The myriad roles of RNA structure in the flavivirus life cycle

ABSTRACT

As positive-sense RNA viruses, the genomes of flaviviruses serve as the template for all stages of the viral life cycle, including translation, replication, and infectious particle production. Yet, they encode just 10 proteins, suggesting that the structure and dynamics of the viral RNA itself helps shepherd the viral genome through these stages. Herein, we highlight advances in our understanding of flavivirus RNA structural elements through the lens of their impact on the viral life cycle. We highlight how RNA structures impact translation, the switch from translation to replication, negative- and positive-strand RNA synthesis, and virion assembly. Consequently, we describe three major themes regarding the roles of RNA structure in flavivirus infections: 1) providing a layer of specificity; 2) increasing the functional capacity; and 3) providing a mechanism to support genome compaction. While the interactions described herein are specific to flaviviruses, these themes appear to extend more broadly across RNA viruses.

KEYWORDS:

• Flavivirus
• Zika virus
• dengue virus
• translation
• replication
• packaging
• stem-loop A
• RNA-dependent RNA polymerase
• methyltransferase
• replication organelle

Acknowledgments

The authors apologize to all colleagues whose work they could not cite due to space limitations. Q.H.A. would like to thank the Frederick Banting and Charles Best Canada Graduate Scholarships – Doctoral Award (CGS-D) and Tomlinson Doctoral Scholarship for graduate support. B.N.L. and A.B.W. were supported by Canada Graduate Scholarship – Master’s Awards (CGS-M) from the Natural Sciences and Engineering Research Council (NSERC).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Q.H.A. and S.M.S. conceived of the article. Q.H.A., B.N.L., A.B.W., R.F.K., and H.C.H.H. researched data for the article. All authors contributed to the discussion of content, as well as drafting and editing of the manuscript.

Data availability statement

The authors confirm that the data supporting the findings of this study are available within the article.

Highlights

• RNA structures provide a layer of specificity across the flavivirus life cycle.

• RNA sequence and structural elements, and their dynamics, increase the functional capacity of flaviviral genomes.

• SLA is a critical element in the switch from translation to replication, negative- and positive-strand RNA synthesis, and capping of newly-synthesized genomic RNAs.

• New models for interactions between SLA and NS5 shed light on potential mechanisms for the initiation of negative- and positive-strand RNA synthesis.

• Long-range RNA-RNA interactions in flavivirus genomes are highly plastic and critical for compaction of the viral genome into replication organelles and infectious viral particles.

Additional information

Funding

This research was supported by funds from the NSERC Discovery Grant [RGPIN-2020-04713] and Canadian Institutes of Health Research (PJT-162212) Operating Grant programs to S.M.S. In addition, this research was undertaken, in part, thanks to funding from the Canada Research Chairs program.