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An E3 ubiquitin ligase, Synoviolin, is involved in the degradation of immature nicastrin, and regulates the production of amyloid β‐protein
Author(s) -
Maeda Tomoji,
Marutani Toshihiro,
Zou Kun,
Araki Wataru,
Tanabe Chiaki,
Yagishita Naoko,
Yamano Yoshihisa,
Amano Tetsuya,
Michikawa Makoto,
Nakajima Toshihiro,
Komano Hiroto
Publication year - 2009
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/j.1742-4658.2009.07264.x
Subject(s) - nicastrin , ubiquitin ligase , ubiquitin , degradation (telecommunications) , amyloid (mycology) , protein degradation , microbiology and biotechnology , production (economics) , chemistry , biochemistry , biology , amyloid precursor protein , computer science , medicine , gene , disease , alzheimer's disease , inorganic chemistry , telecommunications , macroeconomics , economics
The presenilin complex, consisting of presenilin, nicastrin, anterior pharynx defective‐1 and presenilin enhancer‐2, constitutes γ‐secretase, which is required for the generation of amyloid β‐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 β‐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 β‐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 β‐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 )