# Flavivirus non-coding RNAs and the Host mRNA Decay Machinery

> **NIH NIH R01** · COLORADO STATE UNIVERSITY · 2020 · $372,709

## Abstract

The Flaviviridae are a family of positive-sense RNA viruses that contain numerous important human
pathogens. Many of the molecular mechanisms that underlie how these RNA viruses cause cytopathology
and disease are not clearly described. The cellular mRNA decay machinery, in particularly the 5'-3' pathway
mediated by the exoribonuclease Xrn1, plays a major role in regulating the abundance and quality of gene
expression in the cell. Understudied, but nevertheless very important aspects of flavivirus-host interactions,
include how viral RNAs are protected from degradation by the cellular mRNA decay machinery and what are
the implications of the viral RNA stabilization strategies on the regulation of cellular mRNA stability. We have
recently observed that flaviviruses repress the activity of Xrn1 through trapping the enzyme using unique
structured regions of the viral RNA. Interestingly, it is the 5' UTR IRES region that is responsible for this Xrn1
repression in Hepatitis C virus and Bovine Viral Diarrhea virus. These observations serve as the foundation for
this proposal to gain in-depth mechanistic insights into molecular mechanisms of Xrn1 repression and
regulation that are disrupted by flavivirus RNAs. In Aim 1, we will identify the sequence/structural requirements
of IRES-mediated Xrn1 repression and determine whether this is a common property of other viral IRES
elements. The goal of Aim 2 is understand at a mechanistic level why the repression of Xrn1 by flavivirus
RNAs results in the apparent shut down of the entire 5'-3' mRNA decay pathway – not just the exonucleolytic
digestion step. Uncovering the interplay and feedback regulation of the decay factors in the 5'-3' RNA decay
pathway will provide novel insights into how the cell normally regulates this decay pathway and integrate it into
the overall process of gene expression. In the third aim we will expand our studies on Xrn1 stalling and
investigate whether it is an approach used by the cell to remodel cellular transcripts. In the final Aim, we will
characterize key biological aspects of Xrn1 repression from the perspective of both the cell and the virus. A
key focus of this part will be on the dysregulation of cellular mRNA stability by flaviviruses that results in
dramatic changes in cellular gene expression that could play a significant role in HCV-mediated oncogenesis.

## Key facts

- **NIH application ID:** 9985703
- **Project number:** 5R01AI123136-05
- **Recipient organization:** COLORADO STATE UNIVERSITY
- **Principal Investigator:** Jeffrey Wilusz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $372,709
- **Award type:** 5
- **Project period:** 2016-09-28 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9985703

## Citation

> US National Institutes of Health, RePORTER application 9985703, Flavivirus non-coding RNAs and the Host mRNA Decay Machinery (5R01AI123136-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/9985703. Licensed CC0.

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