Investigators of the University of Oxford in collaboration with a research group of the Universidad Autónoma de Madrid (UAM) and other seven european groups have uncovered that virus infection leads to a profound remodelation of cellular proteins involved in the interaction with RNA.
These findings open a new field of research for the design of new antiviral agents using cellular proteins as targets. These proteins should be dispensable for cell growth, but necessary for virus replication.
A recent work carried out by researchers of Oxford University in collaboration with the Universidad Autónoma de Madrid (UAM), and published in the prestigious journal Molecular Cell, have found that the infection of Sindbis virus leads to a global remodelling of the proteins that interact with RNA in infected cells. Based on the novel technique “RNA interactome capture” this work details that the virus activates or inactivates more than 200 proteins involved in the
binding and metabolism of RNA, redirecting them to facilitate viral RNA replication.
It was observed that the proteins activated by the virus modify their cellular location and are recruited to the cellular compartments where viral replication takes place.
“The virus produces huge amounts of RNA as a consequence of its replication – says Dr. Manuel García Moreno, the first author of this work -, and its accumulation produces the effect of a spider web, trapping the proteins needed by the virus in the foci of viral replication”.
“This effect of ‘spider web’ is complemented by the degradation of cellular RNA to eliminate competitors involved in the interaction with these proteins” indicates Dr. García Moreno.
The authors illustrate the importance of the changes in the abundance of cellular and viral RNA molecules by means of knock-out cells in the gene encoding the protein involved in RNA degradation, XRN1.
“After elimination of XRN1 the virus is unable to replicate – says Dr. Alfredo Castelló, director of this work – it is as if we take off the key to the virus in order to open the cell to take its resources”.
“These findings open new avenues for the design of antiviral agents directed to block cellular proteins necessary for virus replication. In addition – indicates Castelló -, it is probable that some of these proteins should also be required for the replication of other human viruses. This possibility would open the development of wide spectrum antiviral agents”.
In this work also collaborate Esther González Almela, Miguel Angel Sanz and Luis Carrasco, researchers of the UAM that are working at the Centro de Biología Molecular Severo Ochoa, that belongs to both the UAM and the CSIC.
Reference:
Manuel Garcia-Moreno, Marko Noerenberg, Shuai Ni, Aino I. Järvelin, Esther González-Almela, Caroline E. Lenz, Marcel Bach-Pages, Victoria Cox, Rosario Avolio, Thomas Davis, Svenja Hester, Thibault J.M. Sohier, Bingnan Li, Gregory Heikel, Gracjan Michlewski, Miguel A. Sanz, Luis Carrasco, Emiliano P. Ricci, Vicent Pelechano, Ilan Davis, Bernd Fischer, Shabaz Mohammed and Alfredo Castello. System-wide profiling of RNA-binding proteins uncovers key regulators of virus infection. Molecular Cell. DOI: 10.1016/j.molcel.2019.01.017
