The main protease of SARS-CoV-2 cleaves histone deacetylases and DCP1A, attenuating the immune defense of the interferon-stimulated genes

  • J Biol Chem. 2023 Feb 7;102990. doi: 10.1016/j.jbc.2023.102990.
Liu Song  1 ,  Dianbing Wang  2 ,  Ghulam Abbas  2 ,  Min Li  2 ,  Mengmeng Cui  2 ,  Jufang Wang  3 ,  Zhanglin Lin  4 ,  Xian-En Zhang  5
Affiliations
  • 1. School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China,; National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 400715, China.
  • 2. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 400715, China.
  • 3. School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China,. Electronic address: [email protected].
  • 4. School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China.
  • 5. National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 400715, China; Faculty of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 215000, China. Electronic address: [email protected].
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 (Mpro) 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, Mpro cleaves histone deacetylases (HDACs) rather than directly targeting IFN signal transducers. Interestingly, Mpro also abolishes the activity of ISG effector decapping mRNA 1A (DCP1A) by cleaving it at residue Q343. In addition, Mpro from different genera of coronaviruses has the protease activity to cleave both HDAC2 and DCP1A, even though the alphacoronaviruse Mpro exhibits weaker catalytic activity in cleaving HDAC2. In conclusion, our findings clearly demonstrate that SARS-CoV-2 Mpro 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.
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