title: A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin.
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.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Omura
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kaneko
authors.forename: Yasunobu
authors.initials: Y
authors.lastname: Okuma
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Orba
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagashima
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.forename: Noboru
authors.initials: N
authors.lastname: Fujitani
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsumura
authors.forename: Akihisa
authors.initials: A
authors.lastname: Hata
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kubota
authors.forename: Karin
authors.initials: K
authors.lastname: Murahashi
authors.forename: Takashi
authors.initials: T
authors.lastname: Uehara
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nomura
mesh_terms: 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
chemical_list: 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