Puertollano Rosa, Bonifacino Juan S
Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nat Cell Biol. 2004 Mar;6(3):244-51. doi: 10.1038/ncb1106. Epub 2004 Feb 22.
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) and mediate the sorting of mannose 6-phosphate receptors. 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. 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.
高尔基体定位、含γ耳、Arf结合（GGA）蛋白构成了网格蛋白衔接蛋白家族，主要与反式高尔基体网络（TGN）相关，并介导甘露糖6-磷酸受体的分选。这种分选依赖于GGA的VHS结构域与受体胞质尾巴中酸性簇双亮氨酸信号的相互作用。在这里，我们证明了存在另一群与早期内体相关的GGA。RNA干扰（RNAi）GGA3表达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）在扩大的早期内体中积累。这种扰动损害了内化EGF的降解，这一过程通常依赖于泛素化的表皮生长因子受体（EGFR）分选至晚期内体。蛋白质相互作用分析表明，GGA与泛素结合。GGA3的VHS和GAT结构域负责这种结合，以及与TSG101（泛素依赖性分选机制的一个组分）的相互作用。因此，GGA可能在泛素化货物的分选中具有额外作用。
