Impact of DJ-1 and Helix 8 on the Proteome and Degradome of Neuron-Like Cells

Cells. 2021 Feb 16;10(2):404. doi: 10.3390/cells10020404.


DJ-1 is an abundant and ubiquitous component of cellular proteomes. DJ-1 supposedly exerts a wide variety of molecular functions, ranging from enzymatic activities as a deglycase, protease, and esterase to chaperone functions. However, a consensus perspective on its molecular function in the cellular context has not yet been reached. Structurally, the C-terminal helix 8 of DJ-1 has been proposed to constitute a propeptide whose proteolytic removal transforms a DJ-1 zymogen to an active hydrolase with potential proteolytic activity. To better understand the cell-contextual functionality of DJ-1 and the role of helix 8, we employed post-mitotically differentiated, neuron-like SH-SY5Y neuroblastoma cells with stable over-expression of full length DJ-1 or DJ-1 lacking helix 8 (ΔH8), either with a native catalytically active site (C106) or an inactive site (C106A active site mutation). Global proteome comparison of cells over-expressing DJ-1 ΔH8 with native or mutated active site cysteine indicated a strong impact on mitochondrial biology. N-terminomic profiling however did not highlight direct protease substrate candidates for DJ-1 ΔH8, but linked DJ-1 to elevated levels of activated lysosomal proteases, albeit presumably in an indirect manner. Finally, we show that DJ-1 ΔH8 loses the deglycation activity of full length DJ-1. Our study further establishes DJ-1 as deglycation enzyme. Helix 8 is essential for the deglycation activity but dispensable for the impact on lysosomal and mitochondrial biology; further illustrating the pleiotropic nature of DJ-1.

Keywords: PARK7; TAILS; cathepsin b; degradation; glycase; lysosome; neurodegenerative disease; parkinson disease; protease; proteomics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cysteine / metabolism*
  • Humans
  • Lysosomes / metabolism
  • Mutation / genetics
  • Neurons / metabolism*
  • Oxidative Stress / physiology
  • Parkinson Disease / genetics
  • Parkinson Disease / metabolism
  • Peptide Hydrolases / metabolism
  • Protein Deglycase DJ-1 / genetics
  • Protein Deglycase DJ-1 / metabolism*
  • Proteome / genetics
  • Proteome / metabolism*


  • Proteome
  • Protein Deglycase DJ-1
  • Peptide Hydrolases
  • Cysteine