A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin
A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin
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DOI：
10.1111/j.1471-4159.2006.04155.x
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发表时间：
2006-12-01
影响因子：
4.7
通讯作者：
Nomura, Yasuyuki
中科院分区：
文献类型：
--
作者：
Omura, Tomohiro;Kaneko, Masayuki;Nomura, Yasuyuki
已经提出，在常染色体隐性青少年帕金森综合征（AR-JP）中，参与内质网相关降解（ERAD）的泛素连接酶（E3）Parkin缺乏E3活性。由此产生的帕金相关内皮素受体样受体（Pael-R）（帕金的底物）的积累导致内质网应激，引起神经元死亡。我们以前报道过，内质网中的人E3 HRD 1可以保护内质网应激诱导的细胞凋亡。本研究表明HRD 1在黑质多巴胺能神经元中表达，并通过HRD 1脯氨酸富集区与Pael-R相互作用，促进Pael-R的泛素化和降解。此外，通过小干扰RNA（siRNA）破坏内源性HRD 1诱导Pael-R积累和caspase-3活化。我们还发现，诱导HRD 1的ATF 6过表达加速并导致Pael-R降解;通过siRNA抑制HRD 1表达部分阻止了这种降解。这些结果表明，除了Parkin，HRD 1也参与了Pael-R的降解。
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.