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

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; John Orban; Tom Gallagher; S Saif Hasan

doi:10.1038/s41467-023-44076-3

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

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, John Orban, Tom Gallagher, S Saif Hasan

Biology

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	8358
Journal	Nature Communications
Volume	14
DOIs	https://doi.org/10.1038/s41467-023-44076-3
Publication status	Published - 15 Dec 2023

Bibliographical note

Keywords

Humans
SARS-CoV-2/genetics
COVID-19/metabolism
Golgi Apparatus/metabolism
Spike Glycoprotein, Coronavirus/genetics

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10.1038/s41467-023-44076-3Licence: CC BY

Cite this

Dey, D., Qing, E., He, Y., Chen, Y., Jennings, B., Cohn, W., Singh, S., Gakhar, L., Schnicker, N. J., Pierce, B. G., Whitelegge, J. P., Doray, B., Orban, J., Gallagher, T., & Hasan, S. S. (2023). A single C-terminal residue controls SARS-CoV-2 spike trafficking and incorporation into VLPs. Nature Communications, 14, Article 8358. https://doi.org/10.1038/s41467-023-44076-3

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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.",

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AU - Dey, Debajit

AU - Qing, Enya

AU - He, Yanan

AU - Chen, Yihong

AU - Jennings, Benjamin

AU - Cohn, Whitaker

AU - Singh, Suruchi

AU - Gakhar, Lokesh

AU - Schnicker, Nicholas J

AU - Pierce, Brian G

AU - Whitelegge, Julian P

AU - Doray, Balraj

AU - Orban, John

AU - Gallagher, Tom

AU - Hasan, S Saif

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AB - 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.

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