May 06 2019 Musashi binding elements in Zika virus 3'UTR

Discovering the characteristic traits of Musashi Binding Elements (MBEs) in Flaviviruses with a Thermodynamic Model

In this study, we investigated how flaviviruses can cause congenital neurological disease by examining the accessibility of a specific binding motif for RNA-binding proteins from the Musashi family in the 3'UTR of flaviviruses. Through evaluating the affinity of different viruses to form RNA-protein complexes, we aimed to understand the role of Musashi proteins in promoting Zika virus replication and inducing congenital neurotropism. Using a well-established biophysical model of RNA structure formation, we conducted computational analysis of the thermodynamic properties of Musashi binding elements. Our findings support the hypothesis that suggest Zika virus (ZIKV) is not the only flavivirus capable of causing severe neuropathology through interaction with the Musashi proteins.

Abstract

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.

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Citation

Musashi Binding Elements in Zika and Related Flavivirus 3’UTRs: A Comparative Study in Silico
Adriano de Bernardi Schneider, Michael T. Wolfinger
Sci. Rep. 9(1):6911 (2019) | doi:10.1038/s41598-019-43390-5 | PDF | Figures

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