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, Elly M. Hol*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

81 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1615-1623
Number of pages9
JournalJournal of Cell Science
Issue number9
Publication statusPublished - 1 May 2007
Externally publishedYes


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