Acute ER stress regulates amyloid precursor protein processing through ubiquitin-dependent degradation.
Beta-amyloid (Aβ), a major pathological hallmark of Alzheimer's disease (AD), is derived from amyloid precursor protein (APP) through sequential cleavage by β-secretase and γ-secretase enzymes. APP is an integral membrane protein, and plays a key role in the pathogenesis of AD; however, the biological function of APP is still unclear. The present study shows that APP is rapidly degraded by the ubiquitin-proteasome system (UPS) in the CHO cell line in response to endoplasmic reticulum (ER) stress, such as calcium ionophore, A23187, induced calcium influx. Increased levels of intracellular calcium by A23187 induces polyubiquitination of APP, causing its degradation. A23187-induced reduction of APP is prevented by the proteasome inhibitor MG132. Furthermore, an increase in levels of the endoplasmic reticulum-associated degradation (ERAD) marker, E3 ubiquitin ligase HRD1, proteasome activity, and decreased levels of the deubiquitinating enzyme USP25 were observed during ER stress. In addition, we found that APP interacts with USP25. These findings suggest that acute ER stress induces degradation of full-length APP via the ubiquitin-proteasome proteolytic pathway.
Department of Biochemistry &Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
Eun Sun
ES
Jung
Medifron DBT, Inc., Gyeongi, 425-838, Republic of Korea.
HyunSeok
H
Hong
Department of Biochemistry &Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
Chaeyoung
C
Kim
Department of Biochemistry &Biomedical Science, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
Inhee
I
Mook-Jung
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D059865:Endoplasmic Reticulum Stress; D060746:Endoplasmic Reticulum-Associated Degradation; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
D016564:Amyloid beta-Protein Precursor; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D002118:Calcium