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 (UBG76Y) 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.

► YUH1 and UCH-L3 can truncate UBB+1 from its C-terminus.
► Hydrolysis of UBB+1 occurs after Y76 yielding a protein equal in length to ubiquitin.
► Biochemical properties of truncated UBB+1 are similar to full length UBB+1.
► Levels of UCH-L3 are unchanged in Alzheimer’s, Huntingtons’s and Parkinson’s disease.
► UCH-L3 is vulnerable to oxidation which is a hallmark in neurodegenerative disorders.