ACE2 Nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues

Abstract

With the emergence of the novel coronavirus SARS-CoV-2 since December 2019, more than 65 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases, leading to over 1.5 million deaths globally. Despite the collaborative and concerted research efforts that have been made, no effective medication for COVID-19 (coronavirus disease-2019) is currently available. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) as an initial mediator for viral attachment and host cell invasion. ACE2 is widely distributed in the human tissues including the cell surface of lung cells which represent the primary site of the infection. Inhibiting or reducing cell surface availability of ACE2 represents a promising therapy for tackling COVID-19. In this context, most ACE2-based therapeutic strategies have aimed to tackle the virus through the use of angiotensin-converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2, which does not directly aim to reduce its membrane availability. However, through this review, we present a different perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, and shedding and cellular trafficking pathways including the internalization are not well elucidated in literature. Therefore, we hereby present an overview of the fate of newly synthesized ACE2, its post translational modifications, and what is known of its trafficking pathways. In addition, we highlight the possibility that some of the identified ACE2 missense variants might affect its trafficking efficiency and localization and hence may explain some of the observed variable severity of SARS-CoV-2 infections. Moreover, an extensive understanding of these processes is necessarily required to evaluate the potential use of ACE2 as a credible therapeutic target.

Keywords: Angiotensin-converting enzyme 2 (ACE2); COVID-19; Localization; SARS-CoV-2; Trafficking.

Fig. 1

ACE, ACE2 and Collectrin chromosomal location and cellular localizations. The 3 type I transmembrane proteins ACE, ACE2, and collectrin located in the plasma membrane with activity differences. ACE acts as a dipeptidyl carboxypeptidase with 2 catalytic active sites for angiotensin I (Ang I) and angiotensin (1–9) (Ang (1–9)), whereas ACE2 acts as a monocarboxypeptidase possessing one active site that cleaves Ang I and angiotensin II (Ang II). However, collectrin lacks a catalytic activity in its extracellular domain. ACE2 and collectrin gene (CLTRN) are both mapped to chromosome Xp22.2 where ACE is located on chromosome 17q23.3

Fig. 2

ACE2 3D-structure and isoforms. a 3D structure of ACE2 adopted from Towler et al. [36] and drawn in iCn3D using PBD ID: 1R4L. The structure was modified based on the newly identified N-glycosylation sites labeled in black. b ACE2 exists in 4 different isoforms along with a soluble form cleaved at residues 716–741 and constitutes 555 amino acids lacking the transmembrane collectrin homology domain. ACE2 isoform 2 shows a truncation of the full-length ACE2 with 100% homology in the 786 residues. ACE2 isoform 3 displays deletions in the transmembrane and collectrin homology domains leading to 95% similarity with ACE2 represented by gradient color in the corresponding domains. The fourth isoform with shorter N-terminus, lacking the carboxypeptidase activity and inability to bind to SARS-CoV-2. SP signal peptide

Fig. 3

ACE2 synthesis, trafficking, proteolysis, and internalization. a Synthesis of ACE2 protein and its translocation to the endoplasmic reticulum (ER) through Golgi apparatus towards the plasma membrane via transport vesicles. Red stars correspond to post-translational modifications. b Truncation of ACE2 by ADAM17 and the release of soluble ACE2 (sACE2) into the extracellular environment. c Internalization of ACE2 in response to increased angiotensin II (Ang II) via ubiquitylation of ACE2 and interaction with angiotensin type I receptor (AT1R). The latter complex is endocytosed where ACE2 is degraded by the lysosome and AT1R is recycled and transported back to the membrane. d ACE2 internalization in response to SARS-CoV-2 binding via clathrin-mediated endocytosis. ACE2 is recycled and transported to the membrane and SARS-CoV-2 is replicated inside the host cell