A Ubiquitin Ligase Hrd1 Promotes the Degradation of Pael Receptor, a Substrate of Parkin.
From: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Journal of neurochemistry
- Publish Date: Dec 2006
- ISSN: 0022-3042
- Volume: 99
- Issue: 6
- Pages: 1456-69
- Medium: Print
- Language: English
- Citation (JAMA): Omura Tomohiro, Kaneko Masayuki, Okuma Yasunobu, et al. A Ubiquitin Ligase Hrd1 Promotes the Degradation of Pael Receptor, a Substrate of Parkin.. J. Neurochem. Dec 2006;99:1456-69
Abstract
It has been proposed that in autosomal recessive juvenile parkinsonism (AR-JP), a ubiquitin ligase (E3) Parkin, which is involved in endoplasmic reticulum-associated degradation (ERAD), lacks E3 activity. The resulting accumulation of Parkin-associated endothelin receptor-like receptor (Pael-R), a substrate of Parkin, leads to endoplasmic reticulum stress, causing neuronal death. We previously reported that human E3 HRD1 in the endoplasmic reticulum protects against endoplasmic reticulum stress-induced apoptosis. This study shows that HRD1 was expressed in substantia nigra pars compacta (SNC) dopaminergic neurons and interacted with Pael-R through the HRD1 proline-rich region, promoting the ubiquitylation and degradation of Pael-R. Furthermore, the disruption of endogenous HRD1 by small interfering RNA (siRNA) induced Pael-R accumulation and caspase-3 activation. We also found that ATF6 overexpression, which induced HRD1, accelerated and caused Pael-R degradation; the suppression of HRD1 expression by siRNA partially prevents this degradation. These results suggest that in addition to Parkin, HRD1 is also involved in the degradation of Pael-R.
Mesh Headings (Keywords): Animals, Blotting, Western, Cell Death, Cell Line, Dopamine, Endoplasmic Reticulum, Gene Expression Regulation, Glial Fibrillary Acidic Protein, Humans, Immunohistochemistry, Immunoprecipitation, Mice, Mice, Transgenic, Models, Biological, Mutagenesis, Neurons, Phosphopyruvate Hydratase, Proline, Protein Binding, RNA Interference, Receptors, G-Protein-Coupled, Substantia Nigra, Ubiquitin-Protein Ligases, alpha-Synuclein
Check for Full Text / PubMed Unique Identifier (PMID): 17059562
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