Global loss of cellular m6A RNA methylation following infection with different SARS-CoV-2 variants
- Roshan Vaid1,
- Akram Mendez1,
- Ketan Thombare1,
- Rebeca Burgos Panadero1,
- Rémy Robinot2,
- Barbara F Fonseca2,
- Nikhil R Gandasi3,
- Johan Ringlander4,
- Mohammad Hassan Baig5,
- Jae-June Dong5,
- Jae Yong Cho5,
- Björn Reinius6,
- Lisa A Chakrabarti2,
- Kristina Nystrom4 and
- Tanmoy Mondal7,8
- 1 Institute of Biomedicine, University of Gothenburg;
- 2 Institut Pasteur, Université Paris Cité, CNRS UMR;
- 3 Indian Institute of Sciences (IISc);
- 4 Sahlgrenska Academy, University of Gothenburg;
- 5 Gangnam Severance Hospital, Yonsei University College of Medicine;
- 6 Karolinska Institute;
- 7 Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital
Abstract
Host-viral interactions during SARS-CoV-2 infection are needed to understand COVID-19 pathogenesis and may help to guide the design of novel antiviral therapeutics. N6-methyladenosine modification (m6A), one of the most abundant cellular RNA modifications, regulates key processes in RNA metabolism during a stress response. Gene expression profiles observed post-infection with different SARS-CoV-2 variants show changes in the expression of genes related to RNA catabolism, including m6A readers and erasers. We found that infection with SARS-CoV-2 variants caused a loss of m6A in cellular RNAs, whereas m6A was detected abundantly in viral RNA. METTL3, the m6A methyltransferase, showed an unusual cytoplasmic localization post-infection. The B.1.351 variant had a less pronounced effect on METTL3 localization and loss of m6A than the B.1 and B.1.1.7 variants. We also observed a loss of m6A upon SARS-CoV-2 infection in air/liquid interface cultures of human airway epithelia, confirming that m6A loss is characteristic of SARS-CoV-2 infected cells. Further, transcripts with m6A modification were preferentially down-regulated post-infection. Inhibition of the export protein XPO1 resulted in the restoration of METTL3 localization, recovery of m6A on cellular RNA, and increased mRNA expression. Stress granule formation, which was compromised by SARS-CoV-2 infection, was restored by XPO1 inhibition and accompanied by a reduced viral infection in vitro. Together, our study elucidates how SARS-CoV-2 inhibits the stress response and perturbs cellular gene expression in an m6A-dependent manner.
- Received November 20, 2021.
- Accepted February 17, 2023.
- Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International license), as described at http://creativecommons.org/licenses/by-nc/4.0/.
