It is not fully understood how the SARS-CoV-2 coronavirus initiates its replication process during infection. In a new study, researchers from the Helmholtz Institute in Germany and other research institutions have found for the first time that the human protein SND1 works together with the SARS-CoV-2 protein NSP9 to stimulate this viral gene replication program in infected cells. To their surprise, they found that NSP9 is the first building block for the generation of new viral genetic material. These findings are significant for further basic research, but may also open up new avenues for treating COVID-19 and other infectious diseases caused by coronaviruses. The findings were published online October 3, 2023, in the journal Cell under the title "SND1 binds SARS-CoV-2 negative-sense RNA and promotes viral RNA synthesis through NSP9 ".
SARS-CoV-2 is the coronavirus that causes COVID-19 disease, which has killed nearly 7 million people worldwide to date. The RNA genome of this virus contains instructions for building new copies of the virus. When SARS-CoV-2 infects a host cell, it takes over the cell's gene expression machinery to replicate and proliferate itself. This requires the construction of multiple types of viral RNA, each of which has a specific role in the replication cycle of this virus.
In the new study, a team of researchers led by the paper's corresponding author, Mathias Munschauer, focused on the interactions between different SARS-CoV-2 RNAs and human host cell proteins.
Munschauer explains, "While we have learned a lot about the function of the virus' own proteins, we are still investigating how proteins in infected human cells affect the replication capacity of SARS-CoV-2."
Nora Schmidt, co-first author of the paper and a postdoctoral fellow in Munschauer's lab, said, "We found that a host protein called SND1 recognizes a specific type of viral RNA called negative-stranded RNA. this negative-stranded RNA is a template for amplifying new viral RNA molecules, but it is not translated into protein. "
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SND1 has been shown to be essential for the efficient replication of viral RNA by this virus in human cells. It not only binds to the negative-strand viral RNA synthesis template, but also interacts with a viral protein called NSP9.
Yuanjie Wei, co-first author of the paper, is pleased to report, "Our study uncovered a key detail. Stimulated by the human factor SND1, this virus utilizes its own protein, NSP9, as a primer to initiate RNA production."
With SND1, these authors describe the first host protein confirmed to recognize negative-stranded viral RNA. They were also able to demonstrate for the first time that the binding of this human protein to SARS-CoV-2 RNA and its interaction with NSP9 helps initiate viral replication. If the host factor SND1 is absent, NSP9's ability to initiate viral RNA synthesis is impaired and viral RNA is produced less efficiently.
Image from Cell, 2023, doi:10.1016/j.cell.2023.09.002.
These authors conclude that these findings are surprising and prompt an update of textbook knowledge about coronaviruses. In addition to basic research, future medicine will benefit from new therapeutic targets. In addition, there is evidence that rare sequence variants in the SND1 gene may be associated with severe COVID-19 infection and hospitalization.
In this case, further studies are needed. It would also be interesting to analyze in the future whether the functions of SND1 and NSP9 are preserved in other coronaviruses or whether the human protein SND1 also stimulates the replication of other RNA viruses that cause human diseases, such as influenza virus or respiratory syncytial virus. In addition, future research efforts will need to elucidate the exact molecular features that drive the binding of SND1 to the negative-strand RNA of SARS-CoV-2 or other coronaviruses.
