Familial prion protein mutants inhibit Hrd1-mediated retrotranslocation of misfolded proteins by depleting misfolded protein sensor BiP
| Autor: | Marc-André Déry, Andréa C. LeBlanc, Sarah L. Peters |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Protein Folding Prions animal diseases Ubiquitin-Protein Ligases Cellular homeostasis macromolecular substances Endoplasmic-reticulum-associated protein degradation Biology Endoplasmic Reticulum Endoplasmic Reticulum Degradation Pathway 03 medical and health sciences 0302 clinical medicine JUNQ and IPOD Cell Line Tumor Genetics ERAD pathway Animals Humans RNA Small Interfering Molecular Biology Endoplasmic Reticulum Chaperone BiP Genetics (clinical) Secretory pathway Heat-Shock Proteins Neurons Cell Death Endoplasmic reticulum Receptors Albumin General Medicine Endoplasmic Reticulum-Associated Degradation Articles Molecular biology nervous system diseases Protein Transport 030104 developmental biology Aggresome Gene Expression Regulation alpha 1-Antitrypsin Mutation Neuroglia 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Human molecular genetics. 25(5) |
| ISSN: | 1460-2083 |
| Popis: | Similar to many proteins trafficking through the secretory pathway, cellular prion protein (PrP) partly retrotranslocates from the endoplasmic reticulum to the cytosol through the endoplasmic reticulum-associated degradation (ERAD) pathway in an attempt to alleviate accumulation of cellular misfolded PrP. Surprisingly, familial PrP mutants fail to retrotranslocate and simultaneously block normal cellular PrP retrotranslocation. That impairments in retrotranslocation of misfolded proteins could lead to global disruptions in cellular homeostasis prompted further investigations into PrP mutant retrotranslocation defects. A gain- and loss-of-function approach identified human E3 ubiquitin ligase, Hrd1, as a critical regulator of PrP retrotranslocation in mammalian cells. Expression of familial human PrP mutants, V210I(129V) and M232R(129V), not only abolished PrP retrotranslocation, but also that of Hrd1-dependent ERAD substrates, transthyretin TTR(D18G) and α1-anti-trypsin A1AT(NHK). Mutant PrP expression decreased binding immunoglobulin protein (BiP) levels by 50% and attenuated ER stress-induced BiP by increasing BiP turnover 6-fold. Overexpression of BiP with PrP mutants rescued retrotranslocation of PrP, TTR(D18G) and A1AT(NHK). PrP mutants-induced cell death was also rescued by co-expression of BiP. These results show that PrP mutants highjack the Hrd1-dependent ERAD pathway, an action that would result in misfolded protein accumulation especially in terminally differentiated neurons. This could explain the age-dependent neuronal degeneration in familial prion diseases. |
| Databáze: | OpenAIRE |
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