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A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin
Author(s) -
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
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04155.x
Subject(s) - endoplasmic reticulum , parkin , ubiquitin ligase , endoplasmic reticulum associated protein degradation , ubiquitin , microbiology and biotechnology , pars compacta , substantia nigra , atf6 , biology , small interfering rna , unfolded protein response , receptor , chemistry , dopaminergic , biochemistry , endocrinology , dopamine , transfection , medicine , parkinson's disease , disease , gene
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.