Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator.
Disease-relevant proteostasis regulation of cystic fibrosis transmembrane conductance regulator.
复制标题
囊性纤维化跨膜电导调节器的疾病相关蛋白质稳态调节。
DOI：
10.1038/cdd.2013.46
复制
发表时间：
2013
影响因子：
12.4
通讯作者：
Maiuri,L
中科院分区：
文献类型：
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作者：
Villella,VR;Esposito,S;Bruscia,EM;Vicinanza,M;Cenci,S;Guido,S;Pettoello-Mantovani,M;Carnuccio,R;DeMatteis,MA;Luini,A;Maiuri,MC;Raia,V;Kroemer,G;Maiuri,L
蛋白质稳态网络的蛋白质运输管理不当导致了几种构象疾病，包括囊性纤维化，这是高加索人最常见的致命遗传性疾病。蛋白质稳态调节剂，如胱胺，使囊性纤维化跨膜传导调节剂（CFTR）增强剂在ΔF508-CFTR气道中的有益作用超过药物洗脱。在这里，我们测试的假设，功能CFTR蛋白可以维持自己的质膜（PM）的稳定性。支气管上皮细胞中存在的野生型CFTR的消耗或抑制通过引起Rab 5在洗涤剂不溶性蛋白质级分内的隔离以及其在侵袭体中的积累来降低小GTdR Rab 5的可用性。CFTR耗竭减少了Rab 5效应早期内体抗原1向内体的募集，从而减少了磷脂酰肌醇-3-磷酸的局部产生。这转移了表面蛋白的再循环，包括转铁蛋白受体和CFTR本身。抑制CFTR功能还导致其在PM处的泛素化和与SQSTM 1/p62的相互作用，有利于其处置。添加胱胺通过增强BECN 1表达和减少SQSTM 1积累来防止CFTR的再循环缺陷。我们的研究结果揭示了CFTR蛋白和功能之间的意外联系，后者在正前馈回路中调节CFTR表面表达水平，并强调CFTR作为支气管上皮细胞蛋白质稳态的枢纽。
Mismanaged protein trafficking by the proteostasis network contributes to several conformational diseases, including cystic fibrosis, the most frequent lethal inherited disease in Caucasians. Proteostasis regulators, as cystamine, enable the beneficial action of cystic fibrosis transmembrane conductance regulator (CFTR) potentiators in ΔF508-CFTR airways beyond drug washout. Here we tested the hypothesis that functional CFTR protein can sustain its own plasma membrane (PM) stability. Depletion or inhibition of wild-type CFTR present in bronchial epithelial cells reduced the availability of the small GTPase Rab5 by causing Rab5 sequestration within the detergent-insoluble protein fraction together with its accumulation in aggresomes. CFTR depletion decreased the recruitment of the Rab5 effector early endosome antigen 1 to endosomes, thus reducing the local generation of phosphatidylinositol-3-phosphate. This diverts recycling of surface proteins, including transferrin receptor and CFTR itself. Inhibiting CFTR function also resulted in its ubiquitination and interaction with SQSTM1/p62 at the PM, favoring its disposal. Addition of cystamine prevented the recycling defect of CFTR by enhancing BECN1 expression and reducing SQSTM1 accumulation. Our results unravel an unexpected link between CFTR protein and function, the latter regulating the levels of CFTR surface expression in a positive feed-forward loop, and highlight CFTR as a pivot of proteostasis in bronchial epithelial cells.