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.

Blank B ，von Blume J 《-》

Secretory cargo sorting by Ca2+-dependent Cab45 oligomerization at the trans-Golgi network.

Sorting and export of transmembrane cargoes and lysosomal hydrolases at the trans-Golgi network (TGN) are well understood. However, elucidation of the mechanism by which secretory cargoes are segregated for their release into the extracellular space remains a challenge. We have previously demonstrated that, in a reaction that requires Ca(2+), the soluble TGN-resident protein Cab45 is necessary for the sorting of secretory cargoes at the TGN. Here, we report that Cab45 reversibly assembles into oligomers in the presence of Ca(2+) These Cab45 oligomers specifically bind secretory proteins, such as COMP and LyzC, in a Ca(2+)-dependent manner in vitro. In intact cells, mutation of the Ca(2+)-binding sites in Cab45 impairs oligomerization, as well as COMP and LyzC sorting. Superresolution microscopy revealed that Cab45 colocalizes with secretory proteins and the TGN Ca(2+) pump (SPCA1) in specific TGN microdomains. These findings reveal that Ca(2+)-dependent changes in Cab45 mediate sorting of specific cargo molecules at the TGN.

Crevenna AH ，Blank B ，Maiser A ，Emin D ，Prescher J ，Beck G ，Kienzle C ，Bartnik K ，Habermann B ，Pakdel M ，Leonhardt H ，Lamb DC ，von Blume J ... -  《-》

Exploring new routes for secretory protein export from the trans-Golgi network.

Sorting of soluble proteins for transport to intracellular compartments and for secretion from cells is essential for cell and tissue homeostasis. The trans-Golgi network (TGN) is a major sorting station that sorts secretory proteins into specific carriers to transport them to their final destinations. The sorting of lysosomal hydrolases at the TGN by the mannose 6-phosphate receptor is well understood. The recent discovery of a Ca2+-based sorting of secretory cargo at the TGN is beginning to uncover the mechanism by which cells sort secretory cargoes from Golgi residents and cargoes destined to the other cellular compartments. This Ca2+-based sorting involves the cytoplasmic actin cytoskeleton, which through membrane anchored Ca2+ ATPase SPCA1 and the luminal Ca2+ binding protein Cab45 sorts of a subset of secretory proteins at the TGN. We present this discovery and highlight important challenges that remain unaddressed in the overall pathway of cargo sorting at the TGN.

Pakdel M ，von Blume J 《-》

Secretory cargo sorting at the trans-Golgi network.

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 Ca(2+) ATPase, SPCA1 (secretory pathway calcium ATPase 1), and the luminal 45 kDa Ca(2+)-binding protein, Cab45, for successful sorting of a subset of proteins at the TGN. We review progress in understanding these processes.

Kienzle C ，von Blume J 《-》

Cab45 is required for Ca(2+)-dependent secretory cargo sorting at the trans-Golgi network.

von Blume J ，Alleaume AM ，Kienzle C ，Carreras-Sureda A ，Valverde M ，Malhotra V ... -  《-》