title: The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein.
abstract: Although the accumulation of a misfolded and protease-resistant form of the prion protein (PrP) is a key event in prion pathogenesis, the cellular factors involved in its folding and quality control are poorly understood. PrP is a glycosylated and disulfide-bonded protein synthesized at the endoplasmic reticulum (ER). The ER foldase ERp57 (also known as Grp58) is highly expressed in the brain of sporadic and infectious forms of prion-related disorders. ERp57 is a disulfide isomerase involved in the folding of a subset of glycoproteins in the ER as part of the calnexin/calreticulin cycle. Here, we show that levels of ERp57 increase mainly in neurons of Creutzfeldt-Jacob patients. Using gain- and loss-of-function approaches in cell culture, we demonstrate that ERp57 expression controls the maturation and total levels of wild-type PrP and mutant forms associated with human disease. In addition, we found that PrP physically interacts with ERp57, and also with the closest family member PDIA1, but not ERp72. Furthermore, we generated a conditional knock-out mouse for ERp57 in the nervous system and detected a reduction in the steady-state levels of the mono- and nonglycosylated forms of PrP in the brain. In contrast, ERp57 transgenic mice showed increased levels of endogenous PrP. Unexpectedly, ERp57 expression did not affect the susceptibility of cells to ER stress in vitro and in vivo. This study identifies ERp57 as a new modulator of PrP levels and may help with understanding the consequences of ERp57 up-regulation observed in human disease.
authors.affiliation: From the Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, the Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago 8380453, Chile.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Torres
authors.affiliation: From the Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, the Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago 8380453, Chile.
authors.forename: Danilo B
authors.initials: DB
authors.lastname: Medinas
authors.affiliation: From the Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, the Department of Neurological Sciences, Faculty of Medicine, University of Chile, Santiago 7500691, Chile.
authors.forename: José Manuel
authors.initials: JM
authors.lastname: Matamala
authors.affiliation: From the Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, the Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago 8380453, Chile.
authors.forename: Ute
authors.initials: U
authors.lastname: Woehlbier
authors.affiliation: From the Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, the Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago 8380453, Chile.
authors.forename: Víctor Hugo
authors.initials: VH
authors.lastname: Cornejo
authors.affiliation: the Institute for Research in Biomedicine, Bellinzona CH6500, Switzerland.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Solda
authors.affiliation: From the Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, the Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago 8380453, Chile.
authors.forename: Catherine
authors.initials: C
authors.lastname: Andreu
authors.affiliation: From the Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, the Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago 8380453, Chile.
authors.forename: Pablo
authors.initials: P
authors.lastname: Rozas
authors.affiliation: From the Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, the Neurounion Biomedical Foundation, CENPAR, Santiago 7630614, Chile.
authors.forename: Soledad
authors.initials: S
authors.lastname: Matus
authors.affiliation: From the Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, the Neurounion Biomedical Foundation, CENPAR, Santiago 7630614, Chile.
authors.forename: Natalia
authors.initials: N
authors.lastname: Muñoz
authors.affiliation: the Department of Neurological Sciences, Faculty of Medicine, University of Chile, Santiago 7500691, Chile.
authors.forename: Carmen
authors.initials: C
authors.lastname: Vergara
authors.affiliation: the Department of Neurological Sciences, Faculty of Medicine, University of Chile, Santiago 7500691, Chile.
authors.forename: Luis
authors.initials: L
authors.lastname: Cartier
authors.affiliation: the Department of Neurology, University of Texas Medical School, Houston, Texas 77030, and.
authors.forename: Claudio
authors.initials: C
authors.lastname: Soto
authors.affiliation: the Institute for Research in Biomedicine, Bellinzona CH6500, Switzerland, the Università della Svizzera Italiana, Lugano CH6900, Switzerland, the Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Lausanne CH1015, Switzerland.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Molinari
authors.affiliation: From the Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago 8380453, Chile, the Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, Center for Molecular Studies of the Cell, University of Chile, Santiago 8380453, Chile, the Harvard School of Public Health, Boston, Massachusetts 02115 chetz@med.uchile.cl chetz@hsph.harvard.edu.
authors.forename: Claudio
authors.initials: C
authors.lastname: Hetz
mesh_terms: D000818:Animals; D002460:Cell Line; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D011328:Prions / Q000378:metabolism*; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D017510:Protein Folding
chemical_list: D011328:Prions; D019704:Protein Disulfide-Isomerases; C085868:PDIA3 protein, human
keywords: ERp57 protein; calnexin/calreticulin cycle; endoplasmic reticulum (ER); endoplasmic reticulum stress (ER stress); prion disease; prion protein; protein-disulfide isomerase; transgenic mice