Updated project metadata. De Antonellis et al. shows the importance of the Ca2+ channel pump ATP2B1 in the regulation of intracellular Ca2+ levels that positively influence SARS-CoV-2 replication in human cells. Our study identifies the mechanism of action of SARS-CoV-2 in the regulation of the expression of ATP2B1 and ATP2A1 loci during infection via FOXO3 transcriptional factor. Furthermore, a small caloxin-derivative molecule (compound PI-7) can inhibit ATP2B1 activity, thus resulting in SARSCoV- 2 impairment. In further support, we have identified a genetic variant within the noncoding upstream region of ATP2B1 in symptomatic patients affected by severe COVID19, thus indicating this polymorphism as a genetic predisposition factor to SARS-CoV-2 infection