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¹ Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development
² Division of Diabetes, Endocrinology, and Metabolism, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Juan S. Bonifacino, Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, Building 18T/Room 101, National Institutes of Health, Bethesda, MD 20892. Tel.: (301) 496-6368. Fax: (301) 402-0078. email: juan{at}helix.nih.gov

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.

Key Words: lysosomal enzymes; multivesicular bodies; sorting nexins; yeast vacuole; clathrin adaptors

R.C. Aguilar's present address is Department of Biology, The Johns Hopkins University, 3400 North Charles Street, Baltimore, MD 21218.

Abbreviations used in this paper: CD-MPR, cation-dependent mannose 6-phosphate receptor; CI-MPR, cation-independent mannose 6-phosphate receptor; MPR, mannose 6-phosphate receptor; PACS-1, phosphofurin acidic cluster sorting protein-1; siRNA, small interfering RNA; Snx, sorting nexin; TfR, transferrin receptor; TIP47, tail-interacting protein of 47 kD.

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