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Ubiquitin–proteasome pathway mediates degradation of APH‐1
Author(s) -
He Guiqiong,
Qing Hong,
Cai Fang,
Kwok Clement,
Xu Huaxi,
Yu Gang,
Bernstein Alan,
Song Weihong
Publication year - 2006
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2006.04184.x
Subject(s) - lactacystin , proteasome , nicastrin , presenilin , ubiquitin , protein degradation , proteolysis , microbiology and biotechnology , biology , amyloid precursor protein , transmembrane protein , biochemistry , chemistry , proteasome inhibitor , alzheimer's disease , enzyme , gene , medicine , disease , pathology , receptor
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.