The Protein-disulfide Isomerase ERp57 Regulates the Steady-state Levels of the Prion Protein

Artículo de publicación ISIAlthough 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.FONDECYT 1140549 1100176 11121524 Millennium Institute P09-015-F Ring Initiative ACT1109 FONDEF D11I1007 CONICYT USA2013-0003 ECOS-CONICYTC13S02 Michael J. Fox Foundation for Parkinson Research Frick Foundation Amyotrophic Lateral Sclerosis Therapy Alliance Muscular Dystrophy Association, Foundation Grant COPEC-UC FONDECYT Postdoctoral Fellowship 3110067 3130351 CONICYT Foundation for Research on Neurodegenerative Diseases Swiss National Science Foundation Comel Foundation Gabriele Foundation Gelu Foundatio