An E3 ubiquitin ligase, Synoviolin, is involved in the degradation of immature nicastrin, and regulates the production of amyloid β-protein.

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 • : Synoviolin (uniprotkb: ) physically interacts ( ) with NCT (uniprotkb: ) by anti tag coimmunoprecipitation ( ) • : Ubiquitin (uniprotkb: ) physically interacts ( ) with NCT (uniprotkb: ) by anti bait coimmunoprecipitation ( ) • : NCT (uniprotkb: ) physically interacts ( ) with Synoviolin (uniprotkb: ) by anti bait coimmunoprecipitation ( ) [ABSTRACT FROM AUTHOR]