Vitamin C promotes ACE2 degradation and protects against SARS‐CoV‐2 infection

Abstract

AbstractACE2 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.