CORDIS - EU research results
CORDIS

Elucidating how XRN1-mediated RNA degradation controls virus infection

Project description

A new host orchestrator of virus infection

Upon infection, viruses induce host mRNA degradation, a process known to be orchestrated by the exonuclease XRN1. Human cells lacking this protein are refractory to the mosquito-borne sindbis (SINV) virus, clearly underscoring the importance of XRN1 in the infection process. However, the precise mechanism of its action remains elusive. The aim of the EU-funded RNAdeg-Virus project is to investigate the targets of XRN1 using cutting-edge system-wide approaches and delineate the molecular events that trigger XRN1 activation. The project's results will lead to the identification of potential targets for antiviral drugs, with obvious medical and socio-economic consequences.

Objective

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.

Coordinator

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Net EU contribution
€ 212 933,76
Address
WELLINGTON SQUARE UNIVERSITY OFFICES
OX1 2JD Oxford
United Kingdom

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Region
South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire
Activity type
Higher or Secondary Education Establishments
Links
Total cost
€ 212 933,76