SARS-CoV-2 virus NSP14 Impairs NRF2/HMOX1 activation by targeting Sirtuin 1.
Shilei ZhangJingfeng WangLulan WangSaba AliyariGenhong ChengPublished in: Cellular & molecular immunology (2022)
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.
Keyphrases
- sars cov
- oxidative stress
- acute respiratory distress syndrome
- respiratory syndrome coronavirus
- extracorporeal membrane oxygenation
- mechanical ventilation
- ischemia reperfusion injury
- diabetic rats
- dna damage
- respiratory failure
- induced apoptosis
- genome wide
- stem cells
- dna methylation
- signaling pathway
- binding protein
- respiratory tract
- coronavirus disease
- copy number
- small molecule
- heat stress
- disease virus