Interactions of GGA3 with the ubiquitin sorting machinery
Interactions of GGA3 with the ubiquitin sorting machinery
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DOI：
10.1038/ncb1106
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发表时间：
2004-03-01
影响因子：
21.3
通讯作者：
Bonifacino, JS
中科院分区：
文献类型：
--
作者：
Puertollano, R;Bonifacino, JS
高尔基体定位的、含有γ-耳的Arf结合（GGA）蛋白构成网格蛋白衔接子家族，其主要与反式高尔基体网络（TGN）（1-3）相关并介导甘露糖6-磷酸受体的分选（4-6）。这种分选依赖于GGA的VHS结构域与受体胞质尾部中的酸性簇双亮氨酸信号的相互作用（4，5）。在这里，我们证明了存在另一个群体的GGA与早期内体。GGA 3表达的RNA干扰（RNAi）导致阳离子非依赖性甘露糖6-磷酸受体和内化的表皮生长因子（EGF）在扩大的早期内体内积累。这种干扰损害了内化EGF的降解，这是一个通常依赖于泛素化EGF受体（EGFR）到晚期内体的分选的过程。蛋白质相互作用分析表明，GGA结合泛素。GGA 3的VHS和GAT结构域负责这种结合，以及与TSG 101的相互作用，TSG 101是泛素依赖性分选机制的组成部分。因此，GGA可能在泛素化货物的分选中具有额外的作用。
The Golgi-localized, gamma-ear-containing, Arf-binding (GGA) proteins constitute a family of clathrin adaptors that are mainly associated with the trans-Golgi network (TGN)(1-3) and mediate the sorting of mannose 6-phosphate receptors(4-6). This sorting is dependent on the interaction of the VHS domain of the GGAs with acidic-cluster-dileucine signals in the cytosolic tails of the receptors(4,5). Here we demonstrate the existence of another population of GGAs that are associated with early endosomes. RNA interference (RNAi) of GGA3 expression results in accumulation of the cation-independent mannose 6-phosphate receptor and internalized epidermal growth factor (EGF) within enlarged early endosomes. This perturbation impairs the degradation of internalized EGF, a process that is normally dependent on the sorting of ubiquitinated EGF receptors (EGFRs) to late endosomes. Protein interaction analyses show that the GGAs bind ubiquitin. The VHS and GAT domains of GGA3 are responsible for this binding, as well as for interactions with TSG101, a component of the ubiquitin-dependent sorting machinery. Thus, GGAs may have additional roles in sorting of ubiquitinated cargo.