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However, the antiviral effect and underlying mechanisms of action of most ISGs in SARS-CoV-2 infection are not yet fully understood. By screening 109 ISG-knockout cell lines, we identify that phospholipid scramblase 1 (PLSCR1), an interferon-inducible protein, acts as a crucial restriction factor against SARS-CoV-2 infection. Cells lacking PLSCR1 are highly susceptible to SARS-CoV-2 infection. Conversely, overexpression of PLSCR1 inhibits SARS-CoV-2 infection. Depletion of PLSCR1 enhances cellular entry of both pseudotyped and authentic SARS-CoV-2. Mechanistically, PLSCR1 inhibits SARS-CoV-2 entry by specifically downregulating plasma membrane expression of ACE2, the virus\u2019s receptor, without affecting the overall levels of ACE2 within the cell. As such, we unraveled previously unappreciated mechanisms by which PLSCR1 exerts its restrictive effect on SARS-CoV-2. These data provide new insights into the interplay between host innate antiviral immunity and SARS-CoV-2 and shed light on novel antiviral therapeutics.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>IMPORTANCE<\/jats:title>\n            <jats:p>Phospholipid scramblase 1 (PLSCR1) has been identified as a critical host restriction factor against SARS-CoV-2 infection. In this study, we demonstrated that PLSCR1 inhibited SARS-CoV-2 entry by downregulating the plasma membrane expression of ACE2, the primary receptor for viral entry. Our findings elucidate a novel host-pathogen interaction that not only deepens our understanding of the innate immune response to SARS-CoV-2 but offers potential strategies for therapeutic interventions against COVID-19.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1128\/jvi.02085-24","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T14:01:16Z","timestamp":1739455276000},"update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["PLSCR1 suppresses SARS-CoV-2 infection by downregulating cell surface ACE2"],"prefix":"10.1128","volume":"99","author":[{"given":"Ruiyi","family":"Ma","sequence":"first","affiliation":[{"name":"NHC Key Laboratory of System Biology of Pathogens, and Christophe Merieux Laboratory National Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College","place":["Beijing, China"]},{"name":"Key Laboratory of Pathogen 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