Viral mRNA translation

Our laboratory focuses on understanding the translation of viral messenger RNAs (mRNAs) that do not have a poly(A) tail. Viruses with non-adenylated mRNAs include important human pathogens such as dengue hemorrhagic fever virus, West Nile virus, and Japanese encephalitis virus. Crossing kingdoms, a number of plant viral mRNAs are also non-adenylated. Protein biosynthesis on cellular mRNAs is thought to involve circularization, where the mRNA ends are brought together through RNA-protein and protein-protein binding interactions. One of the key proteins in this circularization is the poly(A) binding protein (PABP), which binds to the poly(A) tail. Sitting on the opposite end of the RNA is the protein eIF4G, which has a binding site for PABP, thus enabling the circularization.

Whether or not the non-adenylated viral RNAs circularize for their translation is not known. In addition it is puzzling to imagine how non-adenylated viral messenger RNAs are translated early in an infection when they are vastly outnumbered by polyadenylated cellular mRNAs and should be at a significant disadvantage. We know that the downstream ends (the 3’ termini) of the RNAs are important because mutagenesis and nucleotide deletions diminish protein expression.

In collaboration with Nahum Sonenberg's laboratory (McGill), we have generated evidence that the translation of both non-adenylated and polyadenylated messenger RNAs is stimulated by poly(A) binding protein (PABP). Interestingly, reporter mRNAs containing dengue virus 5' and 3' untranslated regions show greater resistance to diminished translation than other reporters containing untranslated regions from a cellular mRNA (globin). These data suggest that non-adenylated mRNAs enhance their translation by PABP binding to the 3' UTR while their efficient translation requires a lower relative concentration of PABP than cellular mRNAs.