Degradation of SARS-CoV-2 receptor ACE2 by the E3 ubiquitin ligase Skp2 in lung epithelial cells
Guizhen Wang1,2, Qun Zhao1,3, Hui Zhang4, Fan Liang1,2, Chen Zhang1,2, Jun Wang5, Zhenyin Chen1,6, Ran Wu1,6, Hong Yu7, Beibei Sun1, Hua Guo1, Ruie Feng4, Kaifeng Xu5, Guangbiao Zhou1()
1. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China 2. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences & University of Chinese Academy of Sciences, Beijing 100101, China 3. Hubei University of Medicine, Shiyan 442000, China 4. Department of Pathology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China 5. Department of Pulmonary and Critical Care Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing 100730, China 6. Guizhou University School of Medicine, Guiyang 550025, China 7. School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing 100029, China
An unexpected observation among the COVID-19 pandemic is that smokers constituted only 1.4%−18.5% of hospitalized adults, calling for an urgent investigation to determine the role of smoking in SARS-CoV-2 infection. Here, we show that cigarette smoke extract (CSE) and carcinogen benzo(a)pyrene (BaP) increase ACE2 mRNA but trigger ACE2 protein catabolism. BaP induces an aryl hydrocarbon receptor (AhR)-dependent upregulation of the ubiquitin E3 ligase Skp2 for ACE2 ubiquitination. ACE2 in lung tissues of non-smokers is higher than in smokers, consistent with the findings that tobacco carcinogens downregulate ACE2 in mice. Tobacco carcinogens inhibit SARS-CoV-2 spike protein pseudovirions infection of the cells. Given that tobacco smoke accounts for 8 million deaths including 2.1 million cancer deaths annually and Skp2 is an oncoprotein, tobacco use should not be recommended and cessation plan should be prepared for smokers in COVID-19 pandemic.
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