Ubiquitin-proteasome pathway mediates degradation of APH-1

Guiqiong He, Hong Qing, Fang Cai, Clement Kwok, Huaxi Xu, Gang Yu, Alan Bernstein, Weihong Song

Research output: Contribution to journalArticle

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1403-1412
Number of pages10
JournalJournal of Neurochemistry
Volume99
Issue number5
DOIs
StatePublished - Dec 1 2006

Keywords

  • Alzheimer's disease
  • Anterior pharynx defective-1
  • Proteasome
  • Ubiquitin
  • γ-secretase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    He, G., Qing, H., Cai, F., Kwok, C., Xu, H., Yu, G., Bernstein, A., & Song, W. (2006). Ubiquitin-proteasome pathway mediates degradation of APH-1. Journal of Neurochemistry, 99(5), 1403-1412. https://doi.org/10.1111/j.1471-4159.2006.04184.x