tetano
Editor, Senior Moderator
J Biol Chem
. 2023 Feb 7;102990.
doi: 10.1016/j.jbc.2023.102990. Online ahead of print.
The main protease of SARS-CoV-2 cleaves histone deacetylases and DCP1A, attenuating the immune defense of the interferon-stimulated genes
Liu Song[SUP] 1 [/SUP], Dianbing Wang[SUP] 2 [/SUP], Ghulam Abbas[SUP] 2 [/SUP], Min Li[SUP] 2 [/SUP], Mengmeng Cui[SUP] 2 [/SUP], Jufang Wang[SUP] 3 [/SUP], Zhanglin Lin[SUP] 4 [/SUP], Xian-En Zhang[SUP] 5 [/SUP]
Affiliations
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), constitutes an emerging human pathogen of zoonotic origin. A critical role in protecting the host against invading pathogens is carried out by interferon-stimulated genes (ISGs), the primary effectors of the type I interferon (IFN) response. All coronaviruses studied thus far have to first overcome the inhibitory effects of the IFN/ISG system before establishing efficient viral replication. However, whether SARS-CoV-2 evades IFN antiviral immunity by manipulating ISG activation remains to be elucidated. Here, we show that the SARS-CoV-2 main protease (M[SUP]pro[/SUP]) significantly suppresses the expression and transcription of downstream ISGs driven by IFN-stimulated response elements (ISREs) in a dose-dependent manner, and similar negative regulations were observed in two mammalian epithelial cell lines (simian Vero E6 and human A549). Our analysis shows that to inhibit the ISG production, M[SUP]pro[/SUP] cleaves histone deacetylases (HDACs) rather than directly targeting IFN signal transducers. Interestingly, M[SUP]pro[/SUP] also abolishes the activity of ISG effector decapping mRNA 1A (DCP1A) by cleaving it at residue Q343. In addition, M[SUP]pro[/SUP] from different genera of coronaviruses has the protease activity to cleave both HDAC2 and DCP1A, even though the alphacoronaviruse M[SUP]pro[/SUP] exhibits weaker catalytic activity in cleaving HDAC2. In conclusion, our findings clearly demonstrate that SARS-CoV-2 M[SUP]pro[/SUP] constitutes a critical anti-immune effector that modulates the IFN/ISG system at multiple levels, thus providing a novel molecular explanation for viral immune evasion, and allowing for new therapeutic approaches against COVID-19 infection.
Keywords: SARS-CoV-2; cleavage; decapping mRNA 1A; histone deacetylases; interferon-stimulated gene; main protease.
. 2023 Feb 7;102990.
doi: 10.1016/j.jbc.2023.102990. Online ahead of print.
The main protease of SARS-CoV-2 cleaves histone deacetylases and DCP1A, attenuating the immune defense of the interferon-stimulated genes
Liu Song[SUP] 1 [/SUP], Dianbing Wang[SUP] 2 [/SUP], Ghulam Abbas[SUP] 2 [/SUP], Min Li[SUP] 2 [/SUP], Mengmeng Cui[SUP] 2 [/SUP], Jufang Wang[SUP] 3 [/SUP], Zhanglin Lin[SUP] 4 [/SUP], Xian-En Zhang[SUP] 5 [/SUP]
Affiliations
- PMID: 36758802
- DOI: 10.1016/j.jbc.2023.102990
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), constitutes an emerging human pathogen of zoonotic origin. A critical role in protecting the host against invading pathogens is carried out by interferon-stimulated genes (ISGs), the primary effectors of the type I interferon (IFN) response. All coronaviruses studied thus far have to first overcome the inhibitory effects of the IFN/ISG system before establishing efficient viral replication. However, whether SARS-CoV-2 evades IFN antiviral immunity by manipulating ISG activation remains to be elucidated. Here, we show that the SARS-CoV-2 main protease (M[SUP]pro[/SUP]) significantly suppresses the expression and transcription of downstream ISGs driven by IFN-stimulated response elements (ISREs) in a dose-dependent manner, and similar negative regulations were observed in two mammalian epithelial cell lines (simian Vero E6 and human A549). Our analysis shows that to inhibit the ISG production, M[SUP]pro[/SUP] cleaves histone deacetylases (HDACs) rather than directly targeting IFN signal transducers. Interestingly, M[SUP]pro[/SUP] also abolishes the activity of ISG effector decapping mRNA 1A (DCP1A) by cleaving it at residue Q343. In addition, M[SUP]pro[/SUP] from different genera of coronaviruses has the protease activity to cleave both HDAC2 and DCP1A, even though the alphacoronaviruse M[SUP]pro[/SUP] exhibits weaker catalytic activity in cleaving HDAC2. In conclusion, our findings clearly demonstrate that SARS-CoV-2 M[SUP]pro[/SUP] constitutes a critical anti-immune effector that modulates the IFN/ISG system at multiple levels, thus providing a novel molecular explanation for viral immune evasion, and allowing for new therapeutic approaches against COVID-19 infection.
Keywords: SARS-CoV-2; cleavage; decapping mRNA 1A; histone deacetylases; interferon-stimulated gene; main protease.