The pathways of secretory cargo export at the endoplasmic reticulum

Abstract

Palade's original model proposed that secretory cargo is transported between stable compartments via vesicles. However, recent findings challenge this view, suggesting that secretory pathway compartments are dynamic, with cargo itself dictating whether transfer occurs via vesicles or through the continuity and maturation of compartmental structures. At the heart of this process is TANGO1, a key component of a molecular machine that works in concert with COPII proteins to construct export routes tailored to the size and quantity of secretory cargo.

Fig. 1. Cargo dictates the composition of the secretory pathway.

In metazoans, the secretion of large cargoes in substantial quantities cannot be managed by standard COPII vesicles alone. Data suggest that export sites at the ER are segregated, with ~40% of the sites dedicated to the export of bulky molecules like collagens. The transport in bulk of large cargoes, such as collagens, mucins, lipoprotein particles, and antibodies, is mediated by tunnels. Once a tunnel is filled with cargo, its connection to the ER exit site (ERES) is severed. It remains unclear whether this cargo-filled saccule fuses with the cis-Golgi cisterna or matures until it consists solely of cargo destined for secretion. In most cell types, both types of exit sites are utilized: small cargoes are exported via COPII vesicles, while large cargoes like collagens are transported via tunnels (left panel). However, depending on the cell type, there may be a preference for one type of exit site over the other (middle and right panels).