Impairment of the Ubiquitin-Proteasome System by Protein Aggregation

• Published in: Science (American Association for the Advancement of Science) 2001-05, Vol.292 (5521), p.1552-1555
• Main Authors: Bence, Neil F., Sampat, Roopal M., Kopito, Ron R.
• Format: Article
• Language: English
• Subjects: Acetylcysteine - analogs & derivatives; Acetylcysteine - pharmacology; Aggregation; Amino Acid Sequence; Biological and medical sciences; Cell aggregates; Cell cycle; Cell Death; Cell Line; Cellular biology; Cellular immunity; Cysteine Endopeptidases - metabolism; Cysteine Proteinase Inhibitors - pharmacology; cystic fibrosis transmembrane conductance regulator; Cystic Fibrosis Transmembrane Conductance Regulator - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Cytometry; Degeneration; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; DNA; Endoplasmic Reticulum - metabolism; Evidence; Fluorescence; G2 Phase; Genetic research; Green Fluorescent Proteins; Humans; Huntingtin Protein; Inclusion bodies; Inclusion Bodies - metabolism; Inhibition; Leupeptins - pharmacology; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Medical sciences; Molecular Sequence Data; Multienzyme Complexes - antagonists & inhibitors; Multienzyme Complexes - metabolism; Nerve degeneration; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Nervous system; Neurology; Neurons; Neuroscience; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Pathology; Proteases; Proteasome Endopeptidase Complex; Protein research; Proteins; Quality Control; Recombinant Fusion Proteins - metabolism; Transfection; Ubiquitin; Ubiquitins; Ubiquitins - metabolism
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.292.5521.1552

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.