A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin.
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.
Omura
Tomohiro
T
Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Kaneko
Masayuki
M
Okuma
Yasunobu
Y
Orba
Yasuko
Y
Nagashima
Kazuo
K
Takahashi
Ryosuke
R
Fujitani
Noboru
N
Matsumura
Satoshi
S
Hata
Akihisa
A
Kubota
Kyoko
K
Murahashi
Karin
K
Uehara
Takashi
T
Nomura
Yasuyuki
Y
D000818:Animals; D015153:Blotting, Western / Q000379:methods; D016923:Cell Death / Q000502:physiology; D002460:Cell Line; D004298:Dopamine / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D047468:Immunoprecipitation; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D016296:Mutagenesis / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D013378:Substantia Nigra / Q000166:cytology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D051844:alpha-Synuclein / Q000235:genetics
C480827:GPR37 receptor, human; D005904:Glial Fibrillary Acidic Protein; D043562:Receptors, G-Protein-Coupled; D051844:alpha-Synuclein; D011392:Proline; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein; D010751:Phosphopyruvate Hydratase; D004298:Dopamine