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Elucidating how XRN1-mediated RNA degradation controls virus infection

Descripción del proyecto

Un nuevo regulador del huésped encargado de las infecciones víricas

Se sabe que, en una infección, la exonucleasa XRN1 se encarga del proceso por el que los virus inducen la degradación del ARNm del hospedador. Las células humanas que carecen de esta proteína son resistentes al virus de Sindbis transmitido por mosquitos, lo que pone de relieve la importancia de la XRN1 en el proceso de infección. Sin embargo, aún se desconocen los mecanismos precisos de este comportamiento. El objetivo del proyecto RNAdeg-Virus, financiado con fondos europeos, es investigar las dianas de la XRN1 a través de métodos de vanguardia a nivel de todo el sistema y determinar los sucesos moleculares que desencadenan la activación de la XRN1. Los resultados del proyecto conducirán a la identificación de posibles dianas para fármacos antivíricos, con evidentes beneficios en el plano médico y socioeconómico.

Objetivo

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.

Régimen de financiación

MSCA-IF-EF-ST - Standard EF

Coordinador

THE CHANCELLOR, MASTERS AND SCHOLARS OF THE UNIVERSITY OF OXFORD
Aportación neta de la UEn
€ 212 933,76
Dirección
WELLINGTON SQUARE UNIVERSITY OFFICES
OX1 2JD Oxford
Reino Unido

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Región
South East (England) Berkshire, Buckinghamshire and Oxfordshire Oxfordshire
Tipo de actividad
Higher or Secondary Education Establishments
Enlaces
Coste total
€ 212 933,76