tailieunhanh - Báo cáo khoa học: An E3 ubiquitin ligase, Synoviolin, is involved in the degradation of immature nicastrin, and regulates the production of amyloid b-protein

The presenilin complex, consisting of presenilin, nicastrin, anterior pharynx defective-1 and presenilin enhancer-2, constitutes c-secretase, which is required for the generation of amyloid b-protein. In this article, we show that Synoviolin (also called Hrd1), which is an E3 ubiquitin ligase implicated in endoplasmic reticulum-associated degradation | ễFEBS Journal An E3 ubiquitin ligase Synoviolin is involved in the degradation of immature nicastrin and regulates the production of amyloid b-protein Tomoji Maeda1 Toshihiro Maruta Kun Zou1 Wataru Araki3 Chiaki Tanabe1 Naoko Yagishita4 Yoshihisa Yamano4 Tetsuya Amano4 Makoto Michikawa2 Toshihiro Nakajima4 5 6 and Hiroto Komano1 1 Department of Neuroscience Schoolof Pharmacy Iwate MedicalUniversity Morioka Japan 2 Department of Alzheimer s Disease Research NationalCenter for Geriatrics and Gerontology Aichi Japan 3 Department of Demyelinating Disease and Aging NationalInstitute of Neuroscience Tokyo Japan 4 Institute of MedicalScience St. Marianna University Schoolof Medicine Kawasaki Japan 5 Choju MedicalInstitute and Fukushimura Hospital Toyohashi Japan 6 Misato Marine Hospital Kochi Japan Keywords amyloid b-protein E3 ubiquitin ligase nicastrin presenilin y-secretase Correspondence H. Komano Department of Neuroscience Schoolof Pharmacy Iwate Medical University 2-1-1 Nishitokuta Yahaba Shiwa Iwate 028-3694 Japan Fax 81 19 698 1864 Tel 81 19 651 5111 extn 5210 E-mail hkomano@ Present address Department of Biology Faculty of Sciences Kyushu University Graduate School Fukuoka Japan Received 13 January 2009 revised 2 August 2009 accepted 6 August 2009 doi The presenilin complex consisting of presenilin nicastrin anterior pharynx defective-1 and presenilin enhancer-2 constitutes y-secretase which is required for the generation of amyloid b-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 b-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 .