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 RNA 
interference (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.