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Title: Functional complexes of Angiotensin-converting enzyme 2 and renin-angiotensin system receptors: expression in adult but not fetal lung tissue
Author: Franco Fernández, Rafael
Lillo, Alejandro
Rivas Santisteban, Rafael
Rodríguez Pérez, Ana I.
Reyes-Resina, Irene
Labandeira García, José L.
Navarro Brugal, Gemma
Keywords: COVID-19
Receptors cel·lulars
Malalties dels pulmons
Cell receptors
Pulmonary diseases
Issue Date: 16-Dec-2020
Publisher: MDPI
Abstract: Angiotensin-converting enzyme 2 (ACE2) is a membrane peptidase and a componentof the renin-angiotensin system (RAS) that has been found in cells of all organs, including thelungs. While ACE2 has been identified as the receptor for severe acute respiratory syndrome (SARS)coronaviruses, the mechanism underlying cell entry remains unknown. Human immunodeficiencyvirus infects target cells via CXC chemokine receptor 4 (CXCR4)-mediated endocytosis. Furthermore,CXCR4 interacts with dipeptidyl peptidase-4 (CD26/DPPIV), an enzyme that cleaves CXCL12/SDF-1,which is the chemokine that activates this receptor. By analogy, we hypothesized that ACE2 mightalso be capable of interactions with RAS-associated G-protein coupled receptors. Using resonanceenergy transfer and cAMP and mitogen-activated protein kinase signaling assays, we found thathuman ACE2 interacts with RAS-related receptors, namely the angiotensin II type 1 receptor (AT1R),the angiotensin II type 2 receptor (AT2R), and the MAS1 oncogene receptor (MasR). Although theseinteractions led to various alterations of signal transduction, but, more importantly, ligand binding toAT1R resulted in the downregulation of ACE2 cell surface expression, while ligand binding to AT2R,but not to MasR, resulted in upregulation of ACE2 cell surface expression. Proximity ligation assaysperformed in situ revealed macromolecular complexes containing ACE2 and AT1R, AT2R or MasR inadult but not fetal mouse lung tissue. These findings highlight the relevance of RAS in SARS-CoV-2infection and the role of ACE2-containing complexes as potential therapeutic targets.
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It is part of: International Journal of Molecular Sciences, 2020, vol. 21(24), num. 9602
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ISSN: 1661-6596
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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