Cytoplasmic control of Rab family small GTPases through BAG6
Cytoplasmic control of Rab family small GTPases through BAG6
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DOI：
10.15252/embr.201846794
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发表时间：
2019-04-01
期刊：
影响因子：
7.7
通讯作者：
Kawahara, Hiroyuki
中科院分区：
文献类型：
--
作者：
Takahashi, Toshiki;Minami, Setsuya;Kawahara, Hiroyuki
Rab家族小GTP酶是真核细胞胞内囊泡运输不同步骤的主要调节因子。GDP结合的细胞质形式的Rab蛋白由于疏水基团的暴露而易于聚集，但是决定Rab种类在胞质溶胶中的命运的机制尚未详细阐明。在这项研究中，我们发现BAG 6（BAT 3/Scythe）主要识别GDP相关Rab 8a的隐藏部分，而其主要的GTP结合活性形式不被识别。Rab 8a的Switch I区域的疏水残基对于Rab 8a与BAG 6的相互作用以及通过泛素-蛋白酶体系统降解GDP-Rab 8a是必不可少的。BAG 6防止无活性Rab 8a的过度积累，其积累损害细胞内膜运输。BAG 6不仅结合Rab 8a，而且结合功能上不同的Rab家族蛋白，并且也是高尔基体和内体标记物的正确分布所需的。从这些观察，我们认为，Rab蛋白代表了一种新的BAG 6底物，BAG 6介导的途径与哺乳动物细胞中的膜囊泡运输事件的调节。
Rab family small GTPases are master regulators of distinct steps of intracellular vesicle trafficking in eukaryotic cells. GDP-bound cytoplasmic forms of Rab proteins are prone to aggregation due to the exposure of hydrophobic groups but the machinery that determines the fate of Rab species in the cytosol has not been elucidated in detail. In this study, we find that BAG6 (BAT3/Scythe) predominantly recognizes a cryptic portion of GDP-associated Rab8a, while its major GTP-bound active form is not recognized. The hydrophobic residues of the Switch I region of Rab8a are essential for its interaction with BAG6 and the degradation of GDP-Rab8a via the ubiquitin-proteasome system. BAG6 prevents the excess accumulation of inactive Rab8a, whose accumulation impairs intracellular membrane trafficking. BAG6 binds not only Rab8a but also a functionally distinct set of Rab family proteins, and is also required for the correct distribution of Golgi and endosomal markers. From these observations, we suggest that Rab proteins represent a novel set of substrates for BAG6, and the BAG6-mediated pathway is associated with the regulation of membrane vesicle trafficking events in mammalian cells.