Cab45-Unraveling key features of a novel secretory cargo sorter at the trans-Golgi network

The accurate and efficient delivery of proteins to specific domains of the plasma membrane or to the extracellular space is critical for the ordered function of surface receptors and proteins such as insulin, collagens, antibodies, extracellular proteases. The trans-Golgi network is responsible for sorting proteins onto specific carriers for transport to their final destination. The role of the mannose-6-phosphate receptor in the sorting of hydrolases destined for lysosomes has been studied extensively, but the sorting mechanisms for secreted proteins remains poorly understood. We recently described a novel process that links the cytoplasmic actin cytoskeleton to the membrane-anchored Ca²⁺ ATPase SPCA1 and the lumenal Ca²⁺-binding protein Cab45, which mediates sorting of a subset of secretory proteins at the TGN. In response to Ca²⁺ influx, Cab45 forms oligomers, enabling it to bind a variety of specific cargo molecules. Thus, we suggest that this represents a novel way to export cargo molecules without the need for a bona fide transmembrane cargo receptor. This review focuses on Cab45's molecular function and highlights its possible role in disease.