Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Insights into the SARS-CoV-2 ORF6 Mechanism of Action

Version 1 : Received: 1 June 2023 / Approved: 8 June 2023 / Online: 8 June 2023 (13:52:38 CEST)

A peer-reviewed article of this Preprint also exists.

Krachmarova, E.; Petkov, P.; Lilkova, E.; Ilieva, N.; Rangelov, M.; Todorova, N.; Malinova, K.; Hristova, R.; Nacheva, G.; Gospodinov, A.; Litov, L. Insights into the SARS-CoV-2 ORF6 Mechanism of Action. Int. J. Mol. Sci. 2023, 24, 11589. Krachmarova, E.; Petkov, P.; Lilkova, E.; Ilieva, N.; Rangelov, M.; Todorova, N.; Malinova, K.; Hristova, R.; Nacheva, G.; Gospodinov, A.; Litov, L. Insights into the SARS-CoV-2 ORF6 Mechanism of Action. Int. J. Mol. Sci. 2023, 24, 11589.

Abstract

ORF6 is responsible for suppressing the immune response of cells infected by the SARS-CoV-2 virus. It is also the most toxic protein of SARS-CoV-2, and its actions are associated with the viral pathogenicity. Here we study in silico and in vitro the structure of the protein, its interaction with RAE1, and the mechanism of action behind its high toxicity. We show both computationally and experimentally that SARS-CoV-2 ORF6, embedded in the membranes of the endoplasmic reticulum, binds to RAE1 and sequesters it in the cytoplasm, thus depleting its availability in the nucleus and impairing nucleocytoplasmic mRNA transport. This negatively affects the cellular genome stability by compromising the cell cycle progression into the S-phase and by promoting the accumulation of RNA-DNA hybrids. Understanding the multiple ways in which ORF6 affects DNA replication may also have important implications for elucidating the pathogenesis of SARS-CoV-2 and developing therapeutic strategies to mitigate its deleterious effects on host cells.

Keywords

SARS-CoV-2 ORF6 – RAE1 binding; 3D molecular structure modelling; molecular dynamics simulations; cell cycle, cyclin E; R-loops; DNA replication stress

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Comments (0)

We encourage comments and feedback from a broad range of readers. See criteria for comments and our Diversity statement.

Leave a public comment
Send a private comment to the author(s)
* All users must log in before leaving a comment
Views 0
Downloads 0
Comments 0
Metrics 0


×
Alerts
Notify me about updates to this article or when a peer-reviewed version is published.
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here.