| TGN46, a single-pass type I transmembrane glycoprotein that cycles between the trans-Golgi network and the plasma membrane, functions as a cargo-sorting receptor that organizes the export of selected soluble secretory proteins from the trans-Golgi network into defined post-Golgi carriers. The luminal domain is heavily glycosylated and projects into the trans-Golgi network lumen, where it directly recognizes soluble cargo such as the pancreatic adenocarcinoma upregulated factor (PAUF), while the short cytosolic tail contains sorting information that couples TGN46 to protein kinase D–dependent CARTS (carriers of the trans-Golgi network to the cell surface) and to the broader machinery that generates tubulovesicular transport intermediates. TGN46 concentrates at the trans-Golgi network where secretory proteins segregate into distinct export routes, and its continuous cycling to the plasma membrane and back through endosomes positions it at the interface of biosynthetic and endocytic pathways, allowing repeated rounds of cargo capture and delivery into nascent carriers. Cargo engagement by the luminal domain drives loading of PAUF and similar secretory proteins into CARTS, which bud from the trans-Golgi network under the control of protein kinase D and move toward the cell surface for constitutive secretion, so that TGN46 activity directly shapes the efficiency and selectivity of soluble protein export toward the extracellular space. Mutational analysis that replaces or truncates the luminal region shows that this domain is both necessary and sufficient for cargo sorting, whereas alterations in the cytosolic tail affect carrier association and routing without abolishing cargo recognition, indicating a division of labor in which the luminal region encodes cargo specificity and the cytosolic region links to budding and transport systems. Loss or depletion of TGN46 disrupts sorting and loading of PAUF and other secretory clients into CARTS, reduces their presence in trans-Golgi–derived tubules, and delays or diminishes their secretion, establishing TGN46 as a central determinant of constitutive secretory flux rather than a generic trans-Golgi marker. In the broader context of secretory pathway organization, TGN46 operates alongside Ca²⁺-dependent luminal sorting factors such as Cab45, with evidence that TGN46 participates in the routing of Cab45 clients and contributes to the formation and correct composition of sphingomyelin-rich secretory vesicles, linking this receptor to lipid-dependent sorting environments and lysosomal versus secretory fate decisions for selected cargo classes. |
