Interferon-γ (IFNγ) orchestrates the immune response to SARS-CoV-2. In Nature, Xu et al. use genome-wide screens in human hepatocyte and lung epithelial cell lines to identify PLSCR1, a phospholipid scramblase upregulated by SARS-CoV-2 infection and type I, II and III IFN in a variety of human cells, including primary tracheal epithelia, as a restriction factor against SARS-CoV-2. Overexpression of PLSCR1, including the bat and mouse orthologues, is protective against SARS-CoV-2, including Delta and Omicron variants, in the absence of IFNγ stimulation or in STAT1-deficient cells, whereas PLSCR1 deletion in primary human or mouse cells increases susceptibility to β-coronaviruses such as SARS-CoV-2, SARS-CoV, MERS-CoV and BatCoV-WIV-1, but not to Ebola virus, hepatitis C virus or dengue virus type 1. PLSCR1 does not affect viral receptor expression, binding, internalization or spike cleavage, but disrupts the virus–endosomal membrane fusion to prevent viral RNA release in the cytosol. PLSCR1 targeting is specific for SARS-CoV-2, rather than all endocytosed cargo, and is dependent on the palmitoylation and β-barrel domains of PLSCR1, but not its lipid scramblase activity (the Ca2+-induced externalization of phosphatidylserine). The molecular details of how the β-barrel domain of PLSCR1 disrupts viral fusion remain to be investigated.
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