A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin

Tomohiro Omura, Masayuki Kaneko, Yasunobu Okuma, Yasuko Orba, Kazuo Nagashima, Ryosuke Takahashi, Noboru Fujitani, Satoshi Matsumura, Akihisa Hata, Kyoko Kubota, Karin Murahashi, Takashi Uehara, Yasuyuki Nomura

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65 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1456-1469
Number of pages14
JournalJournal of Neurochemistry
Volume99
Issue number6
DOIs
Publication statusPublished - Dec 1 2006

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Keywords

  • Endoplasmic reticulum stress
  • Endoplasmic reticulum-associated degradation
  • HRD1
  • Parkin-associated endothelin receptor-like receptor
  • Parkinson's disease
  • Unfolded protein response

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

Cite this

Omura, T., Kaneko, M., Okuma, Y., Orba, Y., Nagashima, K., Takahashi, R., Fujitani, N., Matsumura, S., Hata, A., Kubota, K., Murahashi, K., Uehara, T., & Nomura, Y. (2006). A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin. Journal of Neurochemistry, 99(6), 1456-1469. https://doi.org/10.1111/j.1471-4159.2006.04155.x