Retromer: a master conductor of endosome sorting

Abstract

The endosomal network comprises an interconnected network of membranous compartments whose primary function is to receive, dissociate, and sort cargo that originates from the plasma membrane and the biosynthetic pathway. A major challenge in cell biology is to achieve a thorough molecular description of how this network operates, and in so doing, how defects contribute to the etiology and pathology of human disease. We discuss the increasing body of evidence that implicates an ancient evolutionary conserved complex, termed "retromer," as a master conductor in the complex orchestration of multiple cargo-sorting events within the endosomal network.

Figure 1.

Overview of endosomal sorting pathways. Cargo in the endosome is sorted either into the degradative pathway, leading to its eventual delivery to the lysosome, or into an export pathway that returns it to another organelle for reuse. Recycling export pathways deliver cargo to the plasma membrane, and retrograde export pathways return cargo to the trans-Golgi network. Sorting devices that act in each of these export pathways are listed. Transport carriers of the export pathways bud from the tubular endosomal network, whereas sorting into the lysosomal degradation pathway results in packaging of cargo into vesicles that bud into the lumen of multivesicular endosomes.

Figure 2.

SNX-BAR-retromer-mediated cargo exit from lysosomal-mediated degradation. The VPS26:VPS29: VPS35 CSC engage cargo in a signal-dependent manner. Through WASH-mediated actin polymerization a cargo-enriched endosome subdomain is assembled thereby avoiding ESCRT-mediated sorting into forming intraluminal vesicles. Subsequent transport into recycling pathways back to the plasma membrane or retrograde transport to the TGN is mediated through retromer SNX-BAR-mediated tubule formation. Actin polymerization may aid further membrane remodeling and the efficiency of tubule scission to form a cargo-enriched tubular transport carrier.

Figure 3.

A pictorial representation of the proposed CSC retrieval subdomain on the endosomal surface (based on data from Jia et al. 2012). The CSC is associated with the cytosolic face of the early endosome and the maturing late endosome through association with the phosphatidylinositol 3-monophosphate (PI3P)-binding SNX3 and Rab7-GTP, respectively. In addition to cargo selection mediated by the CSC, associated adaptors also engage cargo (the PI3P-binding SNX27 is depicted). Through association of the unstructured tail of FAM21, multiple CSCs, along with their associated cargoes, become enriched into a retrieval subdomain (retrieval zone) in which lateral mobility is restricted as a result of WASH-mediated actin polymerization. In the lower bird’s-eye view, two associated CSCs are shown to reflect evidence for dimeric assemblies (Norwood et al. 2011).