The insert sequence in SARS-CoV-2 enhances spike protein cleavage by TMPRSS

  1. Tong Meng
  2. Hao Cao
  3. Hao Zhang
  4. Zijian Kang
  5. Da Xu
  6. Haiyi Gong
  7. Jing Wang
  8. Zifu Li
  9. Xingang Cui
  10. Huji Xu
  11. Haifeng Wei
  12. Xiuwu Pan
  13. Rongrong Zhu
  14. Jianru Xiao
  15. Wang Zhou
  16. Liming Cheng
  17. Jianmin Liu

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Abstract

At the end of 2019, the SARS-CoV-2 induces an ongoing outbreak of pneumonia in China 1 , even more spread than SARS-CoV infection 2 . The entry of SARS-CoV into host cells mainly depends on the cell receptor (ACE2) recognition and spike protein cleavage-induced cell membrane fusion 3,4 . The spike protein of SARS-CoV-2 also binds to ACE2 with a similar affinity, whereas its spike protein cleavage remains unclear 5,6 . Here we show that an insertion sequence in the spike protein of SARS-CoV-2 enhances the cleavage efficiency, and besides pulmonary alveoli, intestinal and esophagus epithelium were also the target tissues of SARS-CoV-2. Compared with SARS-CoV, we found a SPRR insertion in the S1/S2 protease cleavage sites of SARS-CoV-2 spike protein increasing the cleavage efficiency by the protein sequence aligment and furin score calculation. Additionally, the insertion sequence facilitates the formation of an extended loop which was more suitable for protease recognition by the homology modeling and molicular docking. Furthermore, the single-cell transcriptomes identified that ACE2 and TMPRSSs are highly coexpressed in AT2 cells of lung, along with esophageal upper epithelial cells and absorptive enterocytes. Our results provide the bioinformatics evidence for the increased spike protein cleavage of SARS-CoV-2 and indicate its potential target cells.

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    SciScore for 10.1101/2020.02.08.926006: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Single cell transcriptome data sources: Single cell transcriptome data were obtained from Single Cell Portal (https://singlecell.broadinstitute.org/single_cell), Human Cell Atlas Data Protal (https://data.humancellatlas.org) and Gene Expression Omnibus
    Gene Expression Omnibus
    suggested: (Gene Expression Omnibus (GEO, RRID:SCR_005012)
    (GEO; https://www.ncbi.nlm.nih.gov/).
    https://www.ncbi.nlm.nih.gov/
    suggested: (GENSAT at NCBI - Gene Expression Nervous System Atlas, RRID:SCR_003923)
    Endocytosis or exocytosis associated genes were obtained from Harmonizome dataset45.
    Harmonizome
    suggested: (Harmonizome, RRID:SCR_016176)

    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.

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  2. Version published to 10.1101/2020.02.08.926006v3 on bioRxiv
  3. Version published to 10.1101/2020.02.08.926006v2 on bioRxiv
  4. Version published to 10.1101/2020.02.08.926006v1 on bioRxiv