title: [Protective effects of HRD1 and 4-phenylbutyric acid against neuronal cell death].
abstract: Endoplasmic reticulum-associated degradation (ERAD) is a system in which unfolded proteins drained from the ER lumen to the cytosol are ubiquitinated then degraded by 26S proteasome. We have identified and characterized human HRD1 as a ubiquitin ligase involved in ERAD that protects against ER stress-induced cell death. Accumulation of Pael receptor (Pael-R), a substrate of Parkin, has been proposed to lead to neuronal death in Autosomal Recessive Juvenile Parkinsonism (AR-JP). HRD1 co-localized with Pael-R in the ER and interacted with Pael-R through the proline-rich region of HRD1. HRD1 ubiquitinated and degraded Pael-R through its ubiqutin ligase activity. Furthermore, we found that ATF6 and XBP1 that induce HRD1 promoted the degradation of Pael-R. A class of compounds known as chemical chaperones, such as 4-phenylbutyric acid (4-PBA), has been demonstrated to repair unfolded proteins. We demonstrated that 4-PBA protected against ER stress-induced neuronal cell death. The tunicamycin-induced up-regulation of GRP78 and GRP94 and phosphorylation of PERK was suppressed by treatment with 4-PBA, indicating that 4-PBA suppresses ER stress responses by decreasing unfolded protein. Furthermore, 4-PBA suppressed ER stress induced by the overexpression of Pael-R. Thus, up-regulation of HRD1 and 4-PBA could decrease accumulation of Pael-R.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kaneko
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Nomura
mesh_terms: D016923:Cell Death / Q000502:physiology; D004721:Endoplasmic Reticulum / Q000502:physiology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D006801:Humans; D009474:Neurons / Q000502:physiology*; D020734:Parkinsonian Disorders / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D010654:Phenylbutyrates; C075773:4-phenylbutyric acid; C482345:SYVN1 protein, human; D044767:Ubiquitin-Protein Ligases