| Flavivirus NS4A-induced autophagy protects cells against death and enhances virus replication. | |
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MedLine Citation:
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PMID: 21511946 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Flaviviruses include the most prevalent and medically challenging viruses. Persistent infection with flaviviruses of epithelial cells and hepatocytes that do not undergo cell death is common. Here, we report that, in epithelial cells, up-regulation of autophagy following flavivirus infection markedly enhances virus replication and that one flavivirus gene, NS4A, uniquely determines the up-regulation of autophagy. Dengue-2 and Modoc (a murine flavivirus) kill primary murine macrophages but protect epithelial cells and fibroblasts against death provoked by several insults. The flavivirus-induced protection derives from the up-regulation of autophagy, as up-regulation of autophagy by starvation or inactivation of mammalian target of rapamycin also protects the cells against insult, whereas inhibition of autophagy via inactivation of PI3K nullifies the protection conferred by flavivirus. Inhibition of autophagy also limits replication of both Dengue-2 and Modoc virus in epithelial cells. Expression of flavivirus NS4A is sufficient to induce PI3K-dependent autophagy and to protect cells against death; expression of other viral genes, including NS2A and NS4B, fails to protect cells against several stressors. Flavivirus NS4A protein induces autophagy in epithelial cells and thus protects them from death during infection. As autophagy is vital to flavivirus replication in these cells, NS4A is therefore also identified as a critical determinant of flavivirus replication. |
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Authors:
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Jeffrey E McLean; Aleksandra Wudzinska; Emmanuel Datan; Daniela Quaglino; Zahra Zakeri |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2011-04-21 |
Journal Detail:
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Title: The Journal of biological chemistry Volume: 286 ISSN: 1083-351X ISO Abbreviation: J. Biol. Chem. Publication Date: 2011 Jun |
Date Detail:
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Created Date: 2011-06-20 Completed Date: 2011-08-30 Revised Date: 2012-09-24 |
Medline Journal Info:
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Nlm Unique ID: 2985121R Medline TA: J Biol Chem Country: United States |
Other Details:
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Languages: eng Pagination: 22147-59 Citation Subset: IM |
Affiliation:
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Department of Biology, Queens College and Graduate Center of City University of New York, Flushing, New York 11367, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Apoptosis Regulatory Proteins / metabolism Autophagy* Cell Line Dengue Virus / metabolism, physiology Dogs Epithelial Cells / cytology, virology Fibroblasts / cytology, virology Flavivirus / metabolism, physiology* Humans Kidney / cytology Macrophages / cytology, virology Membrane Proteins / metabolism Microtubule-Associated Proteins / metabolism Phosphatidylinositol 3-Kinases / metabolism Protein Transport Signal Transduction Up-Regulation Viral Nonstructural Proteins / genetics, metabolism* Virus Replication* |
| Grant Support | |
ID/Acronym/Agency:
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2T34GM070387-03/GM/NIGMS NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/ATG5 protein, human; 0/Apoptosis Regulatory Proteins; 0/BECN1 protein, human; 0/Membrane Proteins; 0/Microtubule-Associated Proteins; 0/NS4A protein, flavivirus; 0/Viral Nonstructural Proteins; 0/light chain 3, human; EC 2.7.1.-/Phosphatidylinositol 3-Kinases |
| Comments/Corrections | |
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