Global loss of cellular m6A RNA methylation following infection with different SARS-CoV-2 variants
- Roshan Vaid1,9,
- Akram Mendez1,9,
- Ketan Thombare1,
- Rebeca Burgos-Panadero1,
- Rémy Robinot2,
- Barbara F. Fonseca2,
- Nikhil R. Gandasi3,
- Johan Ringlander4,
- Mohammad Hassan Baig5,
- Jae-June Dong5,
- Jae Yong Cho6,
- Björn Reinius7,
- Lisa A. Chakrabarti2,
- Kristina Nystrom4 and
- Tanmoy Mondal1,8
- 1Department of Laboratory Medicine, Institute of Biomedicine, University of Gothenburg, Gothenburg 41345, Sweden;
- 2Virus and Immunity Unit, Institut Pasteur, Université Paris Cité, CNRS UMR 3569, Paris, France;
- 3GA08/NRG-Laboratory, Department of Molecular Reproduction, Development and Genetics, Indian Institute of Sciences, Bengaluru 560012, India;
- 4Department of Infectious Diseases, Sahlgrenska Academy, University of Gothenburg, Gothenburg 41345, Sweden;
- 5Department of Family Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Gangnam-gu, Seoul 120-752, Korea;
- 6Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Gangnam-gu, Seoul 120-752, Korea;
- 7Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 17177, Sweden;
- 8Department of Clinical Chemistry, Sahlgrenska University Hospital, University of Gothenburg, Gothenburg 41345, Sweden
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↵9 These authors contributed equally to this work.
Abstract
Insights into host–virus 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 stress response. Gene expression profiles observed postinfection 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 causes a loss of m6A in cellular RNAs, whereas m6A is detected abundantly in viral RNA. METTL3, the m6A methyltransferase, shows an unusual cytoplasmic localization postinfection. The B.1.351 variant has a less-pronounced effect on METTL3 localization and loss of m6A than did 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 are preferentially down-regulated postinfection. Inhibition of the export protein XPO1 results in the restoration of METTL3 localization, recovery of m6A on cellular RNA, and increased mRNA expression. Stress granule formation, which is compromised by SARS-CoV-2 infection, is 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.
Footnotes
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[Supplemental material is available for this article.]
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Article published online before print. Article, supplemental material, and publication date are at https://www.genome.org/cgi/doi/10.1101/gr.276407.121.
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Freely available online through the Genome Research Open Access option.
- Received November 20, 2021.
- Accepted February 17, 2023.
This article, published in Genome Research, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.
