S-Palmitoylation Sorts Membrane Cargo for Anterograde Transport in the Golgi

While retrograde cargo selection in the Golgi is known to depend on specific signals, it is unknown whether anterograde cargo is sorted, and anterograde signals have not been identified. We suggest here that S-palmitoylation of anterograde cargo at the Golgi membrane interface is an anterograde signal and that it results in concentration in curved regions at the Golgi rims by simple physical chemistry. The rate of transport across the Golgi of two S-palmitoylated membrane proteins is controlled by S-palmitoylation. The bulk of S-palmitoylated proteins in the Golgi behave analogously, as revealed by click chemistry-based fluorescence and electron microscopy. These palmitoylated cargos concentrate in the most highly curved regions of the Golgi membranes, including the fenestrated perimeters of cisternae and associated vesicles. A palmitoylated transmembrane domain behaves similarly in model systems. Examples exist of secretory pathway receptor-mediated protein sorting for retrograde cargo, but not for anterograde. Ernst et al. uncover an anterograde cargo sorting mechanism: S-palmitoylation at the Golgi acts as a biophysical switch that induces “self-sorting” of membrane cargo to the cisternal rim, enabling its efficient transport through the Golgi.