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

Research output: Contribution to journalArticlepeer-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 languageEnglish
Article number8358
JournalNature communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

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