An E3 ubiquitin ligase, Synoviolin, is involved in the degradation of immature nicastrin, and regulates the production of amyloid beta-protein.
The presenilin complex, consisting of presenilin, nicastrin, anterior pharynx defective-1 and presenilin enhancer-2, constitutes gamma-secretase, which is required for the generation of amyloid beta-protein. In this article, we show that Synoviolin (also called Hrd1), which is an E3 ubiquitin ligase implicated in endoplasmic reticulum-associated degradation, is involved in the degradation of endogenous immature nicastrin, and affects amyloid beta-protein generation. It was found that the level of immature nicastrin was dramatically increased in synoviolin-null cells as a result of the inhibition of degradation, but the accumulation of endogenous presenilin, anterior pharynx defective-1 and presenilin enhancer-2 was not changed. This was abolished by the transfection of exogenous Synoviolin. Moreover, nicastrin was co-immunoprecipitated with Synoviolin, strongly suggesting that nicastrin is the substrate of Synoviolin. Interestingly, amyloid beta-protein generation was increased by the overexpression of Synoviolin, although the nicastrin level was decreased. Thus, Synoviolin-mediated ubiquitination is involved in the degradation of immature nicastrin, and probably regulates amyloid beta-protein generation. Structured digital abstract: * MINT-7255352: Synoviolin (uniprotkb:Q9DBY1) physically interacts (MI:0915) with NCT (uniprotkb:P57716) by anti tag coimmunoprecipitation (MI:0007) * MINT-7255377: Ubiquitin (uniprotkb:P62991) physically interacts (MI:0915) with NCT (uniprotkb:P57716) by anti bait coimmunoprecipitation (MI:0006) * MINT-7255363: NCT (uniprotkb:P57716) physically interacts (MI:0915) with Synoviolin (uniprotkb:Q9DBY1) by anti bait coimmunoprecipitation (MI:0006).
Maeda
Tomoji
T
Department of Neuroscience, School of Pharmacy, Iwate Medical University, Morioka, Japan.
Marutani
Toshihiro
T
Zou
Kun
K
Araki
Wataru
W
Tanabe
Chiaki
C
Yagishita
Naoko
N
Yamano
Yoshihisa
Y
Amano
Tetsuya
T
Michikawa
Makoto
M
Nakajima
Toshihiro
T
Komano
Hiroto
H
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D019921:Biotinylation; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D053763:Presenilins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D055550:Protein Stability; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; D053763:Presenilins; C413604:nicastrin protein; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053829:Amyloid Precursor Protein Secretases