ACE2 can be described as an enzyme, a transporter, and through its role as a receptor. As an enzyme, it is an important regulator of the RAAS, a major regulator system of human physiology, controlling blood pressure, volume, and electrolytes, thus affecting the heart, vasculature, and kidney, mainly through the actions of the octapeptide hormone angiotensin II (Ang II) [3,4] (Figure 1). As expected, ACE2 is highly expressed in endothelial cells from the heart, kidney, upper airways, lungs, gut, liver, and testis [5]. Specifically, ACE2, as a zinc metallopeptidase with carboxypeptidase activity, hydrolyzes Ang II. Ang II is a vasoconstrictor that promotes inflammation and increases oxidative stress and apoptosis through the AT1 (angiotensin II type 1) receptors. ACE2, as a regulator, prevents its accumulation and thus minimizes its effect [5,6,7] (Figure 2a). When there is a reduced protein expression of ACE2 and, consequently, a buildup of Ang II, an increase in hypertension is observed, as shown in several animal models [5,8]. Additionally, ACE2 also plays an important role in glucose homeostasis. It has been shown that ACE2 overexpression in diabetic mice improves islet function and glycemic control [9,10].

ACE2 acts as the receptor for SARS-CoV and SARS-CoV-2. The binding of these viruses to the membrane-bound form of the ACE2 receptor is necessary for virus internalization [11]. The reason why COVID-19 has had a much bigger global impact than SARS is due to biding affinity. In SARS-CoV-2, the region that interacts with the metallopeptidase domain of ACE2 is the receptor-binding domain (RBD) in the S protein. This binding causes structural changes in the S protein, exposing the cleavage sites at the S1/S2 or adjacent regions, which are attacked by host cellular proteases [12]. The RBD of SARS-CoV-2 has a stronger binding affinity with the ACE2 receptor due to the five out of six changes of vital amino acids, enhancing the connection with stronger hydrophobic interactions, despite the close linkage of the viruses [5]. These five variations are in the amino acids Leu455, Phe486, Gln493, Ser494, and Asn501 in SARS-CoV-2. Out of the five, positions Gln493 and Asn501 have been highlighted as the most critical amino acid residues important for van der Waals interactions and hydrogen bonding [13].

In addition to ACE2, SARS-CoV-2 requires further processing to enter the host cell. Transmembrane Serine Protease 2 (TMPRSS2), a serine endopeptidase primes the S protein. This entails the cleaving of the S protein at the subunit 1 and 2 sites, as well as at the S2 site [14]. This allows for a fusing of both the cellular and viral membranes. SARS-CoV-2 also uses another protease for S protein priming, the endosomal cysteine proteases cathepsin B and L (CatB/L). SARS-CoV requires TMPRSS2 processing for viral spread, while CATB/L activity can be dispensable. This is not the case for SARS-CoV-2, which requires both TMPRSS2 and CATB/L activity for viral entry [14]. There are also data that suggest ACE2 is shed from membranes with the help of TMPRSS2, which leads to membrane fusion and the cellular uptake of the virus [15,16] (Figure 2b).

ACE2 is a type I transmembrane protein of 805 amino acids containing an ectodomain (enzyme) and a C-terminal transmembrane anchor [17]. The extracellular N-terminal domain contains a zinc metallopeptidase catalytic site and the spike protein binding site where SARS-CoV and SARS-CoV-2 bind (amino acids 1–740), a short transmembrane domain (amino acids 741–763), and a C-terminal domain facing the cytosol [18,19,20] (Figure 3). ACE2 has two functional forms, as a membrane bound receptor and as a soluble form (sACE2) with 555 amino acids [21,22]. The enzyme ADAM-17 (a disintegrin and metallopeptidase domain 17) or TACE (tumor necrosis factor-converting enzyme) is responsible for cleaving ACE2 at amino acids 716–741 [23,24]. ADAM-17, a type I transmembrane protein belonging to the family of zinc-dependent metalloproteases, catalyzes ACE2 ectodomain shedding, compromising the role of ACE2 in regulating the RAAS. sACE2 maintains carboxypeptidase activity and thus the ability to bind to the RBD region in the viral S protein. In a study by Haga et al., in 2008, both the cytoplasmic tails of ADAM-17 and of ACE2 were shown to be necessary for SARS-CoV to infect host cells; however, the underlying mechanism is still unknown [25,26]. During SARS-CoV-2 infection, the binding of the ACE2 receptor to the viral S1 protein promotes the cleavage of the ACE2 ectodomain by ADAM-17 and the intracellular C-terminal domain by TMPRSS2, thus facilitating SARS-CoV-2 entry [27] (Figure 2c). ACE2 is internalized with the viral particles into endosomes. Together, ACE2 processing and internalization reduce its expression in the membrane, affecting the regulation of Ang II and promoting RAAS imbalance and the activation of the AT1 receptors [7,28]. In addition, ADAM-17 expression is also increased by ACE2 and SARS-CoV-2 internalization, further increasing ACE2 ectodomain proteolytic cleavage and sACE2 production.

sACE2 can be beneficial for preventing COVID-19. Many studies have reported its preventive role as a therapeutic agent due to its ability to bind to circulating SARS-CoV-2 and thus block viral entry [29,30,31] (Figure 2c). However, other researchers view sACE2 as another key to enter and infect non-ACE2-expressing cells. Yeung et al. showed that sACE2 facilitates SARS-CoV-2 entry through receptor-mediated endocytosis and thus enables its entrance in various tissues [32].

2. ACE2 Variants and COVID-19 Susceptibility