title: The Malat1 long non-coding RNA is upregulated by signalling through the PERK axis of unfolded protein response during flavivirus infection.
abstract: Flavivirus infection causes host cell death by initiation of an unfolded protein response (UPR). UPR is initiated following activation of three ER-membrane resident sensors, PERK, IRE1α and ATF6, which are otherwise kept inactive through association with the ER-chaperone GRP78. Activation precedes cellular and molecular changes that act to restore homeostasis but might eventually initiate apoptosis. These changes involve influencing function of multiple genes by either transcriptional or post-transcriptional or post-translational mechanisms. Transcriptional control includes expression of transcription factor cascades, which influence cognate gene expression. Malat1 is a long non-coding RNA which is over-expressed in many human oncogenic tissues and regulates cell cycle and survival. In this report, for the first time we show activation of Malat1 following infection by two flaviviruses, both of which activate the UPR in host cells. The temporal kinetics of expression was restricted to later time points. Further, Malat1 was also activated by pharmacological inducer of UPR, to a similar degree. Using drugs that specifically inhibit or activate the PERK or IRE1α sensors, we demonstrate that signalling through the PERK axis activates this expression, through a transcriptional mechanism. To our knowledge, this is the first report of an UPR pathway regulating the expression of an lncRNA.
authors.affiliation: Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad - Gurgaon Expressway, Faridabad 121001, Haryana, India.
authors.forename: Sankar
authors.initials: S
authors.lastname: Bhattacharyya
authors.affiliation: Vaccine and Infectious Disease Research Centre, Translational Health Science and Technology Institute, NCR Biotech Science Cluster, 3rd Milestone, Faridabad - Gurgaon Expressway, Faridabad 121001, Haryana, India.
authors.forename: Sudhanshu
authors.initials: S
authors.lastname: Vrati
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics; D017209:Apoptosis / Q000235:genetics*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics*; D005416:Flavivirus / Q000235:genetics / Q000472:pathogenicity; D018177:Flavivirus Infections / Q000235:genetics* / Q000473:pathology; D005786:Gene Expression Regulation; D006360:Heat-Shock Proteins / Q000235:genetics; D054884:Host-Pathogen Interactions / Q000235:genetics; D006801:Humans; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction; D056811:Unfolded Protein Response / Q000187:drug effects / Q000235:genetics; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: C497111:ATF6 protein, human; D051702:Activating Transcription Factor 6; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C557041:MALAT1 long non-coding RNA, human; D062085:RNA, Long Noncoding; C460640:EIF2AK3 protein, human; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; D004722:Endoribonucleases