Issue 25, 2023

The ACE2 receptor accelerates but is not biochemically required for SARS-CoV-2 membrane fusion

Abstract

The SARS-CoV-2 coronavirus infects human cells via the ACE2 receptor. Structural evidence suggests that ACE2 may not just serve as an attachment factor but also conformationally activate the SARS-CoV-2 spike protein for membrane fusion. Here, we test that hypothesis directly, using DNA-lipid tethering as a synthetic attachment factor in place of ACE2. We find that SARS-CoV-2 pseudovirus and virus-like particles are capable of membrane fusion without ACE2 if activated with an appropriate protease. Thus, ACE2 is not biochemically required for SARS-CoV-2 membrane fusion. However, addition of soluble ACE2 speeds up the fusion reaction. On a per-spike level, ACE2 appears to promote activation for fusion and then subsequent inactivation if an appropriate protease is not present. Kinetic analysis suggests at least two rate-limiting steps for SARS-CoV-2 membrane fusion, one of which is ACE2 dependent and one of which is not. Since ACE2 serves as a high-affinity attachment factor on human cells, the possibility to replace it with other factors implies a flatter fitness landscape for host adaptation by SARS-CoV-2 and future related coronaviruses.

Graphical abstract: The ACE2 receptor accelerates but is not biochemically required for SARS-CoV-2 membrane fusion

Supplementary files

Article information

Article type
Edge Article
Submitted
20 dec 2022
Accepted
05 jun 2023
First published
05 jun 2023
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY-NC license

Chem. Sci., 2023,14, 6997-7004

The ACE2 receptor accelerates but is not biochemically required for SARS-CoV-2 membrane fusion

M. Cervantes, T. Hess, G. G. Morbioli, A. Sengar and P. M. Kasson, Chem. Sci., 2023, 14, 6997 DOI: 10.1039/D2SC06967A

This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence. You can use material from this article in other publications, without requesting further permission from the RSC, provided that the correct acknowledgement is given and it is not used for commercial purposes.

To request permission to reproduce material from this article in a commercial publication, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party commercial publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements