Secretory cargo sorting at the trans-Golgi network

•Sorting of secretory cargo at the TGN takes place by selective aggregation and sorting receptors.•Novel secretory cargo sorting pathway by ADF/cofilin, actin, Ca2+, and Cab45.•ADF/cofilin and actin modulate the pumping activity of the Ca2+ ATPase SPCA1 on the TGN surface.•Ca2+ and Cab45 sort secretory proteins in the lumen of the TGN.

Sorting of proteins for secretion from cells is crucial for normal physiology and the regulation of key cellular events. Although the sorting of lysosomal hydrolases at the trans-Golgi network (TGN) for delivery to pre-lysosomes is well characterized, the corresponding mechanism by which secreted proteins are sorted for plasma-membrane delivery remains poorly understood. Recent discoveries have revealed a novel sorting mechanism that requires the linkage between the cytoplasmic actin cytoskeleton to the membrane-anchored Ca2+ ATPase, SPCA1 (secretory pathway calcium ATPase 1), and the luminal 45 kDa Ca2+-binding protein, Cab45, for successful sorting of a subset of proteins at the TGN. We review progress in understanding these processes.