Characterizing Cellular Responses During Oncolytic Maraba Virus Infection

• Main Authors: Golnoush Hassanzadeh, Thet Naing, Tyson Graber, Seyed Mehdi Jafarnejad, David F. Stojdl, Tommy Alain, Martin Holcik
• Format: Article
• Language: English
• Published: MDPI AG 2019-01-01
• Series: International Journal of Molecular Sciences
• Subjects: translation; eIF5B; IRES; XIAP; Bcl-xL; MG-1
• Online Access: https://www.mdpi.com/1422-0067/20/3/580

The rising demand for powerful oncolytic virotherapy agents has led to the identification of Maraba virus, one of the most potent oncolytic viruses from Rhabdoviridae family which displays high selectivity for killing malignant cells and low cytotoxicity in normal cells. Although the virus is readied to be used for clinical trials, the interactions between the virus and the host cells is still unclear. Using a newly developed interferon-sensitive mutant Maraba virus (MG1), we have identified two key regulators of global translation (4E-BP1 and eIF2&#945;) as being involved in the regulation of protein synthesis in the infected cells. Despite the translational arrest upon viral stress, we showed an up-regulation of anti-apoptotic Bcl-xL protein that provides a survival benefit for the host cell, yet facilitates effective viral propagation. Given the fact that eIF5B canonically regulates 60S ribosome subunit end joining and is able to replace the role of eIF2 in delivering initiator tRNA to the 40S ribosome subunit upon the phosphorylation of eIF2&#945; we have tested whether eIF5B mediates the translation of target mRNAs during MG1 infection. Our results show that the inhibition of eIF5B significantly down-regulates the level of <i>Bcl-xL</i> steady-state mRNA, thus indirectly attenuates viral propagation.