Zika virus noncoding sfRNAs sequester multiple host-derived RNA-binding proteins and modulate mRNA decay and splicing...

Area of Science:

• Virology
• Molecular Biology
• RNA Biology

Background:

• Insect-borne flaviviruses generate subgenomic flavivirus RNA (sfRNA) by inhibiting the cellular 5'-3'-exoribonuclease 1 (XRN1).
• sfRNA production is a conserved mechanism across flaviviruses, including Zika virus and dengue type 2 virus.

Purpose of the Study:

• To investigate the interaction of Zika virus sfRNA with cellular RNA-binding proteins.
• To identify host factors that restrict Zika virus infection.
• To determine the impact of sfRNA on post-transcriptional regulatory processes.

Main Methods:

• Protein-RNA reconstitution assays.
• RNA pulldown assays using human choriocarcinoma (JAR) cells.
• Analysis of sfRNA-interacting proteins and their role in viral restriction.

Main Results:

• Zika virus sfRNA represses XRN1, similar to other flaviviruses.
• sfRNAs from Zika and dengue type 2 viruses bind to a common set of 21 RNA-binding proteins involved in post-transcriptional regulation.
• Four sfRNA-interacting proteins (DDX6, EDC3, phosphorylated adaptor for RNA export, APOBEC3C) restrict Zika virus infection.
• Zika virus infection and sfRNA alone disrupt cellular mRNA decay and RNA splicing.

Conclusions:

• Zika virus sfRNA extensively interacts with cellular RNA-binding proteins.
• These interactions lead to widespread dysregulation of post-transcriptional control.
• The disruption of cellular processes likely impairs the host's antiviral response to Zika virus infection.