Mutant ubiquitin (UBB+1) associated with neurodegenerative disorders is hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-L3).

Frank J A Dennissen, Natalia Kholod, Denise J H P Hermes, Nadja Kemmerling, Harry W M Steinbusch, Nico P Dantuma, Fred W van Leeuwen

Department of Neuroscience, Faculty of Health Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands. f.dennissen@maastrichtuniversity.nl

FEBS letters 2011 Aug 19

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Mutant ubiquitin (UBB(+1)) accumulates in the hallmarks of tauopathies and polyglutamine diseases. We show that the deubiquitinating enzyme YUH1 of Saccharomyces cerevisiae and its mouse and human ortholog UCH-L3 are able to hydrolyze the C-terminal extension of UBB(+1). This yields another dysfunctional ubiquitin molecule (UB(G76Y)) with biochemical properties similar to full length UBB(+1). UBB(+1) may be detected in post-mortem tissue due to impaired C-terminal truncation of UBB(+1). Although the level of UCH-L3 protein in several neurodegenerative diseases is unchanged, we show that in vitro oxidation of recombinant UCH-L3 impairs its deubiquitinating activity. We postulate that impaired UCH-L3 function may contribute to the accumulation of full length UBB(+1) in various pathologies. Crown Copyright © 2011. Published by Elsevier B.V. All rights reserved.

Citation

Frank J A Dennissen, Natalia Kholod, Denise J H P Hermes, Nadja Kemmerling, Harry W M Steinbusch, Nico P Dantuma, Fred W van Leeuwen. Mutant ubiquitin (UBB+1) associated with neurodegenerative disorders is hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-L3). FEBS letters. 2011 Aug 19;585(16):2568-74