title: Interplay between the oxidoreductase PDIA6 and microRNA-322 controls the response to disrupted endoplasmic reticulum calcium homeostasis.
abstract: The disruption of the energy or nutrient balance triggers endoplasmic reticulum (ER) stress, a process that mobilizes various strategies, collectively called the unfolded protein response (UPR), which reestablish homeostasis of the ER and cell. Activation of the UPR stress sensor IRE1α (inositol-requiring enzyme 1α) stimulates its endoribonuclease activity, leading to the generation of the mRNA encoding the transcription factor XBP1 (X-box binding protein 1), which regulates the transcription of genes encoding factors involved in controlling the quality and folding of proteins. We found that the activity of IRE1α was regulated by the ER oxidoreductase PDIA6 (protein disulfide isomerase A6) and the microRNA miR-322 in response to disruption of ER Ca2+ homeostasis. PDIA6 interacted with IRE1α and enhanced IRE1α activity as monitored by phosphorylation of IRE1α and XBP1 mRNA splicing, but PDIA6 did not substantially affect the activity of other pathways that mediate responses to ER stress. ER Ca2+ depletion and activation of store-operated Ca2+ entry reduced the abundance of the microRNA miR-322, which increased PDIA6 mRNA stability and, consequently, IRE1α activity during the ER stress response. In vivo experiments with mice and worms showed that the induction of ER stress correlated with decreased miR-322 abundance, increased PDIA6 mRNA abundance, or both. Together, these findings demonstrated that ER Ca2+, PDIA6, IRE1α, and miR-322 function in a dynamic feedback loop modulating the UPR under conditions of disrupted ER Ca2+ homeostasis.
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S7, Canada.
authors.forename: Jody
authors.initials: J
authors.lastname: Groenendyk
authors.affiliation: Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta T6G 2V4, Canada.
authors.forename: Zhenling
authors.initials: Z
authors.lastname: Peng
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S7, Canada.
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Dudek
authors.affiliation: Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta T6G 2V4, Canada.
authors.forename: Xiao
authors.initials: X
authors.lastname: Fan
authors.affiliation: Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta T6G 2V4, Canada.
authors.forename: Marcin J
authors.initials: MJ
authors.lastname: Mizianty
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile. Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Estefanie
authors.initials: E
authors.lastname: Dufey
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile. Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Hery
authors.initials: H
authors.lastname: Urra
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile. Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Denisse
authors.initials: D
authors.lastname: Sepulveda
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile. Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
authors.forename: Diego
authors.initials: D
authors.lastname: Rojas-Rivera
authors.affiliation: College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Korea.
authors.forename: Yunki
authors.initials: Y
authors.lastname: Lim
authors.affiliation: College of Life Sciences, Gwangju Institute of Science and Technology (GIST), Gwangju 500-712, Korea.
authors.forename: Do Han
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S7, Canada.
authors.forename: Kayla
authors.initials: K
authors.lastname: Baretta
authors.affiliation: Department of Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Sonal
authors.initials: S
authors.lastname: Srikanth
authors.affiliation: Department of Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Yousang
authors.initials: Y
authors.lastname: Gwack
authors.affiliation: Department of Life Science, BK21 PLUS Life Science for BDR team, The Research Institute of Natural Sciences, Hanyang University, Seoul 133-791, Korea.
authors.forename: Joohong
authors.initials: J
authors.lastname: Ahnn
authors.affiliation: Degenerative Disease Research Program, Center for Neuroscience, Aging, and Stem Cell Research, Cancer Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Randal J
authors.initials: RJ
authors.lastname: Kaufman
authors.affiliation: Department of Life Science, BK21 PLUS Life Science for BDR team, The Research Institute of Natural Sciences, Hanyang University, Seoul 133-791, Korea.
authors.forename: Sun-Kyung
authors.initials: SK
authors.lastname: Lee
authors.affiliation: Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile. Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile. Neurounion Biomedical Foundation, Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
authors.affiliation: Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta T6G 2V4, Canada.
authors.forename: Lukasz
authors.initials: L
authors.lastname: Kurgan
authors.affiliation: Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S7, Canada. marek.michalak@ualberta.ca.
authors.forename: Marek
authors.initials: M
authors.lastname: Michalak
mesh_terms: D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism*; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism*; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D019704:Protein Disulfide-Isomerases / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; C582672:MIRN322 microRNA, mouse; D035683:MicroRNAs; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; C526507:Pdia6 protein, mouse; D019704:Protein Disulfide-Isomerases; D002118:Calcium