title: PERK regulated miR-424(322)-503 cluster fine-tunes activation of IRE1 and ATF6 during Unfolded Protein Response.
abstract: The endoplasmic reticulum (ER) responds to changes in intracellular homeostasis through activation of the unfolded protein response (UPR). UPR can facilitate the restoration of cellular homeostasis, via the concerted activation of three ER stress sensors, namely IRE1, PERK and ATF6. Global approaches in several cellular contexts have revealed that UPR regulates the expression of many miRNAs that play an important role in the regulation of life and death decisions during UPR. Here we show that expression of miR-424(322)-503 cluster is downregulated during UPR. IRE1 inhibitor (4 μ8C) and deficiency of XBP1 had no effect on downregulation of miR-424(322)-503 during UPR. Treatment of cells with CCT030312, a selective activator of EIF2AK3/PERK signalling, leads to the downregulation of miR-424(322)-503 expression. The repression of miR-424(322)-503 cluster during conditions of ER stress is compromised in PERK-deficient MEFs. miR-424 regulates the expression of ATF6 via a miR-424 binding site in its 3' UTR and attenuates the ATF6 transcriptional activity during UPR. Further miR-424 had no effect on IRE1-XBP1 axis but enhanced the regulated IRE1-dependent decay (RIDD). Our results suggest that miR-424 constitutes an obligatory fine-tuning mechanism where PERK-mediated downregulation of miR-424(322)-503 cluster regulates optimal activation of IRE1 and ATF6 during conditions of ER stress.
authors.affiliation: Discipline of Pathology, School of medicine, Clinical Science Institute, National University of Ireland Galway, Ireland.|Lambe Institute for Translational Research, National University of Ireland Galway, Ireland.
authors.forename: Ananya
authors.initials: A
authors.lastname: Gupta
authors.affiliation: Discipline of Pathology, School of medicine, Clinical Science Institute, National University of Ireland Galway, Ireland.|Lambe Institute for Translational Research, National University of Ireland Galway, Ireland.
authors.forename: Muhammad Mosaraf
authors.initials: MM
authors.lastname: Hossain
authors.affiliation: Discipline of Pathology, School of medicine, Clinical Science Institute, National University of Ireland Galway, Ireland.|Lambe Institute for Translational Research, National University of Ireland Galway, Ireland.
authors.forename: Danielle E
authors.initials: DE
authors.lastname: Read
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.|Program of Cellular and Molecular Biology, Center for Molecular Studies of the Cell, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.|FONDAP Center for Geroscience, Brain Health and Metabolism, Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
authors.affiliation: Apoptosis Research Centre, School of Natural Sciences, National University of Ireland Galway, Ireland.
authors.forename: Afshin
authors.initials: A
authors.lastname: Samali
authors.affiliation: Discipline of Pathology, School of medicine, Clinical Science Institute, National University of Ireland Galway, Ireland.|Lambe Institute for Translational Research, National University of Ireland Galway, Ireland.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Gupta
mesh_terms: D051702:Activating Transcription Factor 6 / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015870:Gene Expression; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D005810:Multigene Family; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D056811:Unfolded Protein Response / Q000235:genetics*; D019892:eIF-2 Kinase / Q000235:genetics* / Q000378:metabolism
chemical_list: D051702:Activating Transcription Factor 6; D008565:Membrane Proteins; D035683:MicroRNAs; D017346:Protein Serine-Threonine Kinases; D019892:eIF-2 Kinase; C497112:Atf6 protein, mouse; C583176:MIRN424 microRNA, mouse; C556275:Mirn503 microRNA, mouse; C486556:Ern2 protein, mouse