title: Flavivirus NS4A-induced autophagy protects cells against death and enhances virus replication.
abstract: 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.
authors.affiliation: Department of Biology, Queens College and Graduate Center of City University of New York, Flushing, New York 11367, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: McLean
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Wudzinska
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Datan
authors.forename: Daniela
authors.initials: D
authors.lastname: Quaglino
authors.forename: Zahra
authors.initials: Z
authors.lastname: Zakeri
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D002460:Cell Line; D003716:Dengue Virus / Q000378:metabolism / Q000502:physiology; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology / Q000821:virology; D005347:Fibroblasts / Q000166:cytology / Q000821:virology; D005416:Flavivirus / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000166:cytology; D008264:Macrophages / Q000166:cytology / Q000821:virology; D008565:Membrane Proteins / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D015854:Up-Regulation; D017361:Viral Nonstructural Proteins / Q000235:genetics / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D019869:Phosphatidylinositol 3-Kinases; D017361:Viral Nonstructural Proteins; C502778:ATG5 protein, human; C491997:BECN1 protein, human; C477012:MAP1LC3A protein, human; C080106:NS4A protein, flavivirus