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. 2024 Oct 22;98(10):e0107224.
doi: 10.1128/jvi.01072-24. Epub 2024 Sep 17.

Palmitoylation of SARS-CoV-2 Envelope protein is central to virus particle formation

Zhaohuan Wang #  1 , Manman Qiu #  1 , Yue Ji  1 , Keli Chai  1 , Chenxi Liu  1 , Fengwen Xu  2 , Fei Guo  2 , Juan Tan  1 , Ruikang Liu  1   3 , Wentao Qiao  1
Affiliations

Palmitoylation of SARS-CoV-2 Envelope protein is central to virus particle formation

Zhaohuan Wang et al. J Virol. .

Abstract

The Envelope (E) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an integral structural protein in the virus particles. However, its role in the assembly of virions and the underlying molecular mechanisms are yet to be elucidated, including whether the function of E protein is regulated by post-translational modifications. In the present study, we report that SARS-CoV-2 E protein is palmitoylated at C40, C43, and C44 by palmitoyltransferases zDHHC3, 6, 12, 15, and 20. Mutating these three cysteines to serines (C40/43/44S) reduced the stability of E protein, decreased the interaction of E with structural proteins Spike, Membrane, and Nucleocapsid, and thereby inhibited the production of virus-like particles (VLPs) and VLP-mediated luciferase transcriptional delivery. Specifically, the C40/43/44S mutation of E protein reduced the density of VLPs. Collectively, these results demonstrate that palmitoylation of E protein is vital for its function in the assembly of SARS-CoV-2 particles.IMPORTANCEIn this study, we systematically examined the biochemistry of palmitoylation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) E protein and demonstrated that palmitoylation of SARS-CoV-2 E protein is required for virus-like particle (VLP) production and maintaining normal particle density. These results suggest that palmitoylated E protein is central for proper morphogenesis of SARS-CoV-2 VLPs in densities required for viral infectivity. This study presents a significant advancement in the understanding of how palmitoylation of viral proteins is vital for assembling SARS-CoV-2 particles and supports that palmitoyl acyltransferases can be potential therapeutic targets for the development of SARS-CoV-2 inhibitors.

Keywords: Envelope protein; SARS-CoV-2; palmitoylation; virus-like particles.

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Conflict of interest statement

The authors declare no conflict of interest.

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