Parkin is recruited to the centrosome in response to inhibition of proteasomes.
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.
Zhao
Jinghui
J
Department of Physiology and Biophysics, State University of New York at Buffalo, Buffalo, NY 14214, USA.
Ren
Yong
Y
Jiang
Qian
Q
Feng
Jian
J
D016475:3T3 Cells; D000111:Acetylcysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001921:Brain; D019556:COS Cells; D018385:Centrosome / Q000378:metabolism*; D002522:Chlorocebus aethiops; D003546:Cysteine Endopeptidases / Q000187:drug effects / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008870:Microtubules / Q000378:metabolism; D009097:Multienzyme Complexes / Q000187:drug effects / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011485:Protein Binding; D011489:Protein Denaturation / Q000502:physiology; D017510:Protein Folding; D051381:Rats; D014404:Tubulin / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D014404:Tubulin; D014452:Ubiquitins; C067713:lactacystin; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine