ACE2 is a major receptor for cellular entry of SARS‐CoV‐2. Despite advances in targeting ACE2 to inhibit SARS‐CoV‐2 binding, strategies to flexibly and sufficiently reduce ACE2 levels for the prevention of SARS‐CoV‐2 infection have not been explored. Here, we reveal vitamin C (VitC) administration as a potent strategy to prevent SARS‐CoV‐2 infection. VitC reduces ACE2 protein levels in a dose‐dependent manner, while even a partial reduction in ACE2 levels can greatly inhibit SARS‐CoV‐2 infection. Further studies reveal that USP50 is a crucial regulator of ACE2 levels. VitC blocks the USP50‐ACE2 interaction, thus promoting K48‐linked polyubiquitination of ACE2 at Lys788 and subsequent degradation of ACE2 without affecting its transcriptional expression. Importantly, VitC administration reduces host ACE2 levels and greatly blocks SARS‐CoV‐2 infection in mice. This study reveals that ACE2 protein levels are down‐regulated by an essential nutrient, VitC, thereby enhancing protection against infection of SARS‐CoV‐2 and its variants.
Rapid and robust induction of antiviral genes is essential for the host to clear the invaded viruses. In addition to the IRF3/7-IFN-I-STAT1 signaling axis, the XAF1-IRF1 positive feedback loop synergistically or independently drives the transcription of antiviral genes.
ACE2 is a major receptor for cell entry of SARS-CoV-2. Despite advances in targeting ACE2 to inhibit SARS-CoV-2's binding, how to efficiently and flexibly control ACE2 levels for prevention of SARS-CoV-2 infection has not been explored. Here, we revealed Vitamin C (VitC) administration as an effective strategy to prevent SARS-CoV-2 infection. VitC reduced ACE2 protein levels in a dose-dependent manner, while partial reduction of ACE2 can greatly restrict SARS-CoV-2 infection. Further studies uncovered that USP50 is a crucial regulator of ACE2 protein levels, and VitC blocks the USP50-ACE2 interaction, thus promoting K48-linked polyubiquitination at Lys788 and degradation of ACE2, without disrupting ACE2 transcriptional expression. Importantly, VitC administration reduced host ACE2 and largely blocked SARS-CoV-2 infection in mice. This study identified an in vivo ACE2 balance controlled by both USP50 and an essential nutrient VitC, and revealed a critical role and application of VitC in daily protection from SARS-CoV-2 infection.
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