A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin

Authors

  • Tomohiro Omura,

    1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
    2. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Chiba, Japan
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  • Masayuki Kaneko,

    1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
    2. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Chiba, Japan
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  • Yasunobu Okuma,

    1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
    2. Department of Pharmacology, Faculty of Pharmaceutical Sciences, Chiba Institute of Science, Choshi, Chiba, Japan
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  • Yasuko Orba,

    1. Laboratory of Molecular and Cellular Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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  • Kazuo Nagashima,

    1. Laboratory of Molecular and Cellular Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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  • Ryosuke Takahashi,

    1. Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan
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  • Noboru Fujitani,

    1. Division of Clinical Laboratory Science, Department of Environmental Security System, Faculty of Risk and Crisis Management, Chiba Institute of Science, Choshi, Chiba, Japan
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  • Satoshi Matsumura,

    1. Division of Clinical Laboratory Science, Department of Environmental Security System, Faculty of Risk and Crisis Management, Chiba Institute of Science, Choshi, Chiba, Japan
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  • Akihisa Hata,

    1. Division of Clinical Laboratory Science, Department of Environmental Security System, Faculty of Risk and Crisis Management, Chiba Institute of Science, Choshi, Chiba, Japan
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  • Kyoko Kubota,

    1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
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  • Karin Murahashi,

    1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
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  • Takashi Uehara,

    1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
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  • Yasuyuki Nomura

    1. Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan
    2. Hokkaido University Graduate School of Medicine, Sapporo, Japan
    3. Yokohama College of Pharmacy, Yokohama, Japan
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Address correspondence and reprint requests to Yasuyuki Nomura, Yokohama College of Pharmacy, Yokohama 245–0066, Japan.
E-mail: nomura@pharm.hokudai.ac.jp

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.

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