Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation

doi:10.1083/jcb.200111034

Published 29 April 2002. doi:10.1083/jcb.200111034

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© The Rockefeller University Press, 0021-9525/2002/4/417 $5.00
The Journal of Cell Biology, Volume 157, Number 3, April 29, 2002 417-427

Article

Mutant ubiquitin found in neurodegenerative disorders is a ubiquitin fusion degradation substrate that blocks proteasomal degradation

Kristina Lindsten¹, Femke M.S. de Vrij², Lisette G.G.C. Verhoef¹, David F. Fischer², Fred W. van Leeuwen², Elly M. Hol², Maria G. Masucci¹ and Nico P. Dantuma¹

¹ Microbiology and Tumor Biology Center, Karolinska Institutet, S-171 77 Stockholm, Sweden
² Graduate School for Neurosciences Amsterdam, Netherlands Institute for Brain Research, Research Group Molecular Misreading, 1105 AZ, Amsterdam, Netherlands

Address correspondence to Nico P. Dantuma, Microbiology and Tumor Biology Center, Karolinska Institutet, Box 280, S-171 77 Stockholm, Sweden. Tel.: 46-8-728-7147. Fax: 46-8-331-399. E-mail: nico.dantuma{at}mtc.ki.se

Loss of neurons in neurodegenerative diseases is usually precededby the accumulation of protein deposits that contain componentsof the ubiquitin/proteasome system. Affected neurons in Alzheimer'sdisease often accumulate UBB⁺¹, a mutant ubiquitin carryinga 19–amino acid C-terminal extension generated by a transcriptionaldinucleotide deletion. Here we show that UBB⁺¹ is a potent inhibitorof ubiquitin-dependent proteolysis in neuronal cells, and thatthis inhibitory activity correlates with induction of cell cyclearrest. Surprisingly, UBB⁺¹ is recognized as a ubiquitin fusiondegradation (UFD) proteasome substrate and ubiquitinated atLys²⁹ and Lys⁴⁸. Full blockade of proteolysis requires bothubiquitination sites. Moreover, the inhibitory effect was enhancedby the introduction of multiple UFD signals. Our findings suggestthat the inhibitory activity of UBB⁺¹ may be an important determinantof neurotoxicity and contribute to an environment that favorsthe accumulation of misfolded proteins.

Key Words: proteasome; neurodegeneration; aggregate; tauopathies; polyglutamine disorders

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