Regulatory role of Golgi brefeldin A resistance factor-1 in amyloid precursor protein trafficking, cleavage and Aβ formation
Regulatory role of Golgi brefeldin A resistance factor-1 in amyloid precursor protein trafficking, cleavage and Aβ formation
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高尔基布雷菲德菌素 A 抗性因子 1 在淀粉样前体蛋白运输、裂解和 Abeta 形成中的调节作用。
DOI：
10.1002/jcb.28827
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发表时间：
2019-09-01
影响因子：
4
通讯作者：
Zhou, Chun
中科院分区：
文献类型：
--
作者：
Liu, Kaifei;Liu, Ying;Zhou, Chun
β-淀粉样肽（A β）沉积是阿尔茨海默病（AD）的一个重要特征，其来源于淀粉样前体蛋白（APP）通过淀粉样蛋白生成途径的连续裂解。在这一过程中，细胞贩运起着至关重要的作用。据报道，含有大Sec 7结构域的ADP-核糖基化因子鸟苷酸交换因子（ARF-GEF）、高尔基布雷菲德菌素A抗性因子1（GBF 1）可启动反式高尔基体网络中的ADP-核糖基化因子（Arf）激活级联反应，在内质网-高尔基体界面发挥关键作用。在这项研究中，我们研究了GBF 1在APP跨膜转运和A β形成中的作用。利用APP/PS1（presenilin 1）过表达转基因小鼠，我们证明GBF 1上调APP的表达，表明GBF 1在APP生理过程中的作用。使用小干扰敲低GBF 1显著增加了APP的细胞内表达，但没有增加APP的表面表达。相反，野生型（WT）和活化形式的鸟嘌呤核苷酸交换因子（GEF）的过表达而不是GEF缺陷突变诱导了GBF 1的持续活化，这随后增加了APP的表面水平。有趣的是，通过c（BFA）抑制GBF 1也损害APP运输并诱导SH-SY 5 Y细胞中的内质网（ER）应激。因此，我们的研究结果确定了GBF 1在APP运输和切割中的作用，并为GBF 1作为AD的可能治疗靶点提供了证据。
beta-amyloid peptide (A beta) deposition derived from sequential cleavage of the amyloid precursor protein (APP) through the amyloidogenic pathway is an important characteristic feature of Alzheimer's disease (AD). During this process, cellular trafficking plays a crucial role. A large Sec7-domain containing ADP-ribosylation factor guanine nucleotide exchange factor (ARF-GEF), Golgi brefeldin A resistance factor 1 (GBF1) has been reported to initiate the ADP-ribosylation factor (Arf) activation cascade at trans-Golgi network, which plays a crucial function at the endoplasmic reticulum-Golgi interface. In this study, we investigated the role of GBF1 in APP transmembrane transport and A beta formation. Using APP/PS1 (presenilin 1) overexpressing transgenic mice, we demonstrate that GBF1 has upregulated the expression of APP, indicating a role for GBF1 in APP physiological process. Knocking down of GBF1 using small interfering has significantly increased the intracellular but not the surface expression of APP. In contrast, overexpression of wild-type (WT) and guanine nucleotide exchange factor (GEF) in the activated form but not the GEF deficient mutation induced continuous activation of GBF1, which subsequently increased the surface level of APP. Interestingly, inhibition of GBF1 by c(BFA) also impaired APP trafficking and induced endoplasmic reticulum (ER) stress in SH-SY5Y cells. Our results thus for identified the role of GBF1 in APP trafficking and cleavage, and provide evidence for GBF1 as a possible therapeutic target in AD.