SARS-CoV-2 spike proteins are massively S-acylated during infection
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ZDHHC20 is the dominant host enzyme in this process
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S-acylation of spike generates cholesterol-rich lipid domains within viral envelopes
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S-acylation and lipid biosynthesis pathways promote SARS-CoV-2 infectivity
Summary
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.
Other specific enquiries and data sets are available from lead contact upon reasonable request. All data that support the findings of this study are available within the article and supplemental information. Table S3 is also publicly available at: https://data.mendeley.com/datasets/47gsfkkjjz/1.
