Mechanism and structural diversity of exoribonuclease-resistant RNA structures in flaviviral RNAs

• Published in: Nature communications Vol. 9; no. 1; p. 119
• Main Authors: MacFadden, Andrea, O’Donoghue, Zoe, Silva, Patricia A. G. C., Chapman, Erich G., Olsthoorn, René C., Sterken, Mark G., Pijlman, Gorben P., Bredenbeek, Peter J., Kieft, Jeffrey S.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.01.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 631/326/596/2557; 631/45/500; 631/535; 82/29; 82/83; Biological evolution; Cell Line; Dengue fever; Enzymes; Exoribonucleases - metabolism; Fever; Flavivirus - genetics; Genome, Viral - genetics; Genomes; Humanities and Social Sciences; Humans; Insects; Laboratorium voor Nematologie; Laboratorium voor Virologie; Laboratory of Nematology; Laboratory of Virology; multidisciplinary; Nucleic Acid Conformation; PE&RC; Protein Unfolding; Ribonucleic acid; RNA; RNA Stability - genetics; RNA, Untranslated - genetics; RNA, Viral - genetics; Science; Science (multidisciplinary); Vector-borne diseases; Viral diseases; Yellow fever
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02604-y

Flaviviruses such as Yellow fever, Dengue, West Nile, and Zika generate disease-linked viral noncoding RNAs called subgenomic flavivirus RNAs. Subgenomic flavivirus RNAs result when the 5′–3′ progression of cellular exoribonuclease Xrn1 is blocked by RNA elements called Xrn1-resistant RNAs located within the viral genome’s 3′-untranslated region that operate without protein co-factors. Here, we show that Xrn1-resistant RNAs can halt diverse exoribonucleases, revealing a mechanism in which they act as general mechanical blocks that ‘brace’ against an enzyme’s surface, presenting an unfolding problem that confounds further enzyme progression. Further, we directly demonstrate that Xrn1-resistant RNAs exist in a diverse set of flaviviruses, including some specific to insects or with no known arthropod vector. These Xrn1-resistant RNAs comprise two secondary structural classes that mirror previously reported phylogenic analysis. Our discoveries have implications for the evolution of exoribonuclease resistance, the use of Xrn1-resistant RNAs in synthetic biology, and the development of new therapies. Subgenomic flavivirus RNAs are generated by a host exoribonuclease and play an important role in virus replication and pathogenesis. Here, the authors show the mechanism by which subgenomic flavivirus RNAs are generated and identify two structurally distinct sfRNA classes in flaviviruses.