AP-1 and retromer play opposite roles in the trafficking of sortilin between the Golgi apparatus and the lysosomes.

Sortilin has been implicated in the sorting of one soluble hydrolase and two sphingolipid activator proteins to the lysosomes. While the GGA adaptor proteins have been demonstrated to play a role in the targeting of sortilin to the endosomes, the recycling of sortilin has not yet been elucidated. Here we examine the role of two adaptor protein complexes, AP-1 and retromer. Our results demonstrate that AP-1 is required for the transport of sortilin to the endosomes and retromer for the recycling of sortilin to the Golgi apparatus. While inhibition of AP-1 causes accumulation of sortilin in the Golgi apparatus, RNAi depletion of retromer results in retention of sortilin in the lysosomes. We also demonstrate that the interaction of sortilin with retromer occurs through a YXXPhi site in its cytosolic tail. In conclusion, our observations indicate that retromer and AP-1 play opposite roles in the trafficking of sortilin.