Nuclear BAG6-UBL4A-GET4 Complex Mediates DNA Damage Signaling and Cell Death
Nuclear BAG6-UBL4A-GET4 Complex Mediates DNA Damage Signaling and Cell Death
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核 BAG6-UBL4A-GET4 复合物介导 DNA 损伤信号传导和细胞死亡
DOI：
10.1074/jbc.m112.443416
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发表时间：
2013-07-12
影响因子：
4.8
通讯作者：
Wang, Yi
中科院分区：
文献类型：
--
作者：
Krenciute, Giedre;Liu, Shangfeng;Wang, Yi
BCL2相关基因6(BAG6)是BAG蛋白家族的一员，参与多种细胞过程，包括细胞凋亡、辅伴蛋白和DNA损伤反应(DDR)。最近的研究表明，BAG6与UBL4A和GET4形成稳定的复合体，在膜蛋白靶向和蛋白质质量控制中发挥作用。BAG6序列包含一个典型的核定位信号，主要定位于细胞核。而GET4和UBL4A主要分布在细胞质中。GET4和UBL4A是否也参与了BAG6复合体中的DDR尚不清楚。在这里，我们提供了核BAG6-UBL4A-GET4复合体介导DDR信号和损伤诱导的细胞死亡的证据。BAG6似乎是这一过程的中心成分，因为BAG6的耗尽导致UBL4A和GET4蛋白的丢失，并抵抗DNA损伤剂对细胞的杀伤。此外，BAG6的核定位和ATM/ATR对BAG6的磷酸化也是细胞杀伤所必需的。UBL4A和GET4在DNA损伤后移位到细胞核，似乎在细胞杀伤中扮演多余的角色，因为其中任何一个的耗尽都没有影响，但共同耗尽会导致耐药性。BAG6复合体的所有三个组成部分都是最佳DDR信号转导所必需的，因为BAG6和GET4和UBL4A在较小程度上调节BRCA1向DNA损伤部位的募集。综上所述，我们的结果表明，核BAG6复合体是DNA损伤反应途径中的效应者，其磷酸化和核定位是其功能的重要决定因素。
BCL2-associated athanogene 6 (BAG6) is a member of the BAG protein family, which is implicated in diverse cellular processes including apoptosis, co-chaperone, and DNA damage response (DDR). Recently, it has been shown that BAG6 forms a stable complex with UBL4A and GET4 and functions in membrane protein targeting and protein quality control. The BAG6 sequence contains a canonical nuclear localization signal and is localized predominantly in the nucleus. However, GET4 and UBL4A are found mainly in cytoplasm. Whether GET4 and UBL4A are also involved in DDR in the context of the BAG6 complex remains unknown. Here, we provide evidence that nuclear BAG6-UBL4A-GET4 complex mediates DDR signaling and damage-induced cell death. BAG6 appears to be the central component for the process, as depletion of BAG6 leads to the loss of both UBL4A and GET4 proteins and resistance to cell killing by DNA-damaging agents. In addition, nuclear localization of BAG6 and phosphorylation of BAG6 by ATM/ATR are also required for cell killing. UBL4A and GET4 translocate to the nucleus upon DNA damage and appear to play redundant roles in cell killing, as depletion of either one has no effect but co-depletion leads to resistance. All three components of the BAG6 complex are required for optimal DDR signaling, as BAG6, and to a lesser extent, GET4 and UBL4A, regulate the recruitment of BRCA1 to sites of DNA damage. Together our results suggest that the nuclear BAG6 complex is an effector in DNA damage response pathway and its phosphorylation and nuclear localization are important determinants for its function.