Role of Rabex-5 in the sorting of ubiquitinated cargo at an early stage in the endocytic pathway

The covalent modification of transmembrane receptors by ubiquitin (Ub) is a key biological mechanism controlling their internalization and endocytic sorting to recycling and degradative pathways to attenuate their signaling potential. In this Ub-dependent endocytic trafficking pathway, Ub-binding proteins (UBPs) play a critical role in the sorting of these ubiquitinated transmembrane proteins at the plasma membrane, early endosomes, and multivesicular bodies. We recently reported that Rabex-5, a UBP and guanine nucleotide exchange factor for Rab5, is translocated to the plasma membrane in an extracellular ligand-dependent manner to regulate the internalization of ligand-induced ubiquitinated transmembrane proteins upon stimulation with extracellular ligands. Here, we show that Rabex-5 predominantly localizes on Rab5- and syntaxin 13-positive endosomes, but not on Rab11-positive recycling endosomes before stimulation with extracellular ligands. We further discuss the significance of Rabex-5-mediated sorting of ubiquitinated transmembrane proteins as cargo at an early stage of the endocytic pathway.