Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation

Eric J Bennett; Neil F Bence; Rajadas Jayakumar; Ron R Kopito

doi:10.1016/j.molcel.2004.12.021

Global impairment of the ubiquitin-proteasome system by nuclear or cytoplasmic protein aggregates precedes inclusion body formation

Mol Cell. 2005 Feb 4;17(3):351-65. doi: 10.1016/j.molcel.2004.12.021.

Authors

Eric J Bennett¹, Neil F Bence, Rajadas Jayakumar, Ron R Kopito

Affiliation

¹ Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.

PMID: 15694337
DOI: 10.1016/j.molcel.2004.12.021

Abstract

The highly conserved ubiquitin-proteasome system (UPS) controls the stability of most nuclear and cytoplasmic proteins and is therefore essential for virtually all aspects of cellular function. We have previously shown that the UPS is impaired in the presence of aggregated proteins that become deposited into cytoplasmic inclusion bodies (IBs). Here, we report that production of protein aggregates specifically targeted to either the nucleus or cytosol leads to global impairment of UPS function in both cellular compartments and is independent of sequestration of aggregates into IBs. The observation of severe UPS impairment in compartments lacking detectable aggregates or aggregation-prone protein, together with the lack of interference of protein aggregates on 26S proteasome function in vitro, suggests that UPS impairment is unlikely to be a consequence of direct choking of proteasomes by protein aggregates. These data suggest a common proteotoxic mechanism for nuclear and cytoplasmic protein aggregates in the pathogenesis of neurodegenerative disease.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Cell Line
Cytoplasm / metabolism
Green Fluorescent Proteins / chemistry
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
Humans
Inclusion Bodies / metabolism*
Multiprotein Complexes
Nuclear Proteins / chemistry
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Peptides / chemistry
Peptides / genetics
Peptides / metabolism
Proteasome Endopeptidase Complex / chemistry
Proteasome Endopeptidase Complex / genetics
Proteasome Endopeptidase Complex / metabolism*
Recombinant Fusion Proteins / chemistry
Recombinant Fusion Proteins / genetics
Recombinant Fusion Proteins / metabolism
Rhodopsin / chemistry
Rhodopsin / genetics
Rhodopsin / metabolism
Transfection
Ubiquitin / chemistry
Ubiquitin / genetics
Ubiquitin / metabolism*

Substances

Multiprotein Complexes
Nuclear Proteins
Peptides
Recombinant Fusion Proteins
Ubiquitin
Green Fluorescent Proteins
polyglutamine
Rhodopsin
Proteasome Endopeptidase Complex
ATP dependent 26S protease