Mesquita, Francisco S.Abrami, LaurenceSergeeva, OksanaTurelli, PriscillaQing, EnyaKunz, BeatriceRaclot, CharleneMontoya, Jonathan PazAbriata, Luciano A.Gallagher, TomDal Peraro, MatteoTrono, DidierD'Angelo, Giovannivan der Goot, F. Gisou2021-11-202021-11-202021-11-202021-10-2510.1016/j.devcel.2021.09.016https://infoscience.epfl.ch/handle/20.500.14299/183078WOS:000711639200004SARS-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 andCell BiologyDevelopmental Biologyrespiratory syndrome coronaviruscoarse-grained modelspike proteincytoplasmic tailcell-surfacepalmitoylationcysteineidentificationparticlesfty720text::journal::journal article::research article