Degradation of SARS-CoV-2 receptor ACE2 by the E3 ubiquitin ligase Skp2 in lung epithelial cells

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-2infection. Here, we show that cigarette smoke extract(CSE) and carcinogen benzo(a)pyrene(BaP) increase ACE2mRNA 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.