The retromer complex - endosomal protein recycling and beyond

Abstract

The retromer complex is a vital element of the endosomal protein sorting machinery that is conserved across all eukaryotes. Retromer is most closely associated with the endosome-to-Golgi retrieval pathway and is necessary to maintain an active pool of hydrolase receptors in the trans-Golgi network. Recent progress in studies of retromer have identified new retromer-interacting proteins, including the WASH complex and cargo such as the Wntless/MIG-14 protein, which now extends the role of retromer beyond the endosome-to-Golgi pathway and has revealed that retromer is required for aspects of endosome-to-plasma membrane sorting and regulation of signalling events. The interactions between the retromer complex and other macromolecular protein complexes now show how endosomal protein sorting is coordinated with actin assembly and movement along microtubules, and place retromer squarely at the centre of a complex set of protein machinery that governs endosomal protein sorting. Dysregulation of retromer-mediated endosomal protein sorting leads to various pathologies, including neurodegenerative diseases such as Alzheimer disease and spastic paraplegia and the mechanisms underlying these pathologies are starting to be understood. In this Commentary, I will highlight recent advances in the understanding of retromer-mediated endosomal protein sorting and discuss how retromer contributes to a diverse set of physiological processes.

Fig. 1.

Schematic depiction of the role of the retromer complex in mediating endosomal protein sorting. The cargo-selective retromer complex operates in the endosome-to-Golgi retrieval pathway to sort cargo, such as CIMPR and sortilin (see Table 1). The interaction of retromer with cargo proteins requires its recruitment to the endosomal membrane, a process that is mediated by Rab7a and Snx3. The sorting nexin (Snx) heterodimer dimer, comprising the Snx-BAR proteins Snx1 or Snx2 and Snx5 or Snx6, mediates tubule formation and links to microtubules through the p150-glued–dynein complex. The cargo-selective retromer subcomplex (Vps35–Vps29–Vps26) recruits the WASH complex, which mediates the production of branched actin networks on the surface of endosomes. The cargo-selective retromer complex together with Snx27 and the WASH complex operate in the endosome-to-cell surface recycling of the GPCR β2-adrenergic receptor and of other proteins including α5β1 integrin. Additionally, the cargo-selective retromer complex also regulates the signalling activity of another GPCR, the parathyroid hormone receptor (PTHR).

Fig. 2.

Schematic diagram of the interactions between retromer and its associated proteins. Here, the many retromer-interacting proteins that have been identified from studies in higher eukaryotes (e.g. mammalian cells) are depicted. Proteins have been grouped according to function, e.g. Snx3, Rab7a and TBC1D5 regulate the membrane association of the cargo-selective retromer complex. Arrows indicate the relationship between the respective proteins, e.g. Vps35 interacts with Fam21 to mediate recruitment of Fam21 and the WASH complex. In some cases, arrows are double-ended as the respective proteins are mutually dependent. Arrows with a dashed outline indicate an interaction that has not yet been experimentally proven, but is likely based on indirect evidence, e.g. native immunoprecipitations.