CHIP is associated with Parkin, a gene responsible for familial Parkinson's disease, and enhances its ubiquitin ligase activity.
Unfolded Pael receptor (Pael-R) is a substrate of the E3 ubiquitin ligase Parkin. Accumulation of Pael-R in the endoplasmic reticulum (ER) of dopaminergic neurons induces ER stress leading to neurodegeneration. Here, we show that CHIP, Hsp70, Parkin, and Pael-R formed a complex in vitro and in vivo. The amount of CHIP in the complex was increased during ER stress. CHIP promoted the dissociation of Hsp70 from Parkin and Pael-R, thus facilitating Parkin-mediated Pael-R ubiquitination. Moreover, CHIP enhanced Parkin-mediated in vitro ubiquitination of Pael-R in the absence of Hsp70. Furthermore, CHIP enhanced the ability of Parkin to inhibit cell death induced by Pael-R. Taken together, these results indicate that CHIP is a mammalian E4-like molecule that positively regulates Parkin E3 activity.
Imai
Yuzuru
Y
Laboratory for Motor System Neurodegeneration, RIKEN Brain Science Institute, Saitama 351-0198, Japan.
Soda
Mariko
M
Hatakeyama
Shigetsugu
S
Akagi
Takumi
T
Hashikawa
Tsutomu
T
Nakayama
Kei Ichi
KI
Takahashi
Ryosuke
R
D000818:Animals; D015153:Blotting, Western; D016923:Cell Death; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008025:Ligases / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances; D008297:Male; D051379:Mice; D008954:Models, Biological; D020734:Parkinsonian Disorders / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D011485:Protein Binding; D017510:Protein Folding; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000648:ultrastructure; D014162:Transfection; D014407:Tumor Cells, Cultured; D044767:Ubiquitin-Protein Ligases
D018840:HSP70 Heat-Shock Proteins; D046911:Macromolecular Substances; C467728:STUB1 protein, human; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D008025:Ligases