title: Ubiquitin-proteasome pathway mediates degradation of APH-1.
abstract: Gamma-secretase catalyzes intramembraneous proteolysis of several type I transmembrane proteins, including beta-amyloid precursor protein (APP), to generate amyloid beta protein (Abeta), a key player in the pathogenesis of Alzheimer's disease (AD). The critical components of the gamma-secretase complex include presenilin (PS), nicastrin (NCT), presenilin enhancer-2 (PEN-2) and anterior pharynx defective-1 (APH-1). Abnormalities of the ubiquitin-proteasome pathway have been implicated in the pathogenesis of AD; while PS and PEN-2 turnover is regulated by this pathway, it is unknown whether the ubiquitin-proteasome pathway is also involved in the degradation of APH-1 protein. In this study, we found that the expression of endogenous and exogenous APH-1 significantly increased in cells treated with proteasome-specific inhibitors. The effect of the proteasome inhibitors on APH-1 was dose- and time-dependent. APH-1 protein was ubiquitinated. Pulse-chase metabolic labeling experiments showed that the degradation of newly synthesized radiolabeled APH-1 proteins was inhibited by lactacystin. Disruption of the PS1 and PS2 genes did not affect the degradation of APH-1 by the ubiquitin-proteasome pathway. Furthermore, over-expression of APH-1 and inhibition of proteasomal APH-1 degradation facilitated gamma-secretase cleavage of APP to generate Abeta. These results demonstrate that the degradation of APH-1 protein is mediated by the ubiquitin-proteasome pathway.
authors.affiliation: Department of Psychiatry, Brain Research Center, The University of British Columbia, Vancouver, British Columbia, and Samuel Lunenfeld Research Institute, Program in Molecular Biology and Cancer, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Guiqiong
authors.initials: G
authors.lastname: He
authors.forename: Hong
authors.initials: H
authors.lastname: Qing
authors.forename: Fang
authors.initials: F
authors.lastname: Cai
authors.forename: Clement
authors.initials: C
authors.lastname: Kwok
authors.forename: Huaxi
authors.initials: H
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.forename: Alan
authors.initials: A
authors.lastname: Bernstein
authors.forename: Weihong
authors.initials: W
authors.lastname: Song
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism*; D045744:Cell Line, Tumor; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010447:Peptide Hydrolases; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors; D034622:RNA Interference / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D025801:Ubiquitin / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
chemical_list: D016564:Amyloid beta-Protein Precursor; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D053764:Presenilin-1; D061988:Proteasome Inhibitors; D025801:Ubiquitin; C067713:lactacystin; C475154:APH1A protein, human; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D010447:Peptide Hydrolases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine