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JCS ePress online publication date 3 Apr 2007
doi: 10.1242/jcs.03438

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Research Article

Dose-dependent inhibition of proteasome activity by a mutant ubiquitin associated with neurodegenerative disease


Paula van Tijn, Femke M.S. de Vrij, Karianne G. Schuurman, Nico P. Dantuma, David F. Fischer, Fred W. van Leeuwen, and Elly M. Hol*
* Author for correspondence (e-mail: e.hol{at}nin.knaw.nl)

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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