ACE2 Nascence, Trafficking and SARS-CoV-2 Pathogenesis: The Saga Continues

Abstract

With the emergence of the novel corona virus SARS-CoV-2 since December 2019, more than 43 million cases have been reported worldwide. This virus has shown high infectivity and severe symptoms in some cases leading to over 1 million deaths globally. Despite the collaborative and concerted research efforts that has been made, no effective treatment for COVID-19 (corona virus 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 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 achieve this through the use of angiotensin converting enzyme (ACE) inhibitors or neutralizing the virus by exogenous administration of ACE2. However, through this review, we present another perspective focusing on the subcellular localization and trafficking of ACE2. Membrane targeting of ACE2, shedding and its cellular trafficking pathways including internalization are not well elucidated. Therefore, hereby we present an overview on the fate of newly synthesized ACE2, its post translational modifications, 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. Extensive understanding of these processes is necessary to evaluate the potential use of ACE2 as a credible therapeutic target.

SARS‐CoV‐2 biology and variants: anticipation of viral evolution and what needs to be done

“…In contrast, ACE2 cleavage was dispensable for activation of the viral S protein for SARS-CoV-1 (Heurich et al, 2014). Yet another protease may be involved as a receptor: dipeptidyl peptidase 4 (DPP-4) has been suggested to be a co-receptor for SARS-CoV-2, but this has not been further substantiated (Badawi and Ali, 2021). In any event, the role of proteolysis in the first steps of infection has to be carefully surveyed as the epidemic develops.…”

COVID-19: A Redox Disease—What a Stress Pandemic Can Teach Us About Resilience and What We May Learn from the Reactive Species Interactome About Its Treatment

“…Recent investigations highlighted the significance of the oral cavity and salivary glands for transmission and disease propagation (166). While interactions between the viral S-protein and ACE2 are important for infection of many cell types with SARS-CoV-2, several alternative receptors and enhancing mechanisms have been identified (16,77,259,330,337) but little is known of their connection to the redox system. In the human lung, the tyrosine-protein kinase receptor AXL rather than ACE2 may be the key cellular receptor for SARS-CoV-2 infection (445); its activation elicits ROS accumulation (165).…”