Parkin is recruited to the centrosome in response to inhibition of proteasomes

J Cell Sci. 2003 Oct 1;116(Pt 19):4011-9. doi: 10.1242/jcs.00700. Epub 2003 Aug 19.

Abstract

Parkin is a protein-ubiquitin E3 ligase linked to Parkinson's disease. Although several substrates of parkin have been identified, the subcellular location for parkin to recognize and ubiquitinate its targets is unclear. Here we report that parkin was accumulated in the centrosome when SH-SY5Y or transfected HEK293 cells were treated with the proteasome inhibitor lactacystin. The specific recruitment of parkin was dependent on concentration and duration of the treatment, and was accompanied by the centrosomal accumulation of ubiquitinated proteins and CDCrel-1, a substrate of parkin. The recruitment of parkin was apparently mediated through its binding to gamma-tubulin, which has been shown to accumulate in the centrosome in response to misfolded proteins. Furthermore, the effect was abrogated by the microtubule-depolymerizing drug colchicine or the microtubule-stabilizing drug taxol, which indicates that the intact microtubule network is required for the centrosomal recruitment of parkin. Taken together, our data suggest that the lactacystin-induced accumulation of parkin in the centrosome plays a significant role in the ubiquitination of misfolded substrates accumulated there. This process may provide a subcellular locale for parkin to ubiquitinate and degrade protein aggregates critically involved in the pathogenesis of Parkinson's disease.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 3T3 Cells
  • Acetylcysteine / analogs & derivatives*
  • Acetylcysteine / pharmacology
  • Animals
  • Brain
  • COS Cells
  • Centrosome / metabolism*
  • Chlorocebus aethiops
  • Cysteine Endopeptidases / drug effects
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Humans
  • Immunohistochemistry
  • Mice
  • Microtubules / metabolism
  • Multienzyme Complexes / drug effects
  • Multienzyme Complexes / metabolism*
  • Parkinson Disease / metabolism*
  • Proteasome Endopeptidase Complex
  • Protein Binding
  • Protein Denaturation / physiology
  • Protein Folding
  • Rats
  • Tubulin / metabolism
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitins / metabolism

Substances

  • Cysteine Proteinase Inhibitors
  • Multienzyme Complexes
  • Tubulin
  • Ubiquitins
  • lactacystin
  • Ubiquitin-Protein Ligases
  • parkin protein
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • Acetylcysteine