Endosomal receptor trafficking: Retromer and beyond

Abstract

The tubular endolysosomal network is a quality control system that ensures the proper delivery of internalized receptors to specific subcellular destinations in order to maintain cellular homeostasis. Although retromer was originally described in yeast as a regulator of endosome-to-Golgi receptor recycling, mammalian retromer has emerged as a central player in endosome-to-plasma membrane recycling of a variety of receptors. Over the past decade, information regarding the mechanism by which retromer facilitates receptor trafficking has emerged, as has the identification of numerous retromer-associated molecules including the WASH complex, sorting nexins (SNXs) and TBC1d5. Moreover, the recent demonstration that several SNXs can directly interact with retromer cargo to facilitate endosome-to-Golgi retrieval has provided new insight into how these receptors are trafficked in cells. The mechanism by which SNX17 cargoes are recycled out of the endosomal system was demonstrated to involve a retromer-like complex termed the retriever, which is recruited to WASH positive endosomes through an interaction with the COMMD/CCDC22/CCDC93 (CCC) complex. Lastly, the mechanisms by which bacterial and viral pathogens highjack this complex sorting machinery in order to escape the endolysosomal system or remain hidden within the cells are beginning to emerge. In this review, we will highlight recent studies that have begun to unravel the intricacies by which the retromer and associated molecules contribute to receptor trafficking and how deregulation at this sorting domain can contribute to disease or facilitate pathogen infection.

Processing and targeting of cathepsin L (TbCatL) to the lysosome inTrypanosoma brucei

“…Consequently, identification may require more biochemical approaches. These receptors are typically recycled from late endolysosomal compartments back to the trans ‐Golgi by the highly conserved retromer complex (Koumandou et al, ; Wang et al, ). Identification of the TbCatL sorting receptor would open a window for future studies of this machinery in trypanosomes.…”

Energetic adaptations: Metabolic control of endocytic membrane traffic

“…Within these early endosomes, sorting of cargo into vesicular or tubular membrane structures allows traffic of cargo to specific locations. This includes a number of pathways undertaken by specific cargo including Rab4‐dependent rapid recycling of cargo to the plasma membrane, and sorting of cargo mediated by a variety of complexes including Retromer, Retriever, WASH and CCC to the trans Golgi network (TGN) or the plasma membrane, or Rab7‐dependent traffic to the late endosome and lysosome…”

A role for the VPS retromer inBrucellaintracellular replication revealed by genome-wide siRNA screening

“…Knockdown of Sec61γ - a central element of the ER-protein translocation machinery (see for instance (34), which has been previously involved in Brucella infection (35), showed a strong decrease in intracellular replication albeit no effect on pathogen entry. Similarly, our assay identified the v acuolar p rotein s orting associated proteins VPS35 and VPS26A - two essential components of the VPS retromer complex (recently reviewed in (32, 33)). These genes and associated pathway(s) thus likely represent novel components controlling the post-entry trafficking of Brucella towards its replicative niche and/or are themselves required for the establishment or maintenance of the rBCVs.…”

“…Formed by a heterotrimeric complex consisting of VPS26, VPS29, and VPS35, the VPS retromer is conserved from yeast to human. However, the individual retromer sub-complexes have functionally diverged to organize multiple distinct sorting pathways, depending on the association with different accessory factors (32, 33). To further decipher the role of the retromer in Brucella trafficking and intracellular replication we specifically browsed our genome-wide siRNA data for retromer-associated proteins (Fig.…”