Niclosamide Prevents the Formation of Large Ubiquitin-Containing Aggregates Caused by Proteasome Inhibition
| Autor: | Thibault Mayor, Maria Brack, Esther A. Gies, Carolina Arias Novoa, Poul H. Sorensen, Inga B. Wilde, Aruna D. Balgi, Barak Rotblat, Jason M. Winget, Michel Roberge |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Proteasome Endopeptidase Complex
Green Fluorescent Proteins lcsh:Medicine Plasma protein binding Protein aggregation Biology Mechanistic Target of Rapamycin Complex 1 Biochemistry Neurological Disorders Microtubules Cell Biology/Cell Signaling 03 medical and health sciences 0302 clinical medicine JUNQ and IPOD Ubiquitin Microtubule Biochemistry/Cell Signaling and Trafficking Structures Autophagy Humans lcsh:Science Cell Biology/Chemical Biology of the Cell 030304 developmental biology Sirolimus 0303 health sciences Multidisciplinary Antinematodal Agents TOR Serine-Threonine Kinases lcsh:R Biochemistry/Chemical Biology of the Cell Fluorescence recovery after photobleaching Proteins Neurodegenerative Diseases Cell Biology Chemical Biology/Chemical Biology of the Cell Cell biology Proteasome Solubility Multiprotein Complexes biology.protein Niclosamide lcsh:Q Lysosomes 030217 neurology & neurosurgery Research Article Protein Binding |
| Zdroj: | PLoS ONE PLoS ONE, Vol 5, Iss 12, p e14410 (2010) |
| ISSN: | 1932-6203 |
| Popis: | Background Protein aggregation is a hallmark of many neurodegenerative diseases and has been linked to the failure to degrade misfolded and damaged proteins. In the cell, aberrant proteins are degraded by the ubiquitin proteasome system that mainly targets short-lived proteins, or by the lysosomes that mostly clear long-lived and poorly soluble proteins. Both systems are interconnected and, in some instances, autophagy can redirect proteasome substrates to the lysosomes. Principal Findings To better understand the interplay between these two systems, we established a neuroblastoma cell population stably expressing the GFP-ubiquitin fusion protein. We show that inhibition of the proteasome leads to the formation of large ubiquitin-containing inclusions accompanied by lower solubility of the ubiquitin conjugates. Strikingly, the formation of the ubiquitin-containing aggregates does not require ectopic expression of disease-specific proteins. Moreover, formation of these focused inclusions caused by proteasome inhibition requires the lysine 63 (K63) of ubiquitin. We then assessed selected compounds that stimulate autophagy and found that the antihelmintic chemical niclosamide prevents large aggregate formation induced by proteasome inhibition, while the prototypical mTORC1 inhibitor rapamycin had no apparent effect. Niclosamide also precludes the accumulation of poly-ubiquitinated proteins and of p62 upon proteasome inhibition. Moreover, niclosamide induces a change in lysosome distribution in the cell that, in the absence of proteasome activity, may favor the uptake into lysosomes of ubiquitinated proteins before they form large aggregates. Conclusions Our results indicate that proteasome inhibition provokes the formation of large ubiquitin containing aggregates in tissue culture cells, even in the absence of disease specific proteins. Furthermore our study suggests that the autophagy-inducing compound niclosamide may promote the selective clearance of ubiquitinated proteins in the absence of proteasome activity. |
| Databáze: | OpenAIRE |
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