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Microbiology Independent Research Journal HYPOTHESIS
DOI: 10.18527/2500-2236-2021-8-1-38-40.
Membrane protein of SARS-CoV-2 plays a pivotal role in the availability of active testosterone through its interaction with AKR1C2 enzyme leading to the upregulation of TMPRSS2 protease expression
Vivek Darapaneni * , Anusha Jaldani
Anvek Institute of Biomolecular Research, 55-18-1, Visakhapatnam, India, 530022
ABSTRACT
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease (COVID-19) and ongoing pandemic that has devastated humankind. During the COVID-19 pandemic, it was noticed that the mortality rate in men is higher than that in women. The membrane (M) protein of SARS-CoV-2 plays a pivotal role in the viral life cycle regulating intracellular trafficking and processing of spike (S) protein. In infected individuals, M protein inhibits the conversion of active testosterone to its inactive form through its interaction with Aldo-keto reductase family 1 member C2 (AKR1C2) protein. This leads to the high availability of active testosterone and boosts the formation of its complex with an androgen receptor that in turn promotes the transcription of the transmembrane protease serine 2 (TMPRSS2) gene. TMPRSS2 is known to play a pivotal role in the priming of S protein that is necessary for the SARS-CoV-2 entry into the host cell. Therefore, the interaction of the M protein of SARS-CoV-2 with AKR1C2 eventually leads to the upregulation of the transcription of the TMPRSS2 gene that results in an enhanced viral infection and in turn higher mortality in men. The interaction of M protein with AKR1C2 could be a possible target for SARS-CoV-2 antiviral drug design.
Keywords: SARS-CoV-2, membrane protein, AKR1C2, TMPRSS2, testosterone, pandemic
#For correspondence: Vivek Darapaneni, Anvek Institute of Biomolecular Research, 55-18-1, Visakhapatnam, India-530022, Department of virology and computational biochemistry, email: [email protected]
Citation: Darapaneni V, Jaldani A. Membrane protein of SARS-CoV-2 plays a pivotal role in the availability of active testosterone
through its interaction with AKR1C2 enzyme leading to the upregulation of TMPRSS2 protease expression. MIR J 2021; 8(1), 38-40.
doi: 10.18527/2500-2236-2021-8-1-38-40.
Received: July 6, 2021
Accepted: August 31, 2021
Published: September 27, 2021
Copyright: © 2021 Darapaneni. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International Public License (CC BYNC-SA), which permits the unrestricted use, distribution, and reproduction in any medium, as long as the material is not used for commercial purposes, provided that the original author and source are cited. Conflict of interest: The authors have no commercial or financial interests.
Viruses of the Coronaviridae family are spherical enveloped particles with a large (27-32 kb) single strand RNA(+) genome encoding four main structural and sixteen non-structural proteins [1]. They have been known to infect humans, bats, cattle, horses, swine, dogs, cats, turkeys, rabbits, chickens, rats, and mice, causing gastroenteritis and respiratory tract diseases in their hosts [2]. Human HKU1, NL63 (alphacoronaviruses), and 229E, OC43 (betacoronaviruses) have been known to cause mild respiratory disease in humans. In 2002, a novel severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1, betacoronavirus) crossed over from bats to humans through palm civet cats as the intermediary
host [3]. A decade later in 2012, another betacoronavirus -Middle East Respiratory Syndrome (MERS) crossed over from bats to humans through dromedary camels [4]. In 2019, a novel betacoronavirus had crossed over from bats to humans using Malayan pangolins (Manis javanica) as the intermediate host [5]. This virus was designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 causes a severe respiratory tract infection and has led to a global pandemic resulting in millions of deaths worldwide. As of September 2021, more than 221 million confirmed cases of SARS-CoV-2 infection were reported globally and has led to more than 4.5 million deaths [6].
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Interactions of the SARS-CoV-2 proteins with the host cell receptors, proteins, and organelles are in the focus of intensive research. One of the areas is the regulation of expression of the cell proteins and enzymes by the viral particles. Previously, it was found that SARS-CoV spike (S) protein downregulates the expression of the angiotensin-converting enzyme 2 (ACE2), which is the main receptor for SARS-CoV-2 entry to the cell [7]. Here, we hypothesize that SARS-CoV-2 can upregulate the expression of transmembrane serine 2 protease (TM-PRSS2) that is necessary for priming S protein by means of membrane (M) glycoprotein interaction with Aldo-keto reductase family 1 member C2 (AKR1C2) enzyme.
It is noteworthy that the mortality rate from COVID-19 for males is higher than that for females [8]. The higher mortality rate observed in males can be due to several lifestyle factors. Men have higher rates of tobacco use and alcohol consumption compared to women and, therefore, that could be linked to higher rates of COVID-19 infection and mortality [9]. Moreover, women have two X chromosomes containing immune related genes while men have one X chromosome. Due to incomplete gene silencing on the second X chromosome, women tend to have a stronger innate and adaptive immune response compared to men [10]. In addition, it was shown recently that the plasma concentrations of ACE2 receptor, which SARS-CoV-2 uses to enter the cell, are higher in males than in females [11]. On the other hand, the higher mortality rate of males from COVID-19 has led scientists to speculate that testosterone might also play a role in disease severity.
SARS-CoV-2 has been shown to reduce serum testosterone levels [12, 13]. The M protein is the most abundant envelope protein of SARS-CoV-2 that plays a key role in the assembly of viral particles by interacting with all of the other structural proteins [14]. During the early stage of infection, the M protein of SARS-CoV-2 targets the Leydig cells. This leads to a drop in the ratio of serum testosterone and luteinizing hormone [15]. Androgen receptor activity is stimulated by testosterone and 5a-dihydrotestosterone [16]. The activated androgen receptor was shown to regulate the expression of TMPRSS2 known to prime the S protein of SARS-CoV-2 providing the cleavage at the S1/S2 and the S2' sites necessary for the fusion of viral and cellular membranes [16]. Protease TMPRSS2 plays an important role in SARS-CoV-2
REFERENCES
1. V'Kovski P, Kratzel A, Steiner S, Stalder H, Thiel V. Coronavirus biology and replication: implications for SARS-CoV-2. Nat Rev Microbiol 2021; 19(3), 155-70. doi: 10.1038/s41579-020-00468-6.
infection because it is expressed in epithelial cells, lining the respiratory tract including nose, trachea, alveoli, and type II pneumocytes - the entry ways for the virus into the organism [17].
AKR1C2 enzyme, which belongs to Aldo-keto re-ductase superfamily, deactivates the potent androgen [18-20]. Recently, the high-confidence proximity interaction between the viral M protein and human AKR1C2 was detected by applying proximity-dependent bioti-nylation (BiolD) with the fast-acting miniTurbo enzyme to SARS-CoV-2 proteins in vitro [21] (not peer reviewed preprint). In the healthy cell, testosterone is converted to 5a-dihydrotestosterone by the enzyme 5a-reductase. The obtained 5a-dihydrotestosterone is an active form of testosterone that is converted to inactive testosterone by the enzyme AKR1C2 [20, 22]. The availability of the active testosterone in the healthy cell is controlled by the feedback loop mechanism. As a result, the availability of active testosterone is maintained at an optimum level. The active testosterone binds to the androgen receptor and activates it. The activated androgen receptor in turn promotes the transcription of the TMPRSS2 gene [23]. By binding to AKR1C2 protein, SARS-CoV-2 M protein inhibits the conversion of active testosterone to its inactive form catalyzed by AKR1C2. As a result, the concentration of active testosterone in the cell increases. That makes the interaction of the viral M protein with AKR1C2 enzyme pivotal for the availability of active testosterone in the cell. This interaction eventually leads to the upregulation of the transcription of the TMPRSS2 gene, enhanced viral infection, and in turn higher mortality in men, since they have a much higher testosterone level than women. The discovery of small drug molecules specifically blocking this interaction will counteract the strategy employed by SARS-CoV-2 and lead to the development of new antiviral agents that can help to suppress the spread of the infection.
Here, for the first time, we trace the link between the viral M protein and the changes in the concentration of active testosterone that eventually lead to the upregula-tion of cell TMPRSS2 expression in the course of a SARS-CoV-2 infection. Since the level of the testosterone in males is significantly higher than in females [24], the action of M protein could lead to much higher concentrations of active testosterone in males that eventually leads to their higher mortality rates from SARS-CoV-2.
2. Guy JS, Breslin JJ, Breuhaus B, Vivrette S, Smith LG. Characterization of a coronavirus isolated from a diarrheic foal. J Clin Microbiol 2000; 38(12), 4523-6. doi: 10.1128/JCM.38.12.4523-4526.2000.
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3. Chan-Yeung M, Xu RH. SARS: epidemiology. Respi-rology 2003; 8(Suppl), S9-14. doi: 10.1046/j.1440-1843.2003.00518.x.
4. Mohd HA, Al-Tawfiq JA, Memish ZA. Middle East Respiratory Syndrome Coronavirus (MERS-CoV) origin and animal reservoir. Virol J 2016; 13, 87. doi: 10.1186/s12985-016-0544-0.
5. Andersen KG, Rambaut A, Lipkin WI, Holmes EC, Garry RF. The proximal origin of SARS-CoV-2. Nat Med 2020; 26(4), 450-2. doi: 10.1038/s41591-020-0820-9.
6. WHO coronavirus disease (COVID-19) dashboard. Available: https://covid19.who.int/. Date accessed: September, 2021.
7. Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, et al. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005; 11(8), 875-9. doi: 10.1038/nm1267.
8. Bienvenu LA, Noonan J, Wang X, Peter K. Higher mortality of COVID-19 in males: sex differences in immune response and cardiovascular comorbidi-ties. Cardiovasc Res 2020; 116(14), 2197-206. doi: 10.1093/cvr/cvaa284.
9. Griffith DM, Sharma G, Holliday CS, Enyia OK, Val-liere M, Semlow AR, et al. Men and COVID-19: A Bio-psychosocial Approach to Understanding Sex Differences in Mortality and Recommendations for Practice and Policy Interventions. Prev Chronic Dis 2020; 17, E63. doi: 10.5888/pcd17.200247.
10. Sharma G, Volgman AS, Michos ED. Sex Differences in Mortality From COVID-19 Pandemic: Are Men Vulnerable and Women Protected? JACC Case Rep 2020; 2(9), 1407-10. doi: 10.1016/j.jaccas.2020.04.027.
11. Sama IE, Ravera A, Santema BT, van Goor H, Ter Maaten JM, Cleland JGF, et al. Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors. Eur Heart J 2020; 41(19), 1810-7. doi: 10.1093/eurheartj/ ehaa373.
12. Dutta S, Sengupta P. SARS-CoV-2 and Male Infertility: Possible Multifaceted Pathology. Reprod Sci 2021; 28(1), 23-6. doi: 10.1007/s43032-020-00261-z.
13. Dutta S, Sengupta P. SARS-CoV-2 infection, oxidative stress and male reproductive hormones: can testicu-lar-adrenal crosstalk be ruled-out? J Basic Clin Physiol Pharmacol 2020; 31(6), 20200205. doi: 10.1515/jb-cpp-2020-0205.
14. Masters PS. The molecular biology of coronaviruses. Adv Virus Res 2006; 66, 193-292. doi: 10.1016/S0065-3527(06)66005-3.
15. Ma L, Xie W, Li D, Shi L, Mao Y, Xiong Y, Zhang Y, Zhang M. Effect of SARS-CoV-2 infection upon male gonadal functions: a single centre-based study. Me-dRxiv 2020. doi: 10.1101/2020.03.21.20037267.
16. Mollica V, Rizzo A, Massari F. The pivotal role of TM-PRSS2 in coronavirus disease 2019 and prostate cancer. Future Oncol 2020; 16(27), 2029-33. doi: 10.2217/ fon-2020-0571.
17. Donaldson SH, Hirsh A, Li DC, Holloway G, Chao J, Boucher RC, et al. Regulation of the epithelial sodium channel by serine proteases in human airways. J Biol Chem 2002; 277(10), 8338-45. doi: 10.1074/jbc. M105044200.
18. Penning TM, Burczynski ME, Jez JM, Hung CF, Lin HK, Ma H, et al. Human 3alpha-hydroxysteroid dehydrogenase isoforms (AKR1C1-AKR1C4) of the aldo-ke-to reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones. Biochem J 2000; 351(1), 67-77. doi: 10.1042/02646021:3510067.
19. Penning TM, Jin Y, Steckelbroeck S, Lanisnik Rizner T, Lewis M. Structure-function of human 3 alpha-hydroxysteroid dehydrogenases: genes and proteins. Mol Cell Endocrinol 2004; 215(1-2), 63-72. doi: 10.1016/j.mce.2003.11.006.
20. Penning TM, Jin Y, Rizner TL, Bauman DR. Pre-receptor regulation of the androgen receptor. Mol Cell Endocrinol 2008; 281(1-2), 1-8. doi: 10.1016/j. mce.2007.10.008.
21. Samavarchi-Tehrani P, Abdouni H, Knight JDR, As-tori A, Samson R, Lin Z-Y, Kim D-K, Knapp JJ, St-Ger-main J, Go CD. A SARS-CoV-2 - host proximity interac-tome. bioRxiv 2020. doi: 10.1101/2020.09.03.282103.
22. Yee DJ, Balsanek V, Bauman DR, Penning TM, Sames D. Fluorogenic metabolic probes for direct activity readout of redox enzymes: Selective measurement of human AKR1C2 in living cells. Proc Natl Acad Sci USA 2006; 103(36), 13304-9. doi: 10.1073/ pnas.0604672103.
23. Lucas JM, Heinlein C, Kim T, Hernandez SA, Malik MS, True LD, et al. The androgen-regulated protease TMPRSS2 activates a proteolytic cascade involving components of the tumor microenvironment and promotes prostate cancer metastasis. Cancer Discov 2014; 4(11), 1310-25. doi: 10.1158/2159-8290.CD-13-1010.
24. Chernecky CC, Berger BJ. Laboratory Tests and Diagnostic Procedures (eBook). Elsevier Health Sciences, 2012. ISBN 978-1-4557-4502-9.
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