Another way viruses modify the machinery of the cells they invade

A new mechanism has been discovered by which viruses modify the cellular machinery so that it better reads the instructions in the genome of the invading virus and thus produces high numbers of viral progeny.

The finding was made by the Molecular Virology Research Group at Pompeu Fabra University (UPF) in Barcelona in collaboration with the Epitranscryptome and RNA Dynamics group at the Center for Genomic Regulation (CRG) in Barcelona. The study has been led by Juana Díez from UPF.

Genes contain the information necessary for the formation of proteins, complex molecules essential for life that are formed from amino acids. The reading of this information is carried out in two main stages, on the one hand, transcription, in which the information of the gene (DNA) is transferred to a molecule called messenger RNA (mRNA). The mRNA consists of a “text” made up of nucleotide triplets (the letters GCT, CAT…). Each triplet corresponds to an amino acid. The second phase is translation, in which a molecule called transfer RNA (tRNA) recognizes each triplet and acts as a translator, bringing the corresponding amino acid. Proteins are built through this process.

There are 61 codons and 20 amino acids, so many triplets code for the same amino acid. Each organism preferentially uses one of these triplets (optimal triplet) because it has a higher concentration of the tRNA that recognizes that triplet. Therefore, when the “text” of the mRNA is enriched in optimal triplets, the proteins will be generated quickly and efficiently, while when they are enriched in non-optimal triplets, the efficiency of expression will decrease because the related tRNAs are not very abundant.

From left to right: René Böetcher, Juana Díez and Jennifer Jungfleisch, from the research team. (Photo: UPF)

Viruses are very simple and in order to multiply and express their proteins they need to hijack the cellular machinery of the host. Viruses make their own mRNA in the cells they infect, which read it and make viral proteins to make more viruses. But the mRNAs of many viruses, including SARS-CoV-2 and mosquito-borne viruses such as dengue, Zika and chikungunya, are enriched in suboptimal triplets and still express viral proteins with great efficiency. “To clarify this dilemma, we have used the chikungunya virus as a model because its genome multiplies at extremely high levels,” explain Jennifer Jungfleisch and René Böetcher, co-authors of the study.

“Our findings show for the first time that viruses modify the host’s tRNA to adapt the host’s translation machinery to the text of the viral mRNA”, comments Marc Talló, also a co-author of the study. “In other words, the virus infection induces a change of language in the cell, so that it expresses the viral proteins very efficiently. As viral proteins are essential for virus production, this change will ultimately be responsible for the generation of high amounts of virus in the infected cell,” he adds.

“Although the study has focused on the chikungunya virus, our proposal is that the modification of tRNAs induced by viral infection is a general mechanism followed by many viruses,” explains Juana Díez, professor at the Department of Medicine and Life Sciences from UPF.

“Furthermore, our results provide a basis for considering tRNA regulation as a new and promising therapeutic target for the development of broad-spectrum antivirals that are effective against multiple viruses”, concludes Díez. The study has had the collaboration of the research group coordinated by Eva María Novoa at the CRG and the rest of the authors are Gemma Pérez-Vilaró and Andres Merits (Institute of Technology, University of Tartu).

The study is titled “CHIKV infection reprograms codon optimality in favor of viral RNA translation by altering the tRNA epitranscriptome.” And it has been published in the academic journal Nature Communications. (Source: UPF)


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