The cation-independent mannose 6-phosphate receptor (CI-MPR) mediates sorting of 
lysosomal hydrolase precursors from the TGN to endosomes. After releasing the 
hydrolase precursors into the endosomal lumen, the unoccupied receptor returns 
to the TGN for further rounds of sorting. Here, we show that the mammalian 
retromer complex participates in this retrieval pathway. The hVps35 subunit of 
retromer interacts with the cytosolic domain of the CI-MPR. This interaction 
probably occurs in an endosomal compartment, where most of the retromer is 
localized. In particular, retromer is associated with tubular-vesicular profiles 
that emanate from early endosomes or from intermediates in the maturation from 
early to late endosomes. Depletion of retromer by RNA interference increases the 
lysosomal turnover of the CI-MPR, decreases cellular levels of lysosomal 
hydrolases, and causes swelling of lysosomes. These observations indicate that 
retromer prevents the delivery of the CI-MPR to lysosomes, probably by 
sequestration into endosome-derived tubules from where the receptor returns to 
the TGN.