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首页> 外文期刊>Cellular Physiology and Biochemistry >BAG-1 Stabilizes Mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner
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BAG-1 Stabilizes Mutant F508del-CFTR in a Ubiquitin-Like-Domain-Dependent Manner

机译：BAG-1以泛素样域依赖性方式稳定突变体F508del-CFTR

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Background: Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), the dysfunctional Cl- channel in Cystic Fibrosis, undergoes complex biosynthesis at the endoplasmic reticulum involving several molecular chaperones including Hsp70 and many co-chaperones. Bcl-2-associated athanogenes (BAGs) constitute a protein family sharing an Hsc70-binding domain. BAG-1 possesses an ubiquitin-like domain (Ub-LD) responsible for proteasomal association and for promoting substrate release from Hsc70/Hsp70 in vitro by accelerating the chaperone ATP/ADP exchange rate. Methods: Herein, we studied the in vivo effect of BAG-1 on the turnover and processing of wild type (wt)- and F508del-CFTR, the most frequent mutation in CF patients. Results: Results show that BAG-1 associates with both wt- and F508del-CFTR (in higher yields with the latter) through its Ub-LD and independently of Hsc70. Moreover, the immature form of F508del-CFTR (but not of wt-CFTR) is stabilized by BAG-1 overexpression, albeit in a cell-type specific way, without detectable maturation. Data also show that BAG-1 and the proteasome inhibitor ALLN are not additive on stabilizing F508del-CFTR and this effect depends on BAG-1 Ub-LD. Moreover, under BAG-1 overexpression, a reduction in ubiquitinylated-CFTR occurs suggesting that BAG-1 competes with Ub. Conclusion: Overall, data are compatible with a mechanism in which BAG-1 stabilizes F508del-CFTR by direct binding, probably competing out ubiquitin to partially avoid its proteasomal degradation.
机译：背景：囊性纤维化中功能异常的Cl通道囊性纤维化跨膜电导调节剂（CFTR）在内质网进行复杂的生物合成，涉及多个分子伴侣，包括Hsp70和许多辅助伴侣。 Bcl-2相关的无烟激素（BAG）构成共享Hsc70结合域的蛋白质家族。 BAG-1具有泛素样结构域（Ub-LD），负责蛋白酶体结合并通过加速伴侣ATP / ADP交换速率促进体外Hsc70 / Hsp70的底物释放。方法：在本文中，我们研究了BAG-1对CF患者中最常见的野生型（wt）-和F508del-CFTR的更新和加工的体内作用。结果：结果表明，BAG-1通过其Ub-LD与wt-和F508del-CFTR缔合（与后者的产率更高），并且独立于Hsc70。此外，F508del-CFTR的未成熟形式（而不是wt-CFTR的形式）通过BAG-1过表达得以稳定，尽管以细胞类型特异性的方式，也没有可检测的成熟。数据还表明，BAG-1和蛋白酶体抑制剂ALLN在稳定F508del-CFTR上不是添加剂，这种作用取决于BAG-1 Ub-LD。此外，在BAG-1过表达下，泛素化CFTR的降低表明BAG-1与Ub竞争。结论：总体而言，数据与BAG-1通过直接结合稳定F508del-CFTR的机制兼容，可能与泛素竞争以部分避免其蛋白酶体降解。

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