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Originally published In Press as doi:10.1074/jbc.M005543200 on September 1, 2000

J. Biol. Chem., Vol. 275, Issue 49, 38699-38704, December 8, 2000
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The Chaperone Protein BiP Binds to a Mutant Prion Protein and Mediates Its Degradation by the Proteasome*

Taocong Jin, Yaping Gu, Gianluigi Zanusso, ManSun Sy, Anil Kumar, Mark Cohen, Pierluigi Gambetti, and Neena SinghDagger

From the Division of Neuropathology, Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106

Familial prion diseases are thought to result from a change in structure of the mutant prion protein (PrP), which takes a pathogenic conformation. We have examined the role of molecular chaperones in the folding of normal and mutant PrP Q217R (PrP217) in transfected neuroblastoma cells. In a previous report we showed that, although most of the PrP217 forms escape the endoplasmic reticulum quality control system and aggregate in post-Golgi compartments, a significant proportion of PrP217 retains the C-terminal glycosylphosphatidyl inositol signal peptide (PrP32), and does not exit the endoplasmic reticulum (Singh, N., Zanusso, G., Chen, S. G., Fujioka, H., Richardson, S., Gambetti, P., and Petersen, R. B. (1997) J. Biol. Chem. 272, 28461-28470). We have now studied the folding and turnover of PrP32 to understand the mechanism by which abnormal PrP forms cause cellular toxicity in our cell culture model and in the human brain carrying the Gerstmann-Sträussler-Scheinker disease Q217R mutation. In this report, we show that PrP32 remains associated with the chaperone BiP for an abnormally prolonged period of time and is degraded by the proteasomal pathway. This study is the first demonstration that BiP is chaperoning the folding of PrP and plays a role in maintaining the quality control in the PrP maturation pathway. Our data provide new insight into the diverse pathways of mutant PrP metabolism and neurotoxicity.

* This study was funded by grants from the National Institutes of Health (to N. S. and P. G.), by the Sateriale fund (to N. S.), and by the Britton fund (to P. G.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Division of Neuropathology, Institute of Pathology, Case Western Reserve University, 2085 Adelbert Rd., Cleveland, OH 44106. Tel.: 216-368-2617, Fax: 216-368-2546; E-mail: nxs2@po.cwru.edu.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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