Abstract

Viral infection involves complex set of events orchestrated by multiple viral proteins. To identify functions of SARS-CoV-2 proteins, we performed transcriptomic analyses of cells expressing individual viral proteins. Expression of Nsp14, a protein involved in viral RNA replication, provoked a dramatic remodeling of the transcriptome that strongly resembled that observed following SARS-CoV-2 infection. Moreover, Nsp14 expression altered the splicing of more than 1,000 genes and resulted in a dramatic increase in the number of circRNAs, which are linked to innate immunity. These effects were independent of the Nsp14 exonuclease activity and required the N7-guanine-methyltransferase domain of the protein. Activation of the NFkB pathway and increased expression of CXCL8 occurred early upon Nsp14 expression. We identified IMPDH2, which catalyzes the rate-limiting step of guanine nucleotides biosynthesis, as a key mediator of these effects. Nsp14 expression caused an increase in GTP cellular levels, and the effect of Nsp14 was strongly decreased in presence of IMPDH2 inhibitors. Together, our data demonstrate an unknown role for Nsp14 with implications for therapy.

Data availability

1.RNAseq data generated in this study is in GEO (GSE179251).2.RNA seq data already published and re-analyzed in this study are the following:-Sun, G., Cui, Q., Garcia, G. et al. Comparative transcriptomic analysis of SARS-CoV-2 infected cell model systems reveals differential innate immune responses. Sci Rep 11, 17146 (2021). https://doi.org/10.1038/s41598-021-96462-w, GSE169158-Blanco-Melo D, Nilsson-Payant BE, Liu WC, Uhl S, Hoagland D, Møller R, Jordan TX, Oishi K, Panis M, Sachs D, Wang TT, Schwartz RE, Lim JK, Albrecht RA, tenOever BR. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell. 2020 May 28;181(5):1036-1045.e9. doi: 10.1016/j.cell.2020.04.026. Epub 2020 May 15. PMID: 32416070; PMCID: PMC7227586, GSE147507All data generated or analyzed during this study are included in the manuscript and supporting files.

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The following previously published data sets were used

Article and author information

Author details

  1. Michela Zaffagni

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Jenna M Harris

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ines L Patop

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Nagarjuna Reddy Pamudurti

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sinead Nguyen

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Sebastian Kadener

    Department of Biology, Brandeis University, Waltham, United States
    For correspondence
    skadener@brandeis.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0080-5987

Funding

there is no external funding for this project

Reviewing Editor

  1. Kevin Struhl, Harvard Medical School, United States

Version history

  1. Preprint posted: July 4, 2021 (view preprint)
  2. Received: July 5, 2021
  3. Accepted: March 10, 2022
  4. Accepted Manuscript published: March 16, 2022 (version 1)
  5. Version of Record published: April 29, 2022 (version 2)

Copyright

© 2022, Zaffagni et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Michela Zaffagni
  2. Jenna M Harris
  3. Ines L Patop
  4. Nagarjuna Reddy Pamudurti
  5. Sinead Nguyen
  6. Sebastian Kadener
(2022)
SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome
eLife 11:e71945.
https://doi.org/10.7554/eLife.71945

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https://doi.org/10.7554/eLife.71945

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