A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin |
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Authors: | Omura Tomohiro Kaneko Masayuki Okuma Yasunobu Orba Yasuko Nagashima Kazuo Takahashi Ryosuke Fujitani Noboru Matsumura Satoshi Hata Akihisa Kubota Kyoko Murahashi Karin Uehara Takashi Nomura Yasuyuki |
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Institution: | Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan. |
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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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Keywords: | endoplasmic reticulum stress endoplasmic reticulum-associated degradation HRD1 Parkin-associated endothelin receptor-like receptor Parkinson's disease unfolded protein response |
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