Elucidating how XRN1-mediated RNA degradation controls virus infection

ended

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.