title: Regulated IRE1-dependent decay pathway is activated during Japanese encephalitis virus-induced unfolded protein response and benefits viral replication.
abstract: Japanese encephalitis virus (JEV) infection-induced encephalitis causes extensive death or long-term neurological damage, especially among children, in south and south-east Asia. Infection of mammalian cells has shown induction of an unfolded protein response (UPR), presumably leading to programmed cell death or apoptosis of the host cells. UPR, a cellular response to accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen, is initiated by three ER-lumen-resident sensors (PERK, IRE1 and ATF6), and involves transcriptional and translational regulation of the expression of several genes. The sensor IRE1 possesses an intrinsic RNase activity, activated through homo-dimerization and autophosphorylation during UPR. Activated IRE1 performs cytoplasmic cleavage of Xbp1u transcripts, thus facilitating synthesis of XBP1S transcription factor, in addition to cleavage of a cohort of cellular transcripts, the later initiating the regulated IRE1-dependent decay (RIDD) pathway. In this study, we report the initiation of the RIDD pathway in JEV-infected mouse neuroblastoma cells (Neuro2a) and its effect on viral infection. Activation of the RIDD pathway led to degradation of known mouse cell target transcripts without showing any effect on JEV RNA despite the fact that both when biochemically purified showed significant enrichment in ER membrane-enriched fractions. Additionally, inhibition of the IRE1 RNase activity by STF083010, a specific drug, diminished viral protein levels and reduced the titre of the virus produced from infected Neuro2a cells. The results present evidence for the first report of a beneficial effect of RIDD activation on the viral life cycle.
authors.affiliation: Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, 496, Udyog Vihar Phase III, Gurgaon 122016, India.
authors.forename: Sankar
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, 496, Udyog Vihar Phase III, Gurgaon 122016, India.
authors.forename: Utsav
authors.initials: U
authors.lastname: Sen
authors.affiliation: Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, 496, Udyog Vihar Phase III, Gurgaon 122016, India.
authors.forename: Sudhanshu
authors.initials: S
authors.lastname: Vrati
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004664:Encephalitis Virus, Japanese / Q000235:genetics / Q000502:physiology*; D004672:Encephalitis, Japanese / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism / Q000821:virology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response; D014779:Virus Replication; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases