ABSTRACT
SARS-CoV-2 virions are surrounded by a lipid bilayer which contains membrane proteins such as Spike, responsible for target-cell binding and virus fusion, the envelope protein E and the accessory protein Orf3a. Here, we show that during SARS-CoV-2 infection, all three proteins become lipid modified, through action of the S- acyltransferase ZDHHC20. 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. ZDHHC20-mediated acylation allows the formation of viruses with enhanced fusion capacity and overall infectivity. Our study points towards S-acylating enzymes and lipid biosynthesis enzymes as novel therapeutic anti-viral targets.Funding: This work was supported by the Swiss National Science Foundation Corona Call, the CARIGEST foundation and the EPFL Corona Research task force to F.G.v.d.G. MD simulations were carried out on the Piz Daint computer at the Swiss Supercomputing Center (CSCS) thanks to access granted by PRACE Covid19 fast track project #17 (pr97) to M.D.P.Conflict of Interest: The authors declare no competing interests.