Circularization of flavivirus genomic RNA inhibits de novo translation initiation

Nucleic Acids Research
Thomas J SanfordTrevor R Sweeney

Abstract

Members of the Flaviviridae family, including dengue virus (DENV) and yellow fever virus, cause serious disease in humans, whilst maternal infection with Zika virus (ZIKV) can induce microcephaly in newborns. Following infection, flaviviral RNA genomes are translated to produce the viral replication machinery but must then serve as a template for the transcription of new genomes. However, the ribosome and viral polymerase proceed in opposite directions along the RNA, risking collisions and abortive replication. Whilst generally linear, flavivirus genomes can adopt a circular conformation facilitated by long-range RNA-RNA interactions, shown to be essential for replication. Using an in vitro reconstitution approach, we demonstrate that circularization inhibits de novo translation initiation on ZIKV and DENV RNA, whilst the linear conformation is translation-competent. Our results provide a mechanism to clear the viral RNA of ribosomes in order to promote efficient replication and, therefore, define opposing roles for linear and circular conformations of the flavivirus genome.

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Citations

Jun 10, 2020·Cell Proliferation·Hui NieChunlin Ou
Aug 14, 2020·Nucleic Acids Research·Tamari Chkuaseli, K Andrew White
Apr 22, 2020·Nucleic Acids Research·Teodoro FajardoTrevor R Sweeney
Nov 30, 2019·Reviews in Medical Virology·Zhong-Yu Liu, Cheng-Feng Qin
Oct 19, 2020·Current Opinion in Microbiology·Shwetha Shivaprasad, Peter Sarnow
May 1, 2021·International Journal of Molecular Sciences·Sara Ramos-LorenteAlfredo Berzal-Herranz
Jun 3, 2021·Viruses·Kaïn van den ElsenDahai Luo
Aug 1, 2021·Journal of Clinical Laboratory Analysis·Mingyu ChuYucui Jin

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Methods Mentioned

BETA
aminoacylation
electrophoresis
protein assay
proximity cross-linking
imaging techniques

Software Mentioned

Mfold
ImageQuant TL
GraphPad Prism
SHAPE

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