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Journal article
Interferon-inducible ribonuclease ISG20 inhibits hepatitis B virus replication through directly binding to the epsilon stem-loop structure of viral RNA
PLoS pathogens, v 13(4), pp e1006296-e1006296
01 Apr 2017
PMID: 28399146
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Hepatitis B virus (HBV) replicates its DNA genome through reverse transcription of a viral RNA pregenome. We report herein that the interferon (IFN) stimulated exoribonuclease gene of 20 KD (ISG20) inhibits HBV replication through degradation of HBV RNA. ISG20 expression was observed at basal level and was highly upregulated upon IFN treatment in hepatocytes, and knock down of ISG20 resulted in elevation of HBV replication and attenuation of IFN-mediated antiviral effect. The sequence element conferring the susceptibility of HBV RNA to ISG20-mediated RNA degradation was mapped at the HBV RNA terminal redundant region containing epsilon (epsilon) stem-loop. Furthermore, ISG20-induced HBV RNA degradation relies on its ribonuclease activity, as the enzymatic inactive form ISG20(D94G) was unable to promote HBV RNA decay. Interestingly, ISG20(D94G) retained antiviral activity against HBV DNA replication by preventing pgRNA encapsidation, resulting from a consequence of ISG20-epsilon interaction. This interaction was further characterized by in vitro electrophoretic mobility shift assay (EMSA) and ISG20 was able to bind HBV epsilon directly in absence of any other cellular proteins, indicating a direct e RNA binding capability of ISG20; however, cofactor(s) may be required for ISG20 to efficiently degrade epsilon. In addition, the lower stem portion of epsilon is the major ISG20 binding site, and the removal of 4 base pairs from the bottom portion of epsilon abrogated the sensitivity of HBV RNA to ISG20, suggesting that the specificity of ISG20-epsilon interaction relies on both RNA structure and sequence. Furthermore, the C-terminal Exonuclease III (ExoIII) domain of ISG20 was determined to be responsible for interacting with epsilon, as the deletion of ExoIII abolished in vitro ISG20-epsilon binding and intracellular HBV RNA degradation. Taken together, our study sheds light on the underlying mechanisms of IFN-mediated HBV inhibition and the antiviral mechanism of ISG20 in general.
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Details
- Title
- Interferon-inducible ribonuclease ISG20 inhibits hepatitis B virus replication through directly binding to the epsilon stem-loop structure of viral RNA
- Creators
- Yuanjie Liu - Indiana UniversityHui Nie - Drexel UniversityRicheng Mao - Indiana UniversityBidisha Mitra - Indiana UniversityDawei Cai - Indiana UniversityRan Yan - Indiana UniversityJu-Tao Guo - Baruch S. Blumberg InstituteTimothy M. Block - Baruch S. Blumberg InstituteNadir Mechti - University of MontpellierHaitao Guo - Indiana University
- Publication Details
- PLoS pathogens, v 13(4), pp e1006296-e1006296
- Publisher
- Public Library Science
- Number of pages
- 35
- Grant note
- R21AI103838; R01AI094474; R01AI110762 / National Institutes of Health of United States; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA R01AI113267 / NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Allergy & Infectious Diseases (NIAID)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Microbiology and Immunology
- Web of Science ID
- WOS:000402555700014
- Scopus ID
- 2-s2.0-85018304100
- Other Identifier
- 991019169525104721
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- Collaboration types
- Domestic collaboration
- International collaboration
- Web of Science research areas
- Microbiology
- Parasitology
- Virology