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

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.