Remodeling the endoplasmic reticulum proteostasis network restores proteostasis of pathogenic GABAA receptors.
Remodeling the endoplasmic reticulum proteostasis network restores proteostasis of pathogenic GABAA receptors.
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DOI：
10.1371/journal.pone.0207948
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发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Mu TW
中科院分区：
文献类型：
--
作者：
Fu YL;Han DY;Wang YJ;Di XJ;Yu HB;Mu TW
膜蛋白的生物发生是由蛋白质稳态网络控制的。γ-氨基丁酸A型受体是哺乳动物中枢神经系统中主要的抑制性神经递质门控离子通道，我们一直致力于其蛋白质质量控制。GABAA受体的蛋白质稳态缺陷导致其表面表达的丧失，从而在质膜上的功能丧失，导致癫痫和其他神经系统疾病。一个充分表征的例子是α1亚基中的A322 D突变，该突变导致其广泛的错误折叠和内质网（ER）中的加速降解，导致常染色体显性青少年肌阵挛性癫痫。我们的目的是纠正ER中α1（A322 D）亚基的错误折叠，作为恢复其功能性表面表达的方法。在这里，我们表明，BIX，一种特异性的，有效的ER驻留HSP 70家族蛋白BiP激活剂的应用，显着增加在人HEK 293 T细胞和神经元SH-SY 5 Y细胞的突变受体的表面表达。BIX减弱α1（A322 D）的降解并增强其前向运输和功能。此外，由于BiP是两个未折叠蛋白反应（UPR）途径：ATF 6和IRE 1的一个主要靶点，我们继续证明ATF 6途径和IRE 1途径的适度激活在遗传上增强了HEK 293 T细胞中α1（A322 D）蛋白的质膜转运。我们的研究结果为调节ER蛋白质稳态网络纠正功能丧失的蛋白质构象疾病奠定了基础。
Biogenesis of membrane proteins is controlled by the protein homeostasis (proteostasis) network. We have been focusing on protein quality control of γ-aminobutyric acid type A (GABAA) receptors, the major inhibitory neurotransmitter-gated ion channels in mammalian central nervous system. Proteostasis deficiency in GABAA receptors causes loss of their surface expression and thus function on the plasma membrane, leading to epilepsy and other neurological diseases. One well-characterized example is the A322D mutation in the α1 subunit that causes its extensive misfolding and expedited degradation in the endoplasmic reticulum (ER), resulting in autosomal dominant juvenile myoclonic epilepsy. We aimed to correct misfolding of the α1(A322D) subunits in the ER as an approach to restore their functional surface expression. Here, we showed that application of BIX, a specific, potent ER resident HSP70 family protein BiP activator, significantly increases the surface expression of the mutant receptors in human HEK293T cells and neuronal SH-SY5Y cells. BIX attenuates the degradation of α1(A322D) and enhances their forward trafficking and function. Furthermore, because BiP is one major target of the two unfolded protein response (UPR) pathways: ATF6 and IRE1, we continued to demonstrate that modest activations of the ATF6 pathway and IRE1 pathway genetically enhance the plasma membrane trafficking of the α1(A322D) protein in HEK293T cells. Our results underlie the potential of regulating the ER proteostasis network to correct loss-of-function protein conformational diseases.
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影响因子：
16
作者：
Feigel, Matthias J.;Hendershot, Linda M.
通讯作者：
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影响因子：
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作者：
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DOI：
10.1126/science.aaa4484
发表时间：
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期刊：
Science (New York, N.Y.)
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影响因子：
4.8
作者：
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