Document Detail

Flavivirus NS4A-induced autophagy protects cells against death and enhances virus replication.
MedLine Citation:
PMID:  21511946     Owner:  NLM     Status:  MEDLINE    
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.
Jeffrey E McLean; Aleksandra Wudzinska; Emmanuel Datan; Daniela Quaglino; Zahra Zakeri
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-04-21
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  286     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-20     Completed Date:  2011-08-30     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  22147-59     Citation Subset:  IM    
Department of Biology, Queens College and Graduate Center of City University of New York, Flushing, New York 11367, USA.
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MeSH Terms
Apoptosis Regulatory Proteins / metabolism
Cell Line
Dengue Virus / metabolism,  physiology
Epithelial Cells / cytology,  virology
Fibroblasts / cytology,  virology
Flavivirus / metabolism,  physiology*
Kidney / cytology
Macrophages / cytology,  virology
Membrane Proteins / metabolism
Microtubule-Associated Proteins / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Protein Transport
Signal Transduction
Viral Nonstructural Proteins / genetics,  metabolism*
Virus Replication*
Grant Support
2T34GM070387-03/GM/NIGMS NIH HHS
Reg. No./Substance:
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

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