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.
Mesh Terms:
Animals, Blotting, Western, Cell Death, Endoplasmic Reticulum, Gene Expression Regulation, HSP70 Heat-Shock Proteins, Humans, Ligases, Macromolecular Substances, Male, Mice, Models, Biological, Parkinsonian Disorders, Protein Binding, Protein Folding, Protein Transport, Rats, Rats, Wistar, Substantia Nigra, Transfection, Tumor Cells, Cultured, Ubiquitin-Protein Ligases
Animals, Blotting, Western, Cell Death, Endoplasmic Reticulum, Gene Expression Regulation, HSP70 Heat-Shock Proteins, Humans, Ligases, Macromolecular Substances, Male, Mice, Models, Biological, Parkinsonian Disorders, Protein Binding, Protein Folding, Protein Transport, Rats, Rats, Wistar, Substantia Nigra, Transfection, Tumor Cells, Cultured, Ubiquitin-Protein Ligases
Mol. Cell
Date: Jul. 01, 2002
PubMed ID: 12150907
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