title: Mutant ubiquitin (UBB+1) associated with neurodegenerative disorders is hydrolyzed by ubiquitin C-terminal hydrolase L3 (UCH-L3).
abstract: 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.
authors.affiliation: Department of Neuroscience, Faculty of Health Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands. f.dennissen@maastrichtuniversity.nl
authors.forename: Frank J A
authors.initials: FJ
authors.lastname: Dennissen
authors.forename: Natalia
authors.initials: N
authors.lastname: Kholod
authors.forename: Denise J H P
authors.initials: DJ
authors.lastname: Hermes
authors.forename: Nadja
authors.initials: N
authors.lastname: Kemmerling
authors.forename: Harry W M
authors.initials: HW
authors.lastname: Steinbusch
authors.forename: Nico P
authors.initials: NP
authors.lastname: Dantuma
authors.forename: Fred W
authors.initials: FW
authors.lastname: van Leeuwen
mesh_terms: D000818:Animals; D003546:Cysteine Endopeptidases / Q000378:metabolism*; D010450:Endopeptidases / Q000172:deficiency / Q000235:genetics; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D006868:Hydrolysis; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000235:genetics*; D010084:Oxidation-Reduction; D017384:Sequence Deletion; D025801:Ubiquitin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D043222:Ubiquitin Thiolesterase
chemical_list: D050505:Mutant Proteins; D025801:Ubiquitin; D010450:Endopeptidases; C509806:UCHL3 protein, human; D043222:Ubiquitin Thiolesterase; D003546:Cysteine Endopeptidases; C059237:ubiquitin-Nalpha-protein hydrolase