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Journal article

The protein disulfide isomerase ERp57 regulates the steady-state levels of the prion protein

  • Torres, Mauricio Neuroscience Biomedical Institute, Faculty of Medicine, University of Chile, Santiago, Chile - Institute of Biomedical Sciences, Center for Molecular Studies of the Cell University of Chile, Santiago, Chile
  • Medinas,Danilo B. Neuroscience Biomedical Institute, Faculty of Medicine, University of Chile, Santiago, Chile - Institute of Biomedical Sciences, Center for Molecular Studies of the Cell University of Chile, Santiago, Chile
  • Matamala, José Manuel Neuroscience Biomedical Institute, Faculty of Medicine, University of Chile, Santiago, Chile - Department of Neurological Sciences, Faculty of Medicine, University of Chile
  • Woehlbier, Ute Neuroscience Biomedical Institute, Faculty of Medicine, University of Chile, Santiago, Chile - Institute of Biomedical Sciences, Center for Molecular Studies of the Cell University of Chile, Santiago, Chile
  • Cornejo, Víctor Hugo Neuroscience Biomedical Institute, Faculty of Medicine, University of Chile, Santiago, Chile - Institute of Biomedical Sciences, Center for Molecular Studies of the Cell University of Chile, Santiago, Chile
  • Solda, Tatiana Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland
  • Andreu, Catherine Neuroscience Biomedical Institute, Faculty of Medicine, University of Chile, Santiago, Chile - Institute of Biomedical Sciences, Center for Molecular Studies of the Cell University of Chile, Santiago, Chile
  • Rozas, Pablo Neuroscience Biomedical Institute, Faculty of Medicine, University of Chile, Santiago, Chile - Institute of Biomedical Sciences, Center for Molecular Studies of the Cell University of Chile, Santiago, Chile
  • Matus, Soledad Neuroscience Biomedical Institute, Faculty of Medicine, University of Chile, Santiago, Chile - Neurounion Biomedical Foundation, CENPAR, Santiago, Chile
  • Muñoz, Natalia Neuroscience Biomedical Institute, Faculty of Medicine, University of Chile, Santiago, Chile - Neurounion Biomedical Foundation, CENPAR, Santiago, Chile
  • Vergara, Carmen Department of Neurological Sciences, Faculty of Medicine, University of Chile
  • Cartier, Luis Department of Neurological Sciences, Faculty of Medicine, University of Chile
  • Soto, Claudio Department of Neurology, University of Texas Medical School, Houston, USA
  • Molinari, Maurizio Institute for Research in Biomedicine (IRB), Faculty of Biomedical Sciences, Università della Svizzera italiana, Switzerland - Ecole Polytechnique Fédérale de Lausanne, School of Life Sciences, Lausanne, Switzerland
  • Hetz, Claudio Neuroscience Biomedical Institute, Faculty of Medicine, University of Chile, Santiago, Chile - Institute of Biomedical Sciences, Center for Molecular Studies of the Cell University of Chile, Santiago, Chile - Harvard School of Public Health, Boston, USA
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    13.07.2015
Published in:
  • The journal of biological chemistry. - 2015, vol. 290, no. 39, p. 23631-23645
ERp57 protein
Calnexin/Calreticulin cycle
Prion protein
Prion diseases
English 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 directly 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 knockout mouse for ERp57 in the nervous system and detected a reduction in the steady-state levels of the mono- and non-glycosylated 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 understanding the consequences of ERp57 upregulation observed in human disease.
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  • English
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Medicine
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https://n2t.net/ark:/12658/srd1318826
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