Sorting of secretory proteins at the trans-Golgi network by TGN46

Secretory proteins are sorted at the trans-Golgi network (TGN) for export into specific transport carriers. However, the molecular players involved in this fundamental process remain largely elusive. Here, we identified the transmembrane protein TGN46 as a cargo receptor for the export of secretory proteins in CARTS – a class of protein kinase D-dependent TGN-to-plasma membrane carriers. We show that TGN46 is necessary for cargo sorting and loading into nascent carriers at the TGN. By combining quantitative fluorescence microscopy and mutagenesis approaches, we further discovered that the TGN46 lumenal domain encodes for its cargo sorting function. Interestingly, this domain forms liquid droplets in vitro by means of liquid-liquid phase separation, a physical mechanism that may assist in TGN46-mediated cargo sorting. In summary, our results define a cellular function of TGN46 in sorting secretory proteins for export from the TGN. These findings could open new therapeutic avenues for diseases that parallel secretory malfunction.