Ubiquitin ligase gp78 targets unglycosylated prion protein PrP for ubiquitylation and degradation.
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.
The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China.
Jia
J
Shao
Department of Molecular Medicine, the University of Texas Health Science Center, San Antonio, Texas, United States of America.
Vitnary
V
Choe
Department of Molecular Medicine, the University of Texas Health Science Center, San Antonio, Texas, United States of America.
Haili
H
Cheng
Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, Maryland, United States of America.
Yien Che
YC
Tsai
Laboratory of Protein Dynamics and Signaling, National Cancer Institute, Frederick, Maryland, United States of America.
Allan M
AM
Weissman
The First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi, China.
Shiwen
S
Luo
Department of Molecular Medicine, the University of Texas Health Science Center, San Antonio, Texas, United States of America.
Hai
H
Rao
D000818:Animals; D006031:Glycosylation; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D059748:Proteolysis; D060285:Receptors, Autocrine Motility Factor / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination
D011328:Prions; D025801:Ubiquitin; C555000:AMFR protein, human; C555002:Amfr protein, mouse; D060285:Receptors, Autocrine Motility Factor