SARS-CoV-2 hijacks a cell damage response, which induces transcription of a more efficient Spike S-acyltransferase

SARS-CoV-2 infection requires Spike protein-mediated fusion between the viral and cellular membranes. The fusogenic activity of Spike depends on its post-translational lipid modification by host S-acyltransferases, predominantly ZDHHC20. Previous observations indicate that SARS-CoV-2 infection augments the S-acylation of Spike when compared to mere Spike transfection. Here, we find that SARS-CoV-2 infection triggers a change in the transcriptional start site of the zdhhc20 gene, both in cells and in an in vivo infection model, resulting in a 67-amino-acid-long N-terminally extended protein with approx. 40 times higher Spike acylating activity, resulting in enhanced fusion of viruses with host cells. Furthermore, we observed the same induced transcriptional change in response to other challenges, such as chemically induced colitis and pore-forming toxins, indicating that SARS-CoV-2 hijacks an existing cell damage response pathway to optimize it fusion glycoprotein. The fusogenic activity of SARS-CoV-2 Spike depends on its post-translational lipid modification by host S-acyltransferases, predominantly ZDHHC20. Here, Mesquita and Abrami et al. show that SARS-CoV-2 infection and colitis in mice induce a damage response resulting in an altered version of the ZDHHC20 enzyme that is more abundant and significantly more efficient at attaching fatty acids to viral Spike.