ACE and ACE2: insights from Drosophila and implications for COVID-19

Abstract

Angiotensin-converting enzyme (ACE) and its homologue ACE2 are key regulators of the renin-angiotensin system and thereby cardiovascular function through their zinc-metallopeptidase activity on vasoactive peptides. ACE2 also serves as the receptor for the cellular entry of various coronaviruses including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for the coronavirus disease 2019 (COVID-19). The unprecedented scale of the COVID-19 pandemic has spurred the use of mammalian models to investigate the SARS-ACE2 relationship and knowledge gained from such research has accelerated development of vaccines and therapeutics. Recent studies have just started to underscore the utility of the fruit fly Drosophila melanogaster as a model system to study virus-host interactions and pathogenicity. Notably, the remarkable existence of catalytically functional ACE and ACE2 orthologues in Drosophila, discovered more than two decades ago, provides a unique opportunity for further developing this model organism to better understand COVID-19 in addition to identifying coronavirus preventative and therapeutic interventions targeting ACE2. Here, we review the studies that revealed crucial insights on the biochemistry and physiology of Ance and Acer, two out of the six Drosophila ACE family members with the greatest homology to human ACE and ACE2. We highlight shared in vivo functions outside of the renin-angiotensin system, which is not conserved in flies. Importantly, we identify knowledge gaps that can be filled by further research and outline ways that can raise Drosophila to a powerful model system to combat SARS-CoV-2 and its threatening vaccine-evading variants.

Keywords: ACE; ACE2; Acer; Ance; COVID-19; Drosophila; SARS-CoV-2.

Figure 1

ACE family members in humans and fruit flies. Active site domains containing the fully conserved zinc-binding motif are indicated in red. In humans, ACE and ACE2 are integral-membrane proteins whereas in Drosophila, only Ance-3 is predicted to be membrane-bound. Figure created with BioRender.

Figure 2

Shared functions of ACE proteins in humans and Drosophila. Functional studies in fruit flies have revealed five mechanisms in which there is an overlapping function between Ance or Acer and its human homologue. Functions, which might be conserved, are most probably RAS-independent considering that Drosophila has an open circulatory system. Figure created with BioRender.