A novel viral protein translation mechanism reveals mitochondria as a target for antiviral drug development

  1. Zhenguo Cheng
  2. Danhua Zhang
  3. Jingfei Chen
  4. Yifan Wu
  5. XiaoWen Liu
  6. Lingling Si
  7. Zhe Zhang
  8. Na Zhang
  9. Zhongxian Zhang
  10. Wei Liu
  11. Hong Liu
  12. Lirong Zhang
  13. Lijie Song
  14. Louisa S Chard Dunmall
  15. Jianzeng Dong
  16. Nicholas R Lemoine
  17. Yaohe Wang

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Abstract

The ongoing Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) pandemic has acutely highlighted the need to identify new treatment strategies for viral infections. Here we present a pivotal molecular mechanism of viral protein translation that relies on the mitochondrial translation machinery. We found that rare codons such as Leu-TTA are highly enriched in many viruses, including SARS-CoV-2, and these codons are essential for the regulation of viral protein expression. SARS-CoV-2 controls the translation of its spike gene by hijacking host mitochondria through 5’ leader and 3’UTR sequences that contain mitochondrial localization signals and activate the EGR1 pathway. Mitochondrial-targeted drugs such as lonidamine and polydatin significantly repress rare codon-driven gene expression and viral replication. This study identifies an unreported viral protein translation mechanism and opens up a novel avenue for developing antiviral drugs.

One Sentence Summary

Mitochondria are a potential target for antiviral therapy

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  1. ScreenIT

    SciScore for 10.1101/2020.10.19.344713: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.
    Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The antibodies used in this study were the following: rabbit anti-RBD polyclonal antibody (Sino Biological, #40592-T62), mouse anti-Actin monoclonal antibody (ProteinTech, 60008-1-Ig)
    anti-RBD
    suggested: None
    anti-Actin
    suggested: None
    mouse anti-his tag monoclonal antibody (Abmart, M20001S), mouse anti-DDK/Flag tag monoclonal antibody (Abmart, M20008L), HRP Goat Anti-Rabbit IgG (ZSBIO, ZB-5301), HRP Goat anti-mouse IgG (ZSBIO, ZB-5305).
    anti-his tag
    suggested: None
    anti-DDK/Flag tag
    suggested: None
    Anti-Rabbit IgG
    suggested: None
    anti-mouse IgG
    suggested: None
    After treatment with 1% triton-100 for 15 min and blocking with unimmunized goat serum for 1 h, cells were incubated with the anti-his tag antibody overnight at 4°C, and then detected with donkey anti-mouse secondary antibody conjugated with alexa fluor plus 488nm (Invitrogen, USA)
    anti-mouse
    suggested: (Thermo Fisher Scientific Cat# A32766, RRID:AB_2762823)
    Experimental Models: Cell Lines
    SentencesResources
    Cells and transfection: Human kidney cell line HEK-293 and lung cancer cell line A549 were purchased from the Cell Bank of Type Culture Collection Committee of the Chinese Academy of Sciences.
    HEK-293
    suggested: None
    In order to evaluate the effect of polydatin and lonidamine on virus replication, 2×105 A549 cells were seeded into 12-wells plates and infected with Ad11 virus (MOI=0.5) in serum-free medium.
    A549
    suggested: None
    Software and Algorithms
    SentencesResources
    Potential TFs on the promoter (upstream 1000bp) of TRL-TAA-4-1 were predicted with JASPAR software (relative profile score threshold was 80%) and Venny 2.1 software was used to performed the gene overlap analysis.
    JASPAR
    suggested: (JASPAR, RRID:SCR_003030)
    The signalling pathway and functional enrichment analysis of related genes were performed with Metascape.
    Metascape
    suggested: (Metascape, RRID:SCR_016620)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.10.19.344713 on bioRxiv