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

FEBS Lett. 2011 Aug 19;585(16):2568-74. doi: 10.1016/j.febslet.2011.06.037. Epub 2011 Jul 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cysteine Endopeptidases / metabolism*
  • Endopeptidases / deficiency
  • Endopeptidases / genetics
  • HEK293 Cells
  • HeLa Cells
  • Humans
  • Hydrolysis
  • Mice
  • Mutant Proteins / metabolism*
  • Neurodegenerative Diseases / genetics*
  • Oxidation-Reduction
  • Sequence Deletion*
  • Ubiquitin / deficiency
  • Ubiquitin / genetics
  • Ubiquitin / metabolism*
  • Ubiquitin Thiolesterase

Substances

  • Mutant Proteins
  • Ubiquitin
  • Endopeptidases
  • UCHL3 protein, human
  • Ubiquitin Thiolesterase
  • Cysteine Endopeptidases
  • ubiquitin-Nalpha-protein hydrolase