Endosomal Retrieval of Cargo: Retromer Is Not Alone

Endosomes are major protein sorting stations in cells. Endosomally localised multi-protein complexes sort integral proteins, including signaling receptors, nutrient transporters, adhesion molecules, and lysosomal hydrolase receptors, for lysosomal degradation or conversely for retrieval and subsequent recycling to various membrane compartments. Correct endosomal sorting of these proteins is essential for maintaining cellular homeostasis, with defects in endosomal sorting implicated in various human pathologies including neurodegenerative disorders. Retromer, an ancient multi-protein complex, is essential for the retrieval and recycling of hundreds of transmembrane proteins. While retromer is a major player in endosomal retrieval and recycling, several studies have recently identified retrieval mechanisms that are independent of retromer. Here, we review endosomal retrieval complexes, with a focus on recently discovered retromer-independent mechanisms. Endosomal cargo are retrieved from degradation by multi-protein complexes before recycling. Retromer, retriever, and the CCC and WASH complexes are required for sequence-specific retrieval of cargo. Retromer is a key orchestrator of endosomal sorting, but retromer-independent pathways exist. Retriever is a retromer-like complex that functions independently of retromer. Retriever requires the CCC and WASH complexes for endosomal localisation and function. Mutations in these multi-protein complexes are increasingly associated with human pathologies including neurodegeneration and developmental disorders.