Maeda, Y.; Toyoda, M.; Kuwata, T.; Terasawa, H.; Tokugawa, U.; Monde, K.; Sawa, T.; Ueno, T.; Matsushita, S. Differential Ability of Spike Protein of SARS-CoV-2 Variants to Downregulate ACE2. Int. J. Mol. Sci.2024, 25, 1353.
Maeda, Y.; Toyoda, M.; Kuwata, T.; Terasawa, H.; Tokugawa, U.; Monde, K.; Sawa, T.; Ueno, T.; Matsushita, S. Differential Ability of Spike Protein of SARS-CoV-2 Variants to Downregulate ACE2. Int. J. Mol. Sci. 2024, 25, 1353.
Maeda, Y.; Toyoda, M.; Kuwata, T.; Terasawa, H.; Tokugawa, U.; Monde, K.; Sawa, T.; Ueno, T.; Matsushita, S. Differential Ability of Spike Protein of SARS-CoV-2 Variants to Downregulate ACE2. Int. J. Mol. Sci.2024, 25, 1353.
Maeda, Y.; Toyoda, M.; Kuwata, T.; Terasawa, H.; Tokugawa, U.; Monde, K.; Sawa, T.; Ueno, T.; Matsushita, S. Differential Ability of Spike Protein of SARS-CoV-2 Variants to Downregulate ACE2. Int. J. Mol. Sci. 2024, 25, 1353.
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of corona-virus disease 19 (COVID-19) and employs angiotensin-converting enzyme 2 (ACE2) as the recep-tor. Although the expression of ACE2 is crucial for cellular entry, we found that the interaction of ACE2 with the Spike (S) protein in the same cells led to its downregulation through degradation in the lysosomal compartment via the endocytic pathway. Interestingly, the ability of the S protein from previous variants of concern (VOCs) to downregulate ACE2 was variant-dependent and correlated with disease severity. The S protein from the Omicron variant, associated with milder disease, exhibited a lower capacity to downregulate ACE2 than that of the Delta variant, which is linked to a higher risk of hospitalization. Chimeric studies between the S proteins from the Delta and Omicron variants revealed that both the receptor-binding domain (RBD) and S2 subunit played crucial roles in the reduced ACE2 downregulation activity observed in the Omicron var-iant. In contrast, three mutations (L452R/P681R/D950N) located in the RBD, S1/S2 cleavage site, and HR1 domain were identified as essential for the higher ACE2 downregulation activity ob-served in the Delta variant than that in the other VOCs. Our results suggested that dysregulation of the renin-angiotensin system due to the ACE2 downregulation activity of the S protein of SARS-CoV-2 may play a key role in the pathogenesis of COVID-19.
Keywords
SARS-CoV-2; COVID-19; ACE2; downregulation; S protein; VOCs
Subject
Medicine and Pharmacology, Epidemiology and Infectious Diseases
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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