IRES-mediated translation during cellular stress

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Cells have two distinct ways to generate proteins which are cap-dependent translation and internal ribosomal entry site (IRES) mediated translation. The majority of cellular proteins are generated via cap-dependent translation while approximately 5% of cellular mRNA and certain viral mRNA are translated by IRES-mediated translation. We still do not have a clear answer as to why mammalian cells have two distinct translation systems. It is known that IRES-mediated translation is often active or maintained when cap-dependent translation is severely impaired under cellular stress and virus infection. Therefore, it is assumed that it is a fail-safe strategy in which IRES-mediated translation maintains cellular homeostasis as a backup of cap-dependent translation under stress conditions. For viruses, the translational machinery driven by IRES elements may be a great advantage for their replication since efficient synthesis of viral proteins can be achieved during cell death. The long-term research goal of our laboratory is to study how cells regulate the two translational machineries in different cellular environment. During the current NSERC funding period (2006-2011), we found that amino acid starvation increase translation efficiency initiated by foot-and-mouth disease virus (FMDV) IRES element. In the proposed study, we will investigate cellular mechanisms of how protein synthesis by FMDV is increased during amino acid starvation. The proposed study will have a significant impact in the field of translational control, virology and cell physiology. In order to understand how protein synthesis is regulated, it is essential that we continue to investigate the mechanisms that underlie IRES-mediated translation and to train the next generation of researchers.