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.
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References
COVID-19 Dashboard by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. (JHU). 2020. https://www.arcgis.com/apps/opsdashboard/index.html#/bda7594740fd40299423467b48e9ecf6 (accessed December 8, 2020)
World Health Organization. Smoking and COVID-19. 2020. https://www.who.int/news-room/commentaries/detail/smoking-and-covid-19 (accessed December 8, 2020)
Lippi G, Henry BM. Active smoking is not associated with severity of coronavirus disease 2019 (COVID-19). Eur J Intern Med 2020; 75: 107–108
Farsalinos K, Barbouni A, Niaura R. Systematic review of the prevalence of current smoking among hospitalized COVID-19 patients in China: could nicotine be a therapeutic option? Intern Emerg Med 2020; 15(5): 845–852
CDC COVID-19 Response Team. Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019—United States, February 12–March 28, 2020. MMWR Morb Mortal Wkly Rep 2020; 69(13): 382–386
Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382(18): 1708–1720
Miyara M, Tubach F, Pourcher V, Morelot-Panzini C, Pernet J, Haroche J, Lebbah S, Morawiec E, Gorochov G, Caumes E, Hausfater P, Combes A, Similowski T, Amoura Z. Low incidence of daily active tobacco smoking in patients with symptomatic COVID-19 infection. Qeios 2020; https://doi.org/10.32388/WPP19W
Vardavas CI, Nikitara K. COVID-19 and smoking: a systematic review of the evidence. Tob Induc Dis 2020; 18: 20
Gebel S, Diehl S, Pype J, Friedrichs B, Weiler H, Schüller J, Xu H, Taguchi K, Yamamoto M, Müller T. The transcriptome of Nrf2−/− mice provides evidence for impaired cell cycle progression in the development of cigarette smoke-induced emphysematous changes. Toxicol Sci 2010; 115(1): 238–252
Wang GZ, Cheng X, Zhou B, Wen ZS, Huang YC, Chen HB, Li GF, Huang ZL, Zhou YC, Feng L, Wei MM, Qu LW, Cao Y, Zhou GB. The chemokine CXCL13 in lung cancers associated with environmental polycyclic aromatic hydrocarbons pollution. eLife 2015; 4: e09419
Carnevali S, Petruzzelli S, Longoni B, Vanacore R, Barale R, Cipollini M, Scatena F, Paggiaro P, Celi A, Giuntini C. Cigarette smoke extract induces oxidative stress and apoptosis in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol 2003; 284(6): L955–L963
Wang GZ, Cheng X, Li XC, Liu YQ, Wang XQ, Shi X, Wang ZY, Guo YQ, Wen ZS, Huang YC, Zhou GB. Tobacco smoke induces production of chemokine CCL20 to promote lung cancer. Cancer Lett 2015; 363(1): 60–70
Liu Z, Ma L, Wen ZS, Hu Z, Wu FQ, Li W, Liu J, Zhou GB. Cancerous inhibitor of PP2A is targeted by natural compound celastrol for degradation in non-small-cell lung cancer. Carcinogenesis 2014; 35(4): 905–914
Wang GZ, Zhang L, Zhao XC, Gao SH, Qu LW, Yu H, Fang WF, Zhou YC, Liang F, Zhang C, Huang YC, Liu Z, Fu YX, Zhou GB. The Aryl hydrocarbon receptor mediates tobacco-induced PD-L1 expression and is associated with response to immunotherapy. Nat Commun 2019; 10(1): 1125
Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA, Drosten C, Pöhlmann S. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 2020; 181(2): 271–280
Zou X, Chen K, Zou J, Han P, Hao J, Han Z. Single-cell RNA-seq data analysis on the receptor ACE2 expression reveals the potential risk of different human organs vulnerable to 2019-nCoV infection. Front Med 2020; 14(2): 185–192
Cai G, Bossé Y, Xiao F, Kheradmand F, Amos CI. Tobacco smoking increases the lung gene expression of ACE2, the receptor of SARS-CoV-2. Am J Respir Crit Care Med 2020; 201(12): 1557–1559
Smith JC, Sausville EL, Girish V, Yuan ML, Vasudevan A, John KM, Sheltzer JM. Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract. Dev Cell 2020; 53(5): 514–529.e3
Zhou G, Chen S, Chen Z. Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies. Front Med 2020; 14(2): 117–125
Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, Raizada MK, Grant MB, Oudit GY. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res 2020; 126(10): 1456–1474
Kamitani T, Kito K, Nguyen HP, Yeh ETH. Characterization of NEDD8, a developmentally down-regulated ubiquitin-like protein. J Biol Chem 1997; 272(45): 28557–28562
Zhang H, Kobayashi R, Galaktionov K, Beach D. p19Skp1 and p45Skp2 are essential elements of the cyclin A-CDK2 S phase kinase. Cell 1995; 82(6): 915–925
Tsay JJ, Tchou-Wong KM, Greenberg AK, Pass H, Rom WN. Aryl hydrocarbon receptor and lung cancer. Anticancer Res 2013; 33(4): 1247–1256
Ou X, Liu Y, Lei X, Li P, Mi D, Ren L, Guo L, Guo R, Chen T, Hu J, Xiang Z, Mu Z, Chen X, Chen J, Hu K, Jin Q, Wang J, Qian Z. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020; 11(1): 1620
World Health Organization. Tobacco fact sheet. 2020. http://www.who.int/mediacentre/factsheets/fs339/en/ (accessed December 8, 2020)
Carter BD, Abnet CC, Feskanich D, Freedman ND, Hartge P, Lewis CE, Ockene JK, Prentice RL, Speizer FE, Thun MJ, Jacobs EJ. Smoking and mortality—beyond established causes. N Engl J Med 2015; 372(7): 631–640
Centers for Disease Control and Prevention (US), National Center for Chronic Disease Prevention and Health Promotion (US), Office on Smoking and Health (US). How tobacco smoke causes disease: the biology and behavioral basis for smoking-attributable disease: a report of the surgeon general. Atlanta (GA): Centers for Disease Control and Prevention (US). 2010. http://www.ncbi.nlm.nih.gov/books/NBK53017/ (accessed December 8, 2020)
Zhou G. Tobacco, air pollution, environmental carcinogenesis, and thoughts on conquering strategies of lung cancer. Cancer Biol Med 2019; 16(4): 700–713
Liu J, Peng Y, Zhang J, Long J, Liu J, Wei W. Targeting SCF E3 ligases for cancer therapies. Adv Exp Med Biol 2020; 1217: 123–146
Xu JY, Zhang C, Wang X, Zhai L, Ma Y, Mao Y, Qian K, Sun C, Liu Z, Jiang S, Wang M, Feng L, Zhao L, Liu P, Wang B, Zhao X, Xie H, Yang X, Zhao L, Chang Y, Jia J, Wang X, Zhang Y, Wang Y, Yang Y, Wu Z, Yang L, Liu B, Zhao T, Ren S, Sun A, Zhao Y, Ying W, Wang F, Wang G, Zhang Y, Cheng S, Qin J, Qian X, Wang Y, Li J, He F, Xiao T, Tan M. Integrative proteomic characterization of human lung adenocarcinoma. Cell 2020; 182(1): 245–261.e17
Deshotels MR, Xia H, Sriramula S, Lazartigues E, Filipeanu CM. Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism. Hypertension 2014; 64(6): 1368–1375
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).
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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.
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Wang, G., Zhao, Q., Zhang, H. et al. Degradation of SARS-CoV-2 receptor ACE2 by the E3 ubiquitin ligase Skp2 in lung epithelial cells. Front. Med. 15, 252–263 (2021). https://doi.org/10.1007/s11684-021-0837-6
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DOI: https://doi.org/10.1007/s11684-021-0837-6