S-acylation controls SARS-Cov-2 membrane lipid organization and enhances infectivity
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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.
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SciScore for 10.1101/2021.03.14.435299: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Within the limitations of high MOIs and incomplete loss of ZDHHC expression following siRNA, the observation suggest that ZDHHC9 influences the first round of infection, while ZDHHC20 might not. Next, we utilized the viral supernatants produced from the 10 h infections in cells silenced for either ZDHHC20 or ZDHHC9, and used them to infect …
SciScore for 10.1101/2021.03.14.435299: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
No key resources detected.
Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:Within the limitations of high MOIs and incomplete loss of ZDHHC expression following siRNA, the observation suggest that ZDHHC9 influences the first round of infection, while ZDHHC20 might not. Next, we utilized the viral supernatants produced from the 10 h infections in cells silenced for either ZDHHC20 or ZDHHC9, and used them to infect naïve control cells. Supernatants were first adjusted to comparable amounts of E-RNA copies per ml (Figure S7D). Approximately 50 E copies were then added per target cell for infection. The infectivity was monitored 6 h after viral inoculation by measuring the total RNA of E and RdRP, as well as sub-genomic E RNA (E-sub_gen), which is a more accurate proxy for viral replication. The infectivity of virions produced from either ZDHHC20 and ZDHHC9 silenced cells was 25% to 30% lower than that of control virions, based on total and sub-genomic E RNA, respectively (Figure 7H). A similar trend was observed for RdRp RNA. These data indicate that ZDHHC20-mediated S-acylation contributes to SARS-CoV-2 infection by promoting the production of fully infectious virions. Finally, given the here identified importance of cholesterol and sphingolipid-rich domains, we tested whether pharmacological inhibition of sphingolipid biogenesis, could affect SARS-CoV-2 infection. We used the fungal metabolite Myriocin, which targets serine palmitoyltransferase-1 at early steps of sphingosine biosynthesis and fully depletes sphingolipids in cells in 5 days. We also t...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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