, our findings reveal a novel mechanism by which SARS-CoV-2 dysregulates the host antioxidant defense system and emphasize the vital role played by the SIRT1/NRF2 axis in host defense against SARS-CoV-2.
大多数 COVID-19 大流行死亡是由于急性呼吸窘迫综合征（ARDS）相关的呼吸衰竭。细胞因子风暴和氧化应激是呼吸道病毒感染期间 ARDS 发展的主要因素。然而，目前尚不清楚氧化应激如何通过病毒和宿主因子来调节 SARS-CoV-2 感染的反应。在这里，我们发现 NRF2/HMOX1 的激活通过产生代谢产物胆红素显著抑制了多种细胞类型中的 SARS-CoV-2 复制，而 SARS-CoV-2 通过非结构病毒蛋白 NSP14 的作用破坏了 NRF2/HMOX1 轴。在机制上，NSP14 与 NAD 依赖性去乙酰化酶 Sirtuin 1（SIRT1）的催化结构域相互作用，并抑制其激活 NRF2/HMOX1 途径的能力。此外，遗传和药物证据都证实了 SIRT1 对 SARS-CoV-2 的新型抗病毒活性。因此，我们的研究结果揭示了 SARS-CoV-2 失调宿主抗氧化防御系统的新机制，并强调了 SIRT1/NRF2 轴在宿主防御 SARS-CoV-2 中的重要作用。
