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J Gen Virol. 2017 May;98(5):1027-1039. doi: 10.1099/jgv.0.000792. Epub 2017 May 23.

Japanese encephalitis virus activates autophagy through XBP1 and ATF6 ER stress sensors in neuronal cells.

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Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, Faridabad, Haryana, India.
Department of Biotechnology, Faculty of Science, Jamia Hamdard, New Delhi, India.
Present address: Department of Neuroscience, The Scripps Research Institute, Jupiter, Florida, USA.
Jaypee Institute of Information Technology, Noida, Uttar Pradesh, India.
Regional Centre for Biotechnology, NCR Biotech Science Cluster, Faridabad, Haryana, India.


Endoplasmic reticulum (ER) stress and autophagy are key cellular responses to RNA virus infection. Recent studies have shown that Japanese encephalitis virus (JEV)-induced autophagy negatively influences virus replication in mouse neuronal cells and embryonic fibroblasts, and delays virus-induced cell death. Here, we evaluated the role of ER stress pathways in inducing autophagy during JEV infection. We observed that JEV infection of neuronal cells led to activation of all three sensors of ER stress mediated by eIF2α/PERK, IRE1/XBP1 and ATF6. The kinetics of autophagy induction as monitored by levels of SQSTM1 and LC3-II paralleled activation of ER stress. Inhibition of the eIF2α/PERK pathway by siRNA-mediated depletion of proteins and by the PERK inhibitor had no effect on autophagy and JEV replication. However, depletion of XBP1 and ATF6, alone or in combination, prevented autophagy induction and significantly enhanced JEV-induced cell death. JEV-infected cells depleted of XBP1 or ATF6 showed reduced transcription of ER chaperones, ERAD components and autophagy genes, resulting in reduced protein levels of the crucial autophagy effectors ATG3 and BECLIN-1. Conversely, pharmacological induction of ER stress in JEV-infected cells further enhanced autophagy and reduced virus titres. Our study thus demonstrates that a crucial link exists between the ER stress pathways and autophagy in virus-infected cells, and that these processes are highly regulated during virus infection.

[Indexed for MEDLINE]

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