The sortilin cytoplasmic tail conveys Golgi-endosome transport and binds the VHS domain of the GGA2 sorting protein

Sortilin belongs to a growing family of multiligand type-1 receptors with h omology to the yeast receptor Vps10p. Based on structural features and sort ilin's intracellular predominance, we have proposed it to be a sorting rece ptor for ligands in the synthetic pathway as well as on the cell membrane. To test this hypothesis we examine here the cellular trafficking of chimeri c receptors containing constructs of the sortilin tail. We report that sort ing signals conforming to YXX Phi, and dileucine motifs mediate rapid endoc ytosis of sortilin chimeras, which subsequently travel to the trans-Golgi n etwork, showing little or no recycling. Furthermore, we found that cation-i ndependent mannose 6-phosphate receptor (MPR300)-sortilin chimeras, express ed in mannose 6-phosphate receptor knockout cells, were almost as efficient as MPR300 itself for transport of newly synthesized beta -hexosaminidase a nd beta -glucuronidase to lysosomes, and established that the sortilin tail contains potent signals for Golgi-endosome sorting. Finally, we provide ev idence suggesting that sortilin is the first example of a mammalian recepto r targeted by the recently described GGA family of cytosolic sorting protei ns, which condition the Vps10p-mediated sorting of yeast carboxypeptidase Y .