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Science 25 May 2001:
Vol. 292. no. 5521, pp. 1552 - 1555
DOI: 10.1126/science.292.5521.1552
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Reports

Impairment of the Ubiquitin-Proteasome System by Protein Aggregation

Neil F. Bence, Roopal M. Sampat, Ron R. Kopito*

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.

Department of Biological Sciences, Stanford University, Stanford, CA 94305-5020, USA.
*   To whom correspondence should be addressed. E-mail: kopito{at}stanford.edu

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High Levels of Heat Shock Protein Hsp72 in Cancer Cells Suppress Default Senescence Pathways.
J. A. Yaglom, V. L. Gabai, and M. Y. Sherman (2007)
Cancer Res. 67, 2373-2381
   Abstract »    Full Text »    PDF »
Soluble Androgen Receptor Oligomers Underlie Pathology in a Mouse Model of Spinobulbar Muscular Atrophy.
M. Li, E. S. Chevalier-Larsen, D. E. Merry, and M. I. Diamond (2007)
J. Biol. Chem. 282, 3157-3164
   Abstract »    Full Text »    PDF »
Effects of Ubiquitin System Alterations on the Formation and Loss of a Yeast Prion.
K. D. Allen, T. A. Chernova, E. P. Tennant, K. D. Wilkinson, and Y. O. Chernoff (2007)
J. Biol. Chem. 282, 3004-3013
   Abstract »    Full Text »    PDF »
The 3'-untranslated region of the Ste20-like kinase SLK regulates SLK expression.
A. V. Cybulsky, T. Takano, J. Papillon, W. Hao, A. Mancini, J. A. Di Battista, and M. I. Cybulsky (2007)
Am J Physiol Renal Physiol 292, F845-F852
   Abstract »    Full Text »    PDF »
Proteasome dysfunction inhibits surfactant protein gene expression in lung epithelial cells: mechanism of inhibition of SP-B gene expression.
A. Das and V. Boggaram (2007)
Am J Physiol Lung Cell Mol Physiol 292, L74-L84
   Abstract »    Full Text »    PDF »
HSP70 Induction by ING Proteins Sensitizes Cells to Tumor Necrosis Factor Alpha Receptor-Mediated Apoptosis.
X. Feng, S. Bonni, and K. Riabowol (2006)
Mol. Cell. Biol. 26, 9244-9255
   Abstract »    Full Text »    PDF »
Synergistic Effects of the SAPK/JNK and the Proteasome Pathway on Glial Fibrillary Acidic Protein (GFAP) Accumulation in Alexander Disease.
G. Tang, Z. Xu, and J. E. Goldman (2006)
J. Biol. Chem. 281, 38634-38643
   Abstract »    Full Text »    PDF »
Heart Failure and Protein Quality Control.
X. Wang and J. Robbins (2006)
Circ. Res. 99, 1315-1328
   Abstract »    Full Text »    PDF »
Expression of Expanded Polyglutamine Proteins Suppresses the Activation of Transcription Factor NF{kappa}B.
A. Goswami, P. Dikshit, A. Mishra, N. Nukina, and N. R. Jana (2006)
J. Biol. Chem. 281, 37017-37024
   Abstract »    Full Text »    PDF »
O-GlcNAc Integrates the Proteasome and Transcriptome To Regulate Nuclear Hormone Receptors.
D. B. Bowe, A. Sadlonova, C. A. Toleman, Z. Novak, Y. Hu, P. Huang, S. Mukherjee, T. Whitsett, A. R. Frost, A. J. Paterson, et al. (2006)
Mol. Cell. Biol. 26, 8539-8550
   Abstract »    Full Text »    PDF »
Narrative review: protein degradation and human diseases: the ubiquitin connection..
E. Reinstein and A. Ciechanover (2006)
Ann Intern Med 145, 676-684
   Abstract »    Full Text »    PDF »
Insoluble Mutant SOD1 Is Partly Oligoubiquitinated in Amyotrophic Lateral Sclerosis Mice.
M. Basso, T. Massignan, G. Samengo, C. Cheroni, S. De Biasi, M. Salmona, C. Bendotti, and V. Bonetto (2006)
J. Biol. Chem. 281, 33325-33335
   Abstract »    Full Text »    PDF »
Cleavage of misfolded nuclear receptor corepressor confers resistance to unfolded protein response-induced apoptosis..
A. P. P. Ng, J. Howe Fong, D. Sijin Nin, J. L. Hirpara, N. Asou, C.-S. Chen, S. Pervaiz, and M. Khan (2006)
Cancer Res. 66, 9903-9912
   Abstract »    Full Text »    PDF »


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