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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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Characterization of erasin (UBXD2): a new ER protein that promotes ER-associated protein degradation.
J. Liang, C. Yin, H. Doong, S. Fang, C. Peterhoff, R. A. Nixon, and M. J. Monteiro (2006)
J. Cell Sci. 119, 4011-4024
   Abstract »    Full Text »    PDF »
Dysregulation of the Ubiquitin-Proteasome System in Human Carotid Atherosclerosis.
D. Versari, J. Herrmann, M. Gossl, D. Mannheim, K. Sattler, F. B. Meyer, L. O. Lerman, and A. Lerman (2006)
Arterioscler. Thromb. Vasc. Biol. 26, 2132-2139
   Abstract »    Full Text »    PDF »
Archaeal Proteasomes Effectively Degrade Aggregation-prone Proteins and Reduce Cellular Toxicities in Mammalian Cells.
S.-i. Yamada, J.-i. Niwa, S. Ishigaki, M. Takahashi, T. Ito, J. Sone, M. Doyu, and G. Sobue (2006)
J. Biol. Chem. 281, 23842-23851
   Abstract »    Full Text »    PDF »
Glutathiolation Enhances the Degradation of {gamma}C-crystallin in Lens and Reticulocyte Lysates, Partially via the Ubiquitin-Proteasome Pathway..
M. Zetterberg, X. Zhang, A. Taylor, B. Liu, J. J. Liang, and F. Shang (2006)
Invest. Ophthalmol. Vis. Sci. 47, 3467-3473
   Abstract »    Full Text »    PDF »
Modulation of D-Serine Levels via Ubiquitin-dependent Proteasomal Degradation of Serine Racemase.
E. Dumin, I. Bendikov, V. N. Foltyn, Y. Misumi, Y. Ikehara, E. Kartvelishvily, and H. Wolosker (2006)
J. Biol. Chem. 281, 20291-20302
   Abstract »    Full Text »    PDF »
Folding and Fibril Formation of the Cell Cycle Protein Cks1.
R. Bader, M. A. Seeliger, S. E. Kelly, L. L. Ilag, F. Meersman, A. Limones, B. F. Luisi, C. M. Dobson, and L. S. Itzhaki (2006)
J. Biol. Chem. 281, 18816-18824
   Abstract »    Full Text »    PDF »
Biologically active molecules that reduce polyglutamine aggregation and toxicity.
U. A. Desai, J. Pallos, A. A. K. Ma, B. R. Stockwell, L. M. Thompson, J. L. Marsh, and M. I. Diamond (2006)
Hum. Mol. Genet. 15, 2114-2124
   Abstract »    Full Text »    PDF »
The ubiquitin-proteasome system in cardiac physiology and pathology.
S. R. Powell (2006)
Am J Physiol Heart Circ Physiol 291, H1-H19
   Abstract »    Full Text »    PDF »
Cytoplasmic Lipid Droplets Are Sites of Convergence of Proteasomal and Autophagic Degradation of Apolipoprotein B.
Y. Ohsaki, J. Cheng, A. Fujita, T. Tokumoto, and T. Fujimoto (2006)
Mol. Biol. Cell 17, 2674-2683
   Abstract »    Full Text »    PDF »
The ubiquitin-proteasome system: Focus on the heart.
O. Zolk, C. Schenke, and A. Sarikas (2006)
Cardiovasc Res 70, 410-421
   Abstract »    Full Text »    PDF »
Proteasomal dysfunction in sporadic Parkinson's disease.
K. St. P. McNaught, T. Jackson, R. JnoBaptiste, A. Kapustin, and C. W. Olanow (2006)
Neurology 66, S37-S49
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From the Cover: Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice.
Y. Furukawa, R. Fu, H.-X. Deng, T. Siddique, and T. V. O'Halloran (2006)
PNAS 103, 7148-7153
   Abstract »    Full Text »    PDF »
GFP reporter mouse models of UPS proteolytic function.
K. Lindsten, V. Menendez-Benito, M. G. Masucci, N. P. Dantuma, A. R. K. Kumarapeli, K. M. Horak, H. Zheng, and X. Wang (2006)
FASEB J 20, 1027-1028
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