Descrizione del progetto
Un nuovo orchestratore ospite dell’infezione virale
In caso di infezione, i virus inducono una degradazione dell’mRNA dell’ospite, un processo notoriamente orchestrato dall’esonucleasi XRN1. Le cellule umane prive di questa proteina sono refrattarie al virus sindbis (SINV) trasmesso dalle zanzare, sottolineando chiaramente l’importanza dell’XRN1 nel processo di infezione. Tuttavia, il preciso meccanismo della sua azione rimane sfuggente. L’obiettivo del progetto RNAdeg-Virus, finanziato dall’UE, consiste nell’investigare i bersagli dell’XRN1 utilizzando approcci di avanguardia che coinvolgono l’intero sistema e nel delineare gli eventi molecolari che attivano l’XRN1. I risultati del progetto condurranno all’identificazione di potenziali bersagli per i farmaci antivirali, con ovvie conseguenze mediche e socio-economiche.
Obiettivo
Commandeering the cellular gene expression machinery is essential for viruses in order to replicate their genome and ensure the production of their progeny. One of the major events occurring during viral infection is the virus-induced host mRNA degradation, process orchestrated by the exonuclease XRN1. However, the exact role of this enzyme remains controversial and largely elusive. An exciting stepping stone for studying XRN1 involvement in virus infection is the observation that human cells depleted of this protein are refractory to the infection of sindbis (SINV), a mosquito-borne virus. This suggests that this exonuclease is essential for SINV infection. It has been shown that the cellular RNA is massively degraded upon infection and that RNA degradation is the main force shaping the host transcriptome. Thus, I propose to identify the cellular and viral RNAs directly bound to and regulated by XRN1, using cutting-edge system-wide approaches, which will shed light on the targetome of this protein. Moreover, I plan to study how XRN1 is triggered, for instance by virus-induced posttranslational modifications or by differential protein complex assembly using mass-spectrometry analysis. Discovering the molecular events that activate XRN1 will be fundamental for determining its precise molecular mechanism of action and why it is important for viral infection. Additionally, the outcomes of this multidisciplinary approach will be beneficial for studying gene expression and RNA degradation-related processes, such as cancer. This innovative project will generate a vast amount of valuable data, which will allow to dissect the infection mechanisms of a mosquito-borne virus, leading to the identification of potential targets for antiviral drugs, with a consequent strong medical and socio-economic impact.
Campo scientifico
- natural sciencesbiological sciencesmicrobiologyvirology
- medical and health sciencesclinical medicineoncology
- natural sciencesbiological sciencesgeneticsRNA
- natural sciencesbiological sciencesbiochemistrybiomoleculesproteinsenzymes
- medical and health sciencesbasic medicinepharmacology and pharmacypharmaceutical drugsantivirals
Programma(i)
Argomento(i)
Meccanismo di finanziamento
MSCA-IF-EF-ST - Standard EFCoordinatore
OX1 2JD Oxford
Regno Unito