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.
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
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.