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

Research output: Contribution to journalArticle

64 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 2006
Externally publishedYes

Fingerprint

Endothelin Receptors
Ligases
Ubiquitin
Degradation
Endoplasmic Reticulum Stress
Substrates
Small Interfering RNA
Endoplasmic Reticulum-Associated Degradation
Ubiquitin-Protein Ligases
Ubiquitination
Dopaminergic Neurons
Parkinsonian Disorders
Proline
Caspase 3
Endoplasmic Reticulum
Neurons
Apoptosis
Chemical activation

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., ... 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

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

In: Journal of Neurochemistry, Vol. 99, No. 6, 12.2006, p. 1456-1469.

Research output: Contribution to journalArticle

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, vol. 99, no. 6, pp. 1456-1469. https://doi.org/10.1111/j.1471-4159.2006.04155.x
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. / A ubiquitin ligase HRD1 promotes the degradation of Pael receptor, a substrate of Parkin. In: Journal of Neurochemistry. 2006 ; Vol. 99, No. 6. pp. 1456-1469.
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