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- Title
Ubiquitin–proteasome pathway mediates degradation of APH-1.
- Authors
Guiqiong He; Hong Qing; Fang Cai; Clement Kwok; Huaxi Xu; Gang Yu; Bernstein, Alan; Song, Weihong
- Abstract
γ-Secretase catalyzes intramembraneous proteolysis of several type I transmembrane proteins, including β-amyloid precursor protein (APP), to generate amyloid β protein (Aβ), a key player in the pathogenesis of Alzheimer's disease (AD). The critical components of the γ-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 γ-secretase cleavage of APP to generate Aβ. These results demonstrate that the degradation of APH-1 protein is mediated by the ubiquitin–proteasome pathway.
- Subjects
ALZHEIMER'S disease; PHARYNGEAL diseases; MEMBRANE proteins; UBIQUITIN; GLYCOPROTEINS
- Publication
Journal of Neurochemistry, 2006, Vol 99, Issue 5, p1403
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/j.1471-4159.2006.04184.x