Zika virus noncoding sfRNA sequesters viral restriction factors involved in RNA splicing and nucleic acid editing
Date
2019
Authors
Ontiveros Valles, Jesús Gustavo, author
Wilusz, Jeffrey, advisor
Geiss, Brian, committee member
Chen, Chaoping, committee member
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Abstract
ZIka virus (ZIKV) is a single-stranded positive sense RNA flavivirus that is transmitted primarily by Aedes aegypti. To date, all vector-borne flaviviruses are known to generate stable subgenomic flavivirus RNAs (sfRNA), due to the stalling of the major cytoplasmic 5'-3' exoribonuclease XRN1 at a knot-like three helix junction structure located in viral 3' untranslated regions (UTRs). Formation of sfRNAs not only stalls XRN1, but also represses its function. sfRNA decay intermediates accumulate to high levels in infected cells and studies with other flaviviruses have implicated sfRNAs in cytopathology. Our objective was to characterize the function of ZIKV sfRNAs to gain insight into ZIKV pathogenesis. Specifically, we identified host proteins that interact with ZIKV sfRNA and have begun to evaluate their role in cytopathology and pathogenesis. RNA pull-down experiments revealed that PHAX and SF3B1, critically important RNA splicing factors involved in nuclear-cytoplasmic shuttling, bind sfRNA. Additionally, the cytidine deaminase APOBEC3C was found to bind ZIKV sfRNA. Knockdown and subsequent overexpression of these RNA Binding Proteins (RBPs) identified the nucleic acid deaminase APOBEC3C and the splicing-associated factor PHAX as negative viral restriction factors whose activity may be suppressed and/or altered by sfRNA interaction during ZIKV infection. sfRNA interactions with the splicing factors also resulted in the accumulation of aberrantly spliced transcripts, possibly due to sequestration of the host cell proteins. Thus, in addition to targeting XRN1, sfRNAs appear to interact with a set of RBPs to disrupt cellular mRNA decay regulation as well as other RNA processing events in an effort to compromise multiple steps of RNA metabolism and promote pathogenesis.
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Subject
PHAX
RNA
SF3B1
Zika
APOBEC3C
XRN1