The role of the 5'-3' exoribonuclease Xrn2 in RNA virus infection
Abstract/Contents
- Abstract
- Hepatitis C virus (HCV) is a small, hepatotropic, RNA virus that can establish persistent infections leading to chronic hepatitis and hepatocellular carcinoma (HCC). With an estimated 2% of the world's population infected, HCV is a serious global health problem. Curiously, this virus has the unique feature of depending on the liver-specific, microRNA miR-122. In the current model, miR-122 interacts with the 5'-end of the HCV RNA genome, protecting it from hitherto unknown degradation machinery. The work described in this dissertation highlights a novel cytoplasmic antiviral function for the mammalian 5'-3' exoribonuclease Xrn2, and enzyme best known for its role in RNA polymerase II transcription termination. We discovered that Xrn2 modulates HCV RNA abundance by destabilizing the viral RNA genome. Importantly, during sequestration of miR-122, Xrn2 depletion restored HCV RNA abundance, suggesting that Xrn2 depletion eliminates the miR-122 requirement for viral RNA stability. Thus, Xrn2 is an antiviral effector so potent that HCV has evolved a mechanism to evade it, through the subversion of miR-122 to form a protective oligomeric complex at the 5' end of the viral genome. To determine if Xrn2's antiviral function is specific to HCV, we studied its role in poliovirus (PV) infection. Our experiments showed that Xrn2 interacts with PV RNA early during infection, and that Xrn2 activity may be suppressed by proteolytic cleavage that is mediated by the PV protease 2A. This work revealed an unprecedented role for Xrn2 and highlighted the broad function of this novel antiviral factor in RNA virus infection. In this dissertation, we also investigated the regulation of noncoding RNAs in HCV infection. Sucrose-gradient analysis of miR-122 during HCV infection uncovered that this highly conserved miRNA and its isomiR variants form unique complexes, which are specifically modulated during infection. This highlights the ability of HCV to modulate the engagement of specific miR-122-complexes, and the distinct functions in gene regulation these complexes may play. We also examined the role of Xrn2 in mammalian long noncoding RNA (lncRNA) degradation, and their regulation during HCV infection, by performing lncRNA microarrays. Our analyses will provide important insights into the biological functions of lncRNAs and help us identify novel therapeutic targets for HCV infection and HCC. Taken together, the work described here has uncovered a novel cytoplasmic antiviral function for Xrn2 in RNA virus infection. Our research highlights the potential of studying lncRNAs and miRNA variants during viral infection, which can lead the way for the discovery of new biomarkers and therapeutics.
Description
| Type of resource | text |
|---|---|
| Form | electronic; electronic resource; remote |
| Extent | 1 online resource. |
| Publication date | 2014 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Associated with | Sedano, Cecilia D |
|---|---|
| Associated with | Stanford University, Department of Genetics. |
| Primary advisor | Sarnow, P. (Peter) |
| Thesis advisor | Sarnow, P. (Peter) |
| Thesis advisor | Cohen, Stanley |
| Thesis advisor | Fire, Andrew Zachary |
| Thesis advisor | Kay, Mark Allan |
| Advisor | Cohen, Stanley |
| Advisor | Fire, Andrew Zachary |
| Advisor | Kay, Mark Allan |
Subjects
| Genre | Theses |
|---|
Bibliographic information
| Statement of responsibility | Cecilia D. Sedano. |
|---|---|
| Note | Submitted to the Department of Genetics. |
| Thesis | Thesis (Ph.D.)--Stanford University, 2014. |
| Location | electronic resource |
Access conditions
- Copyright
- © 2014 by Cecilia D. Sedano
- License
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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