Differential Downregulation of ACE2 by the Spike Proteins of Severe Acute Respiratory Syndrome Coronavirus and Human Coronavirus NL63

Abstract

The human coronaviruses (CoVs) severe acute respiratory syndrome (SARS)-CoV and NL63 employ angiotensin-converting enzyme 2 (ACE2) for cell entry. It was shown that recombinant SARS-CoV spike protein (SARS-S) downregulates ACE2 expression and thereby promotes lung injury. Whether NL63-S exerts a similar activity is yet unknown. We found that recombinant SARS-S bound to ACE2 and induced ACE2 shedding with higher efficiency than NL63-S. Shedding most likely accounted for the previously observed ACE2 downregulation but was dispensable for viral replication. Finally, SARS-CoV but not NL63 replicated efficiently in ACE2-positive Vero cells and reduced ACE2 expression, indicating robust receptor interference in the context of SARS-CoV but not NL63 infection.

Downregulation of angiotensin-converting enzyme 2 by the neuraminidase protein of influenza A (H1N1) virus

“…SARS-CoV downregulated its receptor ACE2 and induced TACE-dependent ACE2 shedding. ACE2 shedding most likely accounted for SARS-CoV induced ACE2 downregulation (Glowacka et al, 2010). However, influenza virus-induced ACE2 decline was most likely related to ACE2 protein degradation by proteasome pathway rather than ACE2 shedding.…”

Proteolytic activation of the SARS-coronavirus spike protein: Cutting enzymes at the cutting edge of antiviral research

“…Furthermore, it was demonstrated that an ADAM17 inhibitor displays modest antiviral activity in SARS-CoV infected mice (Haga et al, 2010). Reduced cellular levels of ACE2 were noted in SARS-CoV infected cell cultures (Glowacka et al, 2010; Haga et al, 2008), animals (Kuba et al, 2005; Rockx et al, 2009) and humans (Oudit et al, 2009) and might be accounted for by SARS-S-induced shedding of ACE2. Notably, ACE2 expression protects mice against experimentally induced lung injury (Imai et al, 2005; Kuba et al, 2005).…”

Trilogy of ACE2: A peptidase in the renin–angiotensin system, a SARS receptor, and a partner for amino acid transporters

“…Interestingly, in rabbit atherosclerosis models, co-localization of ACE2 in CD34+ Oct4+ cells was also observed in the atherosclerotic plaques (Zulli et al, 2006). However, it should be noted that ACE2 expression is downregulated by SARS infection at the transcriptional and posttranslational level (Glowacka et al, 2010;Inoue et al, 2007;Haga et al, 2008;Wang et al, 2008), and therefore one would actually expect low ACE2-immunoreactivity in SARS-CoV infected cells. Nevertheless, these observations suggest a potential role of ACE2 for lung stem/ progenitor cells, in addition to type-1/type-2 pneumocytes, in the continued destruction of lung tissues and apparent loss in the capacity for lung repair after SARS-CoV infections.…”

“…Moreover, calmodulinbinding sites were identified in the cytoplasmic tail of ACE2 (Lambert et al, 2008), and inhibition of calmodulin increased the release of the ACE2 ectodomain to the culture supernatants (Lambert et al, 2008;Lai et al, 2009). Although the physiological role of ACE2 ectodomain shedding remains elusive as roles for circulating ACE2 and remnant Cterminal domain have yet to be identified, shedding seems to be involved in SARS-CoV cellular entry and replication and an ADAM17 inhibitor suppresses SARS-CoV replication in vitro (Glowacka et al, 2010;Haga et al, 2008).…”