The study, published in Nature Communications, shows a new mechanism by which viruses modify the cellular machinery so that it can better read the instructions in the genome of the invading virus. The results provide a basis for considering tRNA regulation as a novel therapeutic target for the development of antiviral drugs that are effective against multiple viruses.
The Molecular Virology Research Group at Pompeu Fabra University (UPF), in collaboration with the Epitranscriptomics and RNA Dynamics group at the Center for Genomic Regulation (CRG), has discovered a new mechanism by which viruses modify cellular machinery to better read the instructions in the genome of the invading virus and thus produce large numbers of viral progeny. The study has been published in Nature Communications and has been led by Juana Díez.
Genes contain the information required for the formation of proteins, complex molecules that are essential for life, formed from amino acids. The reading of this information takes place 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, etc.). 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, and as 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. Thus, when the mRNA “text” is enriched in optimal triplets, proteins will be generated quickly and efficiently whereas when it is enriched in non-optimal triplets, the efficiency of expression will decrease because related tRNAs are in short supply.
Viruses are very simple and in order to multiply and express their proteins they need to hijack the host’s cellular machinery. Viruses make their own mRNA in the cells they infect, which the cells read and make viral proteins to make more viruses. But the mRNAs of many viruses, including SARS-CoV-2 and the mosquito-borne viruses dengue, Zika and chikungunya, are enriched in suboptimal triplets and still express viral proteins with great efficiency. “To address 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 host tRNA to adapt the host’s translation machinery to the text of the viral mRNA. In other words, viral infection induces a language change in the cell, so that it expresses viral proteins very efficiently. Since viral proteins are essential for virus production, this change will ultimately be responsible for generating a large amount of virus in the infected cell.”
Marc Talló, co-author of the article
“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 research group coordinated by Eva María Novoa at the CRG has participated in the study, and the other authors are Gemma Pérez-Vilaró and Andres Merits (Technological Institute, University of Tartu).
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Pompeu Fabra University – Barcelona
Magazine Reference:
Jungfleisch, J., et al. (2022) CHIKV infection reprograms codon optimization to favor viral RNA translation by altering the tRNA epitranscryptome. Nature Communications. doi.org/10.1038/s41467-022-31835-x.
Source: www.news-medical.net