Abstract
Prion protein PrP is a central player in several devastating neurodegenerative disorders, including mad cow disease and Creutzfeltd-Jacob disease. Conformational alteration of PrP into an aggregation-prone infectious form PrPSc can trigger pathogenic events. How levels of PrP are regulated is poorly understood. Human PrP is known to be degraded by the proteasome, but the specific proteolytic pathway responsible for PrP destruction remains elusive. Here, we demonstrate that the ubiquitin ligase gp78, known for its role in protein quality control, is critical for unglycosylated PrP ubiquitylation and degradation. Furthermore, C-terminal sequences of PrP protein are crucial for its ubiquitylation and degradation. Our study reveals the first ubiquitin ligase specifically involved in prion protein PrP degradation and PrP sequences crucial for its turnover. Our data may lead to a new avenue to control PrP level and pathogenesis.
Highlights
Ubiquitin (Ub) is an abundant small protein best known as a molecular flag that marks proteins for destruction by the 26S proteasome in eukaryotes [1,2]
We demonstrated that unglycosylated form of human PrP is the preferred target of the proteasome in yeast, and further determined that the yeast Hrd1 E3 pathway, a branch of ERAD, is key to ugPrP ubiquitylation and degradation [21]
We examined whether gp78 associated with wild-type PrP proteins that bear mixed forms (Figure 2C). ugPrP was included as a control (Figure 2C, lane 4)
Summary
Ubiquitin (Ub) is an abundant small protein best known as a molecular flag that marks proteins for destruction by the 26S proteasome in eukaryotes [1,2]. Ub-mediated proteolysis serves two major purposes: protein concentration modulation and protein quality control [2,3,4,5]. One protein that is subject to Ub-mediated proteolysis is the prion protein PrP [8,9,10,11], the scrapie form of which (PrPSc) is a causative agent in transmissible spongiform encephalopathies (TSEs) or prion disorders that include fatal familial insomnia, Kuru, Creutzfeltd-Jacob disease, scrapie in sheep and mad cow disease [12,13]. PrP normally adopts a predominately a-helical structure but can be switched to a mostly b-sheet form termed PrPSc, which triggers insoluble protein aggregation, clogs the proteasome, and elicits neurotoxicity [12,13]. The mechanism underlying the conversion of PrP’s conformation remains poorly understood [12,13,14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
