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Dose-dependent inhi...
Dose-dependent inhibition of proteasome activity by a mutant ubiquitin associated with neurodegenerative disease
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van Tijn, P (författare)
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de Vrij, FMS (författare)
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Schuurman, KG (författare)
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- Dantuma, NP (författare)
- Karolinska Institutet
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Fischer, DF (författare)
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van Leeuwen, FW (författare)
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Hol, EM (författare)
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(creator_code:org_t)
- The Company of Biologists, 2007
- 2007
- Engelska.
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Ingår i: Journal of cell science. - : The Company of Biologists. - 0021-9533 .- 1477-9137. ; 120:9Pt 9, s. 1615-1623
- Relaterad länk:
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http://jcs.biologist...
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http://kipublication...
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https://doi.org/10.1...
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Abstract
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- The ubiquitin-proteasome system is the main regulated intracellular proteolytic pathway. Increasing evidence implicates impairment of this system in the pathogenesis of diseases with ubiquitin-positive pathology. A mutant ubiquitin, UBB+1, accumulates in the pathological hallmarks of tauopathies, including Alzheimer's disease, polyglutamine diseases, liver disease and muscle disease and serves as an endogenous reporter for proteasomal dysfunction in these diseases. UBB+1 is a substrate for proteasomal degradation, however it can also inhibit the proteasome. Here, we show that UBB+1 properties shift from substrate to inhibitor in a dose-dependent manner in cell culture using an inducible UBB+1 expression system. At low expression levels, UBB+1 was efficiently degraded by the proteasome. At high levels, the proteasome failed to degrade UBB+1, causing its accumulation, which subsequently induced a reversible functional impairment of the ubiquitin-proteasome system. Also in brain slice cultures, UBB+1 accumulation and concomitant proteasome inhibition was only induced at high expression levels. Our findings show that by varying UBB+1 expression levels, the dual proteasome substrate and inhibitory properties can be optimally used to serve as a research tool to study the ubiquitin-proteasome system and to further elucidate the role of aberrations of this pathway in disease.
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