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Inhibition of Host Factor Enzyme Inhibits Ebola Virus in Cell Culture; Host Phosphatase Is Potential Target for Therapeutic Intervention

A single enzyme. That is all the researchers behind a new study need to manipulate to prevent the feared Ebola virus from spreading. Because with the enzyme they also take away the virus' ability to copy itself and thus produce more virus particles and more infection. The study was published online on December 28, 2017 in Molecular Cell and was conducted by researchers from the University of Copenhagen and Phillips Universität Marburg in Germany. The article is titled “The Ebola Virus Nucleoprotein Recruits the Host PP2A-B56 Phosphatase to Activate Transcriptional Support Activity of VP30.” “When the Ebola virus enters the human cell, its only purpose is to copy itself, fast. First, it must copy all its proteins, then its genetic material. But by inhibiting a specific enzyme we rob the Ebola virus of its ability to copy itself. And that may potentially prevent an Ebola infection from spreading,” says Professor Jakob Nilsson from the Novo Nordisk Foundation Center for Protein Research. A few years ago, the Ebola virus ravaged West Africa, where thousands of people died from the extremely infectious Ebola infection. Once you are infected, all you can do is hope that your own immune system is able to kill the infection because there is currently no available treatment. However, the researchers behind the new study have found what is called a new host factor for Ebola virus. It can be described as a small part of the host's - for example the human body's - own cells, which the Ebola virus uses to copy itself and produce more infection. The virus uses the host factor enzyme PP2A-B56 to start producing proteins. So, if the researchers switch off PP2A-B56, the virus' ability to copy itself and produce more infection is never “switched on.”

“When we inhibit the PP2A-B56 enzyme, we remove the first link in a long process, which ends with Ebola spreading. And we can tell that it works. The Ebola infection in cell cultures where we have inhibited the PP2A-B56 enzyme is 10 times smaller after 24 hours compared to infections where we have not inhibited this enzyme,” says Professor Nilsson.

But because the researchers have so far focused on cell cultures, there is still work to be done before their results can be used to treat people infected with Ebola. Initially the researchers hope to be able to test it on animals and, in the long term, develop a drug that inhibits the relevant enzyme.

The potential of the new discovery may turn out to work on other viruses too, because the structure of Ebola virus is very similar to the other so-called filoviruses, Lloviu virus and Marburg virus. But whether the same mechanisms apply to them too still needs to be uncovered.

MORE DETAIL

In the Summary published in Molecular Cell, the authors write the following. “Transcription of the Ebola virus genome depends on the viral transcription factor VP30 in its unphosphorylated form, but the underlying molecular mechanism of VP30 dephosphorylation is unknown. Here we show that the Ebola virus nucleoprotein (NP) recruits the host PP2A-B56 protein phosphatase through a B56-binding LxxIxE motif and that this motif is essential for VP30 dephosphorylation and viral transcription. The LxxIxE motif and the binding site of VP30 in NP are in close proximity, and both binding sites are required for the dephosphorylation of VP30. We generate a specific inhibitor of PP2A-B56 and show that it suppresses Ebola virus transcription and infection. This work dissects the molecular mechanism of VP30 dephosphorylation by PP2A-B56, and it pinpoints this phosphatase as a potential target for therapeutic intervention.”

[Press release] [Molecular Cell abstract]