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A single C-terminal residue controls SARS-CoV-2 spike trafficking and incorporation into VLPs

Author

Listed:
  • Debajit Dey

    (University of Maryland School of Medicine)

  • Enya Qing

    (Loyola University Chicago)

  • Yanan He

    (University of Maryland Institute for Bioscience and Biotechnology Research)

  • Yihong Chen

    (University of Maryland Institute for Bioscience and Biotechnology Research)

  • Benjamin Jennings

    (Washington University School of Medicine)

  • Whitaker Cohn

    (University of California)

  • Suruchi Singh

    (University of Maryland School of Medicine)

  • Lokesh Gakhar

    (University of Iowa
    University of Iowa
    PAQ Therapeutics)

  • Nicholas J. Schnicker

    (University of Iowa
    University of Iowa)

  • Brian G. Pierce

    (University of Maryland Institute for Bioscience and Biotechnology Research
    University of Maryland)

  • Julian P. Whitelegge

    (University of California
    University of California, Los Angeles
    University of California, Los Angeles)

  • Balraj Doray

    (Washington University School of Medicine)

  • John Orban

    (University of Maryland Institute for Bioscience and Biotechnology Research
    University of Maryland)

  • Tom Gallagher

    (Loyola University Chicago)

  • S. Saif Hasan

    (University of Maryland School of Medicine
    University of Maryland Marlene and Stewart Greenebaum Cancer Center, University of Maryland Medical Center
    University of Maryland School of Medicine)

Abstract

The spike (S) protein of SARS-CoV-2 is delivered to the virion assembly site in the ER-Golgi Intermediate Compartment (ERGIC) from both the ER and cis-Golgi in infected cells. However, the relevance and modulatory mechanism of this bidirectional trafficking are unclear. Here, using structure-function analyses, we show that S incorporation into virus-like particles (VLP) and VLP fusogenicity are determined by coatomer-dependent S delivery from the cis-Golgi and restricted by S-coatomer dissociation. Although S mimicry of the host coatomer-binding dibasic motif ensures retrograde trafficking to the ERGIC, avoidance of the host-like C-terminal acidic residue is critical for S-coatomer dissociation and therefore incorporation into virions or export for cell-cell fusion. Because this C-terminal residue is the key determinant of SARS-CoV-2 assembly and fusogenicity, our work provides a framework for the export of S protein encoded in genetic vaccines for surface display and immune activation.

Suggested Citation

  • Debajit Dey & Enya Qing & Yanan He & Yihong Chen & Benjamin Jennings & Whitaker Cohn & Suruchi Singh & Lokesh Gakhar & Nicholas J. Schnicker & Brian G. Pierce & Julian P. Whitelegge & Balraj Doray & J, 2023. "A single C-terminal residue controls SARS-CoV-2 spike trafficking and incorporation into VLPs," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-44076-3
    DOI: 10.1038/s41467-023-44076-3
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