Researchers have shown that the activation sequence the SARS-CoV-2 S protein is cleaved by the cellular enzyme furin which is also required for the infection of lung cells.
A group of researchers has shown that the activation sequence of the Spike (S) protein of SARS-CoV-2, which causes COVID-19, is cleaved by the cellular enzyme furin. They also found that this cleavage is important for the infection of lung cells.
The study was conducted at the Infection Biology Unit of the German Primate Center (DPZ) – Leibniz Institute for Primate Research. According to the researchers, these results define new starting points for therapy and vaccine research.
The S protein on the SARS-CoV-2 surface serves as a key for the virus to enter host cells. It facilitates viral attachment to cells and fuses the viral and cellular membranes, thereby allowing the virus to deliver its genome into the cell, which is essential for viral replication. For this, activation sequences of the S protein need to be cleaved by cellular enzymes, called proteases. The S protein carries an activation sequence at the so-called S1/S2 cleavage site, which is similar to those observed in highly pathogenic avian influenza viruses, but which has so far not been found in viruses closely related to SARS-CoV-2. The importance of this sequence for the virus was so far unknown.
In their current study, the infection biologists were able to show that the S1/S2 activation sequence of the S protein is cleaved by the cellular protease furin and that this cleavage event is essential for the infection of lung cells. It is also important for the fusion of infected cells with non-infected cells, which might allow the virus to spread in the body without leaving the host cell.
(A) Schematic representation of SARS-CoV-2, the viral S protein and the cleavage sites for furin (green, S1/S2 position; the cleavage sequence is shown below the protein structure) and TMPRSS2 (orange, S2′ position). (B) First, in already infected cells, the enzyme furin cuts the S protein at the S1/S2 site. The S protein then mediates viral attachment to a new host cell. In order to efficiently enter the cell, the S protein still needs to be activated by the enzyme TMPRSS2. Activation by TMPRSS2 is only possible if the S protein has previously been cleaved by furin [credit: Markus Hoffmann].
“Our results suggest that inhibition of furin should block the spread of SARS-CoV-2 in the lung,” said one of the lead researchers Stefan Pöhlmann, head of the Infection Biology Unit at DPZ. “Furthermore, our present study and previous work demonstrate that the virus uses a two-step activation mechanism: In infected cells, the S protein has to be cleaved by the protease furin so that newly formed viruses can then use the protease TMPRSS2 for further cleavage of the spike protein, which is important for the entry into lung cells.”
For a live attenuated vaccine to trigger a strong immune response, the researchers say it has to be able to replicate in the body to a limited extent, for example locally at the site of injection. “SARS-CoV-2 variants, in which the activation sequence for furin has been removed, could be used as a basis for the development of such live attenuated vaccines, since the lack of cleavage of the S protein should greatly limit the spread of the virus in the body. A sufficiently attenuated virus would no longer be able to cause disease, but would still enable the immune system to react to the pathogen and for example, produce neutralising antibodies,” said one of the lead researchers Markus Hoffmann, also first author of the study.
Necessary cookies enable the core functionality of the website, including security, network management and accessibility. These cookies do not store any personal information. You may disable these by changing your browser settings, but this may affect how the website functions.
The cookie is set by GDPR cookie consent to record the user consent for the cookies in the category “Advertising & Targeting”.
This cookie is set by GDPR Cookie Consent WordPress Plugin. The cookie is used to remember the user consent for the cookies under the category “Analytics”.
This cookie is set by GDPR Cookie Consent plugin. The cookie is used to store the user consent for the cookies in the category “Necessary”.
This cookie is set by GDPR Cookie Consent WordPress Plugin. The cookie is used to remember the user consent for the cookies under the category “Performance”.
This cookie is native to PHP applications. The cookie is used to store and identify a users’ unique session ID for the purpose of managing user session on the website. The cookie is a session cookies and is deleted when all the browser windows are closed.
This session cookie is served by our membership/subscription system and controls whether you are able to see content which is only available to logged in users.
The cookie is set by CloudFare. The cookie is used to identify individual clients behind a shared IP address and apply security settings on a per-client basis. It does not correspond to any user ID in the web application and does not store any personally identifiable information.
This cookie is set by Advanced Ads and sets geo-location, user role and user capabilities. It is used by cache busting in Advanced Ads Pro when the appropriate visitor conditions are used.
This cookie is set by Google DoubleClick and stores information about how the user uses the website and any other advertisement before visiting the website. This is used to present users with ads that are relevant to them according to the user profile.
This cookie is set by Linkedin and is used to track visitors on multiple websites, in order to present relevant advertisement based on the visitor’s preferences.
This cookie is set by YouTube. Used to track the information of the embedded YouTube videos on a website.
Analytics cookies collect information about your use of the content, and in combination with previously collected information, are used to measure, understand, and report on your usage of this website.
This cookie is set by LinkedIn. The purpose of the cookie is to enable LinkedIn functionalities on the page.
This cookie is set by YouTube and registers a unique ID for tracking users based on their geographical location
This cookie is set by LinkedIn and is used to store the language preferences of a user to serve up content in that stored language the next time user visit the website.
We embed videos from our official Vimeo channel. When you press play, Vimeo will drop third party cookies to enable the video to play and to see how long a viewer has watched the video. This cookie does not track individuals.
This cookie is set by Spotler and enables it to track the Load Balance Session Queue.
This cookie is set by Spotler and stores the UTM values for the session. UTM values are specific text strings that are appended to URLs that allow Communigator to track the URLs and the UTM values when they get clicked on.
This cookie is set by Google Analytics and is used to calculate visitor, session, campaign data and keep track of site usage for the site’s analytics report. It stores information anonymously and assign a randomly generated number to identify unique visitors.
This cookies is set by Google Universal Analytics to throttle the request rate to limit the collection of data on high traffic sites.
This cookie is set by Google Analytics and is used to store information of how visitors use a website and helps in creating an analytics report of how the website is doing. The data collected including the number visitors, the source where they have come from, and the pages visited in an anonymous form.
Performance cookies include cookies that deliver enhanced functionalities of the website, such as caching. These cookies do not store any personal information.
This cookie is set by Cloudflare content delivery network and, in conjunction with the cookie ‘cf_use_ob’, is used to determine whether it should continue serving “Always Online” until the cookie expires.
This cookie is set by Cloudflare content delivery network and is used to determine whether it should continue serving “Always Online” until the cookie expires.
This session cookie is served by our membership/subscription system and controls which types of content you are able to access.
This cookie is set by Litespeed Server and allows the server to store settings to help improve performance of the site.
This cookie is set by Youtube and is used to track the views of embedded videos.
World news – US – Activation sequence of COVID-19 S protein cleaved by furin protease