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....

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Bibliographic Details
Published in:Molecular cell 2002-07, Vol.10 (1), p.55-67
Main Authors: Imai, Yuzuru, Soda, Mariko, Hatakeyama, Shigetsugu, Akagi, Takumi, Hashikawa, Tsutomu, Nakayama, Kei-Ichi, Takahashi, Ryosuke
Format: Article
Language:English
Subjects:
Animals
Blotting, Western
Cell Death
Endoplasmic Reticulum - metabolism
Gene Expression Regulation
HSP70 Heat-Shock Proteins - metabolism
Humans
Ligases - genetics
Ligases - metabolism
Macromolecular Substances
Male
Mice
Models, Biological
Parkinsonian Disorders - enzymology
Parkinsonian Disorders - genetics
Parkinsonian Disorders - pathology
Protein Binding
Protein Folding
Protein Transport
Rats
Rats, Wistar
Substantia Nigra - ultrastructure
Transfection
Tumor Cells, Cultured
Ubiquitin-Protein Ligases
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Summary: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.
ISSN:1097-2765
1097-4164
DOI:10.1016/S1097-2765(02)00583-X