The calcium binding Cab45 regulates the polarized apical secretion of soluble proteins in epithelial cells.

Protein secretion is essential for the epithelial tissue homoeostasis and therefore has to be tightly regulated. However, while the mechanisms regulating polarized protein sorting and trafficking have been widely studied in the last decade, those governing polarized secretion remain elusive. The calcium manganese pump SPCA1 and the calcium binding protein Cab45 were recently shown to regulate the secretion of a subset of soluble cargoes in non polarized HeLa cells. Interestingly, we demonstrated that in polarized epithelial cells calcium levels in the TGN, controlled by SPCA1, and Cab45, are critical for the apical sorting of glycosylphosphatidylinositol-anchored proteins (GPI-APs), a class of integral membrane proteins containing a soluble protein attached to the membrane by the GPI anchor, prompting us to investigate the mechanism regulating the polarized secretion of soluble cargoes. By reducing Cab45 expression level or overexpressing an inactive mutant of SPCA1, we found that Cab45 and calcium levels in the TGN drive the polarized apical secretion of a secretory form of PLAP, exogenously expressed, and the endogenous soluble protein clusterin/Gp80 in MDCK cells. These data highlight the critical role of a calcium-dependent Cab45 mechanism regulating apical exocytosis in polarized MDCK cells.