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

Abstract: bioRxiv preprint doi: https://doi.org/10.1101/2022.07.14.499651; this version posted July 15, 2022. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Vitamin C is an efficient natural product for prevention of 2 SARS-CoV-2 infection by targeting ACE2 in both cell and in 3 vivo mouse models 4 5 Yibo Zuo,1,2 Zhijin Zheng,1,2 Yingkang Huang,5 Jiuyi He,1,2 Lichao Zang,4 6 Tengfei Ren,1,2 Xinhua Cao,1,2 Ying Miao,1,2 Yukang Yuan,1,2 Yanli Liu,3 Feng 7 Ma,5 Sheng Tian,3 Jianfeng Dai,1,2 Qiang Ding,6 Hui Zheng1,2,7,* 8 9 1 International Institute of Infection and Immunity, Institutes of Biology and Medical 10 Sciences, Suzhou 11 2 Jiangsu Key Laboratory of Infection and Immunity, Suzhou 12 3 College of Pharmaceutical Sciences, Suzhou 13 4 The Third Affiliated Hospital of Soochow University, Changzhou 14 Soochow University, Jiangsu 215123, China 15 5 16 of Medical Sciences and Peking Union Medical College, Beijing 10005; Suzhou 17 Institute of Systems Medicine, Jiangsu 215123, China 18 6 19 Innovation Center for Structural Biology, Tsinghua University, Beijing 10084, China 20 7 21 *Correspondence: huizheng@suda.edu.cn CAMS Key Laboratory of Synthetic Biology Regulatory Elements, Chinese Academy Center for Infectious Disease Research, School of Medicine, Beijing Advanced Lead contact 22 23 24 1 bioRxiv preprint doi: https://doi.org/10.1101/2022.07.14.499651; this version posted July 15, 2022. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 25 SUMMARY 26 ACE2 is a major receptor for cell entry of SARS-CoV-2. Despite advances in 27 targeting ACE2 to inhibit SARS-CoV-2's binding, how to efficiently and flexibly 28 control ACE2 levels for prevention of SARS-CoV-2 infection has not been 29 explored. Here, we revealed Vitamin C (VitC) administration as an effective 30 strategy to prevent SARS-CoV-2 infection. VitC reduced ACE2 protein levels in 31 a dose-dependent manner, while partial reduction of ACE2 can greatly restrict 32 SARS-CoV-2 infection. Further studies uncovered that USP50 is a crucial 33 regulator of ACE2 protein levels, and VitC blocks the USP50-ACE2 interaction, 34 thus promoting K48-linked polyubiquitination at Lys788 and degradation of 35 ACE2, without disrupting ACE2 transcriptional expression. Importantly, VitC 36 administration reduced host ACE2 and largely blocked SARS-CoV-2 infection 37 in mice. This study identified an in vivo ACE2 balance controlled by both 38 USP50 and an essential nutrient VitC, and revealed a critical role and 39 application of VitC in daily protection from SARS-CoV-2 infection. 40 41 Highlights 42 VitC reduces ACE2 protein levels in a dose-dependent manner 43 VitC and USP50 regulate K48-linked ubiquitination at Lys788 of ACE2 44 VitC blocks the interaction between USP50 and ACE2 45 VitC administration lowers host ACE2 and prevents SARS-CoV-2 infection 46 in vivo 47 48 2 bioRxiv preprint doi: https://doi.org/10.1101/2022.07.14.499651; this version posted July 15, 2022. The copyright holder for this preprint (which was not certified by..