Dengue, a hemorrhagic fever virus, belongs to flavivirus genus, whose members share these two features: 1) they are positive-sense, single-stranded RNA viruses, and 2) the genomic RNAs do not have a 3’ poly(A) tail. As an approach for understanding virus-host interactions, we are interested in defining the host proteins that bind to viral RNAs, and in understanding how the non-adenylated viral RNAs are translated by ribosomes.
By comparison with host messenger RNAs, translation without a poly(A) tail seems very strange. Textbook models (right) show that cellular messenger RNAs are circularized for translation by protein-protein interactions between protein synthesis initiation factor eIF4G at one end, and the poly(A) binding protein (which, as you might predict, binds to the poly(A) tail) at the other end. The strict interpretation of the textbook model cannot apply to dengue and other flaviviruses because they lack a poly(A) tail.
In collaboration with Nahum Sonenberg’s laboratory (McGill), and led by Glover Martin in our laboratory, we have generated evidence that the translation of both non-adenylated and polyadenylated messenger RNAs is stimulated by poly(A) binding protein (PABP). Biochemical data suggest that PABP binds specifically to the 3’ untranslated region of dengue virus RNAs. These data suggest that non-adenylated mRNAs enhance their translation by PABP binding in the same way as poly(A) mRNAs. An implication of these results is that the lack of a poly(A) tail is advantageous for the replication of the viral RNAs. Current work is directed at understanding how and where PABP binds the viral RNAs, and whether there is evidence for circularization of the genome through PABP-eIF4G interactions. This work has further implications for understanding translation of cellular histone mRNAs, which also lack a poly(A) tail.