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MBC in Press, published online ahead of print June 27, 2007
Mol. Biol. Cell 10.1091/mbc.E07-02-0190

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Submitted on March 1, 2007
Revised on June 11, 2007
Accepted on June 18, 2007

The TGN Accessory Protein p56 Promotes Long-Range Movement of GG A/Clathrin-containing Transport Carriers and Lysosomal Enzyme Sorting

Gonzalo A. Mardones,*{dagger} Patricia V. Burgos,*{dagger} Doug A. Brooks,{ddagger}{sect} Emma Parkinson-Lawrence,{ddagger}{sect} Rafael Mattera,* and Juan S. Bonifacino*

*Cell Biology and Metabolism Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892; {ddagger}Sansom Institute, University of South Australia, Adelaide, SA 5001, Australia; {sect}Lysosomal Diseases Research Unit, Department of Genetic Medicine, Children Youth and Women’s Health Service, North Adelaide, SA 5006, Australia

Monitoring Editor: Sandra Schmid

The sorting of acid hydrolase precursors at the trans-Golgi network (TGN) is mediated by binding to mannose 6-phosphate receptors (MPRs) and subsequent capture of the hydrolase-MPR complexes into clathrin-coated vesicles or transport carriers (TCs) destined for delivery to endosomes. This capture depends on the function of three monomeric clathrin adaptors named GGAs. The GGAs comprise a C-terminal "ear" domain that binds a specific set of accessory proteins. Herein we show that one of these accessory proteins, p56, colocalizes and physically interacts with the three GGAs at the TGN. Moreover, overexpression of the GGAs enhances the association of p56 with the TGN, and RNAi-mediated depletion of the GGAs decreases the TGN association and total levels of p56. RNAi-mediated depletion of p56 or the GGAs causes various degrees of missorting of the precursor of the acid hydrolase, cathepsin D. In the case of p56 depletion, this missorting correlates with decreased mobility of GGA-containing TCs. Transfection with an RNAi-resistant p56 construct, but not with a p56 construct lacking the GGA-ear-interacting motif, restores the mobility of the TCs. We conclude that p56 tightly cooperates with the GGAs in the sorting of cathepsin D to lysosomes, probably by enabling the movement of GGA-containing TCs.

{dagger}These authors contributed equally to this work.

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




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