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

Abstract

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.

Keywords

SARS-CoV-2 / tobacco smoke / benzo(a)pyrene / ACE2 / Skp2

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Acknowledgements

This work was jointly supported by the National Key Research and Development Program of China (Nos. 2020YFA0803300 and 2018YFC1313600), the National Natural Science Funds for Distinguished Young Scholar (No. 81425025), the Key Project of the National Natural Science Foundation of China (No. 81830093), the CAMS Innovation Fund for Medical Sciences (CIFMS; No. 2019-I2M-1-003), and the National Natural Science Foundation of China (Nos. 81672765 and 81802796).

Compliance with ethics guidelines

Guizhen Wang, Qun Zhao, Hui Zhang, Fan Liang, Chen Zhang, Jun Wang, Zhenyin Chen, Ran Wu, Hong Yu, Beibei Sun, Hua Guo, Ruie Feng, Kaifeng Xu, and Guangbiao Zhou declare that they have no conflict of interest. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975 as revised in 2000. Additional informed consent was obtained from all patients whose identifying information is included in this article.

Electronic Supplementary Material

Supplementary material is available in the online version of this article at https://doi.org/10.1007/s11684-021-0837-6 and is accessible for authorized users.

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