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- Title
A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin.
- 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
- 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.
- Publication
Journal of neurochemistry, 2006, Vol 99, Issue 6, p1456
- ISSN
0022-3042
- Publication type
Journal Article
- DOI
10.1111/j.1471-4159.2006.04155.x