Mattera Rafael, Bonifacino Juan S
Cell Biology and Metabolism Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
EMBO J. 2008 Oct 8;27(19):2484-94. doi: 10.1038/emboj.2008.177. Epub 2008 Sep 4.
Rab GTPases and ubiquitination are critical regulators of transmembrane cargo sorting in endocytic and lysosomal targeting pathways. The endosomal protein Rabex-5 intersects these two layers of regulation by being both a guanine nucleotide exchange factor (GEF) for Rab5 and a substrate for ubiquitin (Ub) binding and conjugation. The ability of trafficking machinery components to bind ubiquitinated proteins is known to have a function in cargo sorting. Here, we demonstrate that Ub binding is essential for the recruitment of Rabex-5 from the cytosol to endosomes, independently of its GEF activity and of Rab5. We also show that monoubiquitinated Rabex-5 is enriched in the cytosol. These observations are consistent with a model whereby a cycle of Ub binding and monoubiquitination regulates the association of Rabex-5 with endosomes.
Rab GTP酶和泛素化是内吞和溶酶体靶向途径中跨膜货物分选的关键调节因子。内体蛋白Rabex-5通过既是Rab5的鸟嘌呤核苷酸交换因子（GEF）又是泛素（Ub）结合和缀合的底物，从而交叉这两层调节。已知运输机制组件结合泛素化蛋白的能力在货物分选中起作用。在这里，我们证明Ub结合对于将Rabex-5从细胞质募集到内体至关重要，这与其GEF活性和Rab5无关。我们还表明，单泛素化的Rabex-5在细胞质中富集。这些观察结果与一个模型一致，即Ub结合和单泛素化循环调节Rabex-5与内体的结合。
