title: The ubiquitin ligase synoviolin up-regulates amyloid β production by targeting a negative regulator of γ-secretase, Rer1, for degradation.
abstract: Alzheimer's disease is characterized by the deposition of Aβ, which is generated from the amyloid precursor protein through its cleavage by β- and γ-secretases. The γ-secretase complex component nicastrin (NCT) plays significant roles in the assembly and proper trafficking of the γ-secretase complex and in the recognition of amyloid precursor protein. NCT is incorporated into the γ-secretase complex in the endoplasmic reticulum (ER) and glycosylated in the Golgi. In contrast, unassembled NCT is retrieved or retained in the ER by the protein Retention in endoplasmic reticulum 1 (Rer1). We reported previously that synoviolin (Syvn), an E3 ubiquitin ligase, degrades NCT and affects the generation of Aβ. Here, we examined in more detail the effect of Syvn on the generation of Aβ. We found that overexpression of a dominant negative form of Syvn (C307A mutant) and a Syvn-RNAi decreased the generation of Aβ. These results indicate that the ubiquitin ligase activity of Syvn up-regulates the generation of Aβ. We hypothesized, therefore, that Syvn regulates the assembly or localization of the γ-secretase complex by ubiquitinating Rer1, resulting in its subsequent degradation. Our findings that the level of Rer1 was increased in Syvn knockout fibroblasts because of inhibition of its degradation support this hypothesis. Moreover, we found that Rer1 interacts with Syvn in the ER, is ubiquitinated by Syvn, and is then degraded via the proteasome or lysosomal pathways. Finally, we showed that localization of mature NCT to the plasma membrane as well as γ-secretase complex levels are decreased in fibroblasts of Syvn knockout mice. Thus, it is likely that Syvn regulates the assembly of the γ-secretase complex via the degradation of Rer1, which results in the generation of Aβ.
authors.affiliation: Department of Neuroscience, School of Pharmacy, Iwate Medical University, 2-1-1 Nishitokuta, Yahaba, Shiwa, Iwate 028-3694, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Tanabe
authors.forename: Tomoji
authors.initials: T
authors.lastname: Maeda
authors.forename: Kun
authors.initials: K
authors.lastname: Zou
authors.forename: Junjun
authors.initials: J
authors.lastname: Liu
authors.forename: Shuyu
authors.initials: S
authors.lastname: Liu
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Nakajima
authors.forename: Hiroto
authors.initials: H
authors.lastname: Komano
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D008562:Membrane Glycoproteins; C109546:RER1 protein, human; D012097:Repressor Proteins; C498235:Syvn1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D053829:Amyloid Precursor Protein Secretases