Sorting of mannose 6-phosphate receptors mediated by the GGAs

The delivery of soluble hydrolases to lysosomes is mediated by the cation-i ndependent and cation-dependent mannose 6-phosphate receptors. The cytosoli c tails of both receptors contain acidic-cluster-dileucine signals that dir ect sorting from the trans-Golgi network to the endosomal-lysosomal system. We found that these signals bind to the VHS domain of the Golgi-localized, gamma -ear-containing, ARF-binding proteins (GGAs). The receptors and the GGAs left the trans-Golgi network on the same tubulo-vesicular carriers. A dominant-negative GGA mutant blocked exit of the receptors from the trans-G olgi, network. Thus, the GGAs appear to mediate sorting of the mannose 6-ph osphate receptors at the trans-Golgi network.