Musashi Binding Elements in the 3'UTR of Zika and related Flaviviruses
Zika virus (ZIKV) contains multiple binding motifs for the Musashi (MSI) RNA-binding protein in its 3'UTR. While Musashi has been shown to promote ZIKV replication, the question of why ZIKV 3'UTRs are preferred MSI targets has not been addressed. In this study we assess characteristic traits of Musashi binding elements (MBEs) in the 3'UTR of flaviviruses using a thermodynamic model for RNA folding. Our data suggest that ZIKV MBEs are maximally accessible among mosquito-borne flaviviruses.
Adriano de Bernardi Schneider, Michael T. Wolfinger
Sci. Rep. 9(1):6911 (2019) | doi: 10.1038/s41598-019-43390-5
Zika virus (ZIKV) belongs to a class of neurotropic viruses that have the ability to cause congenital infection, which can result in microcephaly or fetal demise. Recently, the RNA-binding protein Musashi-1 (Msi1), which mediates the maintenance and self-renewal of stem cells and acts as a translational regulator, has been associated with promoting ZIKV replication, neurotropism, and pathology. Msi1 predominantly binds to single-stranded motifs in the 3′ untranslated region (UTR) of RNA that contain a UAG trinucleotide in their core. We systematically analyzed the properties of Musashi binding elements (MBEs) in the 3′UTR of flaviviruses with a thermodynamic model for RNA folding. Our results indicate that MBEs in ZIKV 3′UTRs occur predominantly in unpaired, single-stranded structural context, thus corroborating experimental observations by a biophysical model of RNA structure formation. Statistical analysis and comparison with related viruses show that ZIKV MBEs are maximally accessible among mosquito-borne flaviviruses. Our study addresses the broader question of whether other emerging arboviruses can cause similar neurotropic effects through the same mechanism in the developing fetus by establishing a link between the biophysical properties of viral RNA and teratogenicity. Moreover, our thermodynamic model can explain recent experimental findings and predict the Msi1-related neurotropic potential of other viruses.