In the Golgi, mannose-6-phosphate receptors (M6PRs) grab newly synthesized lysosomal hydrolases by their sugars to whizz them to their final destination, lysosomes. But how do the receptors themselves know where to go? Two groups now report in Science that the GGA coat adaptors show them the way.

The lysosomal sorting signal was identified almost a decade ago — an acidic cluster followed by a dileucine motif in the cytoplasmic tail of the M6PR. The AP-1 adaptor complex was the prime suspect for binding M6PRs and assembling the clathrin coat. It now turns out that it is, in fact, the most recently discovered adaptors — the GGAs (for Golgi-localized, γ-ear-containing, ARF-binding) — that bind to the lysosomal targeting signals of M6PRs and sort them to lysosomes.

GGAs are made of four domains: a VHS domain; a GTP–ARF-binding domain (GAT); a hinge that contains binding sites for clathrin; and a GAE domain that interacts with γ-synergin and other regulators of coat assembly. The sorting signals of M6PRs interacted specifically with the VHS domains of GGAs in two-hybrid assays, in pull-down assays and by surface plasmon resonance spectroscopy. Specifically, the cation-independent M6PR bound all three human GGAs, whereas the cation-dependent M6PR preferred GGA1 over GGA3, and did not bind GGA2. Immunofluorescence studies showed that M6PRs and GGA1 colocalize in the trans-Golgi network (TGN) and in the cell periphery, and time-lapse imaging of live cells revealed that GGA1 associates with tubules and vesicles that bud from the TGN.

Kornfeld and colleagues show that there is a correlation between reduced in vitro binding of the cation-independent MPR to GGA2 and mis-sorting of lysosomal enzymes. Last, Bonifacino and colleagues provide evidence for a functional involvement of GGAs in sorting of M6PRs, as overexpression of a dominant-negative GGA1 construct blocks exit of the cation-dependent M6PR from the TGN.

So GGAs probably function as adaptors between M6PRs, ARF, clathrin and regulators of coat assembly. But do they recruit receptors into AP-1–clathrin vesicles or do they build clathrin-coated vesicles of their own?