S-acylation controls SARS-CoV-2 membrane lipid organization and enhances infectivity.

Francisco S Mesquita,Laurence Abrami,Matteo Dal Peraro,Charlène Raclot,Jonathan Paz Montoya,F Gisou Van Der Goot,Didier Trono,Béatrice Kunz,Tom Gallagher,Luciano A Abriata,Oksana Sergeeva,Giovanni D’Angelo,Priscilla Turelli,Enya Qing

doi:10.1016/j.devcel.2021.09.016

Francisco S Mesquita, Laurence Abrami + Show 12 more

Open Access

https://doi.org/10.1016/j.devcel.2021.09.016

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Abstract

SARS-CoV-2 virions are surrounded by a lipid bilayer that contains membrane proteins such as spike, responsible for target-cell binding and virus fusion. We found that during SARS-CoV-2 infection, spike becomes lipid modified, through the sequential action of the S-acyltransferases ZDHHC20 and 9. Particularly striking is the rapid acylation of spike on 10 cytosolic cysteines within the ER and Golgi. Using a combination of computational, lipidomics, and biochemical approaches, we show that this massive lipidation controls spike biogenesis and degradation, and drives the formation of localized ordered cholesterol and sphingolipid-rich lipid nanodomains in the early Golgi, where viral budding occurs. Finally, S-acylation of spike allows the formation of viruses with enhanced fusion capacity. Our study points toward S-acylating enzymes and lipid biosynthesis enzymes as novel therapeutic anti-viral targets.

Highlights

The CoV membrane envelope has 3 primary structural proteins: spike (S), membrane (M), and envelope (E) (Boson et al, 2021; Siu et al, 2008; V’kovski et al, 2021) as well as accessory proteins such as Orf3a (Ito et al, 2005; Tan et al, 2004)
Infections were performed with the severe acute respiratory syndrome (SARS)-CoV-2 D614G variant, which appeared early during the pandemic and rapidly spread worldwide (Korber et al, 2020)
Acylation prevents premature degradation promoting the biogenesis of spike, which is subsequently transported to the ER-Golgi intermediate compartment (ERGIC) where it arrives with up to 30 acyl chains decorating each trimer

Summary

Introduction

The CoV membrane envelope has 3 primary structural proteins: spike (S), membrane (M), and envelope (E) (Boson et al, 2021; Siu et al, 2008; V’kovski et al, 2021) as well as accessory proteins such as Orf3a (Ito et al, 2005; Tan et al, 2004). Viral assembly only requires E and M (Boson et al, 2021; Siu et al, 2008; Vennema et al, 1996). S is essential for infectivity as it mediates attachment to host cell receptors, angiotensin-converting enzyme 2 (ACE2) for SARS-CoV-2 (Hoffmann et al, 2020b; Letko et al, 2020), and fusion between viral and target cell membranes

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