Impairment of the Ubiquitin-Proteasome System by Protein Aggregation
Abstract
Intracellular deposition of aggregated and ubiquitylated proteins is a prominent cytopathological feature of most neurodegenerative disorders. Whether protein aggregates themselves are pathogenic or are the consequence of an underlying molecular lesion is unclear. Here, we report that protein aggregation directly impaired the function of the ubiquitin-proteasome system. Transient expression of two unrelated aggregation-prone proteins, a huntingtin fragment containing a pathogenic polyglutamine repeat and a folding mutant of cystic fibrosis transmembrane conductance regulator, caused nearly complete inhibition of the ubiquitin-proteasome system. Because of the central role of ubiquitin-dependent proteolysis in regulating fundamental cellular events such as cell division and apoptosis, our data suggest a potential mechanism linking protein aggregation to cellular disregulation and cell death.
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We thank R. Frizzell for FLAG-CFTR, A. Tobin for huntingtin plasmids, M. Bucci for the GFP cell line, M. Rexach for anti-GFP, and C. Carswell-Crumpton for assistance with flow cytometry. We also thank R. Rajan and other members of the Kopito laboratory for stimulating discussions. Supported in part by a research grant from the National Institutes of Health, a Howard Hughes Summer Fellowship from the Department of Biological Sciences at Stanford University, and an NIH predoctoral training grant.
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Published In
Science
Volume 292 | Issue 5521
25 May 2001
25 May 2001
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Received: 6 February 2001
Accepted: 19 April 2001
Published in print: 25 May 2001
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- Neil F. Bence et al.
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