کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
10815431 | 1058473 | 2013 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Presenilins are novel substrates for TRAF6-mediated ubiquitination
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کلمات کلیدی
NEMOPresenilin1HEK293TTRAF6AICDPS2PS1Aph-1C99APPAβTRAFsNF-κB essential modifierMEFPEN-2NF-κBJnkc-Jun N-terminal kinase - C-Jun N-terminal kinaseMAPK - MAPKamyloid β - آمیلوئید βPresenilin enhancer-2 - افزایش دهنده پریسینیلین-2FAD - بدAlzheimer's disease - بیماری آلزایمرfamilial Alzheimer's disease - بیماری آلزایمر خانوادگیImmunoprecipitation - تخریب ایمنیRing - حلقهAPP intracellular domain - دامنه داخل سلولی APPendoplasmic reticulum - شبکه آندوپلاسمی Nuclear factor-kappa B - فاکتور هسته ای-کاپا Bmurine embryonic fibroblast - فیبروبلاست جنینی جنینیPresenilin - پرنسیلینregulated intramembrane proteolysis - پروتئولیز داخل سلولی تنظیم شده استamyloid precursor protein - پروتئین پیش ماده آمیلوئیmitogen-activated protein kinase - پروتئین کیناز فعال با mitogenreally interesting new gene - ژن جدید واقعا جالبgamma-secretase - گاما دگرسازubiquitination - یوبی کوئیتینه شدن
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
زیست شیمی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Mutations in presenilins (PS1 and PS2) have been linked to the pathogenesis of early onset familial Alzheimer's disease. Presenilins function as the catalytic component of the γ-secretase protease complexes responsible for the cleavage of the amyloid precursor protein (APP), subsequent generation of amyloid-β and associated amyloid plaques in Alzheimer's disease. Biochemical and genetic studies have revealed that through interactions with several proteins, the presenilins are functionally involved in a range of cellular processes, including the regulation of intracellular calcium homeostasis. Our group has previously reported an association between presenilins and members of the tumour necrosis factor receptor-associated factor (TRAF) family of proteins. In this study we further investigated the association between TRAF6, an E3 ubiquitin ligase, and the presenilins. Here we show that the presenilin full-length holoproteins are novel substrates of TRAF6-mediated Lysine-63-linked ubiquitination. Interestingly, co-expression of catalytically active TRAF6 with the presenilins leads to decreased turnover of PS1 full-length holoprotein accompanying elevated presenilin protein levels. Similarly, while overexpression of TRAF6 increases presenilin holoprotein levels and ubiquitination in HEK293 cells, expression of catalytically deficient TRAF6 or TRAF6-deficiency leads to a reduction in presenilin protein levels and reduced PS1 ubiquitination. We also demonstrate that TRAF6 induces PS1 gene transcription in a JNK-dependent manner. Notably, we reveal that TRAF6-mediated ubiquitination of presenilin does not affect γ-secretase enzyme activity, but may regulate presenilin function in calcium signalling. Taken together, we propose that presenilins are novel substrates for TRAF6-mediated K63-linked ubiquitination and that ubiquitination of presenilins by TRAF6 increases presenilin holoprotein levels and in conditions in which TRAF6 ubiquitination of presenilins is reduced results in reduction of calcium release from the endoplasmic reticulum.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Cellular Signalling - Volume 25, Issue 9, September 2013, Pages 1769-1779
Journal: Cellular Signalling - Volume 25, Issue 9, September 2013, Pages 1769-1779
نویسندگان
Run Yan, Sean Farrelly, Justin V. McCarthy,