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MBC in Press, published online ahead of print March 26, 2008
Mol. Biol. Cell 10.1091/mbc.E07-11-1189

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Submitted on November 29, 2007
Revised on February 26, 2008
Accepted on March 19, 2008

Requirement of the Human GARP Complex for Mannose 6-phosphate-receptor-dependent Sorting of Cathepsin D to Lysosomes

F. Javier Pérez-Victoria, Gonzalo A. Mardones, and Juan S. Bonifacino

Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892

Monitoring Editor: Jean Gruenberg

The biosynthetic sorting of acid hydrolases to lysosomes relies on transmembrane, mannose 6-phosphate receptors (MPRs) that cycle between the TGN and endosomes. Herein we report that maintenance of this cycling requires the function of the mammalian Golgi-associated retrograde protein (GARP) complex. Depletion of any of the three GARP subunits, Vps52, Vps53 or Vps54, by RNAi impairs sorting of the precursor of the acid hydrolase, Cathepsin D, to lysosomes and leads to its secretion into the culture medium. As a consequence, lysosomes become swollen, likely due to a build-up of undegraded materials. Missorting of Cathepsin D in GARP-depleted cells results from accumulation of recycling MPRs in a population of light, small vesicles downstream of endosomes. These vesicles might correspond to intermediates in retrograde transport from endosomes to the TGN. Depletion of GARP subunits also blocks the retrograde transport of the TGN protein, TGN46, and the B subunit of Shiga toxin. These observations indicate that the mammalian GARP complex plays a general role in the delivery of retrograde cargo into the TGN. We also report that a Vps54 mutant protein in the Wobbler mouse strain is active in retrograde transport, thus explaining the viability of these mutant mice.

Address correspondence to: Juan S. Bonifacino (juan{at}helix.nih.gov)






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