The retromer complex – endosomal protein recycling and beyond

Abstract

SummaryThe 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.

A mechanism for retromer endosomal coat complex assembly with cargo

“…At the steady state, SNX3 and RAB7 localize predominantly to early and late endosomes, respectively, indicating that the SNX3-and RAB7-dependent recruitment mechanism is restricted to maturing sorting endosomes as they accrue RAB7 by Rab conversion (2,13). From these endosomes, the mechanism defined here initiates sorting into retrograde pathways that direct cargo to the TGN and the recycling endosome (13,17,25).…”

“…The retromer trimer, also called the "cargo recognition complex," is the core functional unit of retromer, serving as a platform for recruiting many other factors to the endosome (2), and we shall refer herein to the trimer as retromer. It is now appreciated that retromer constitutes an ancient, evolutionarily conserved protein sorting complex that operates in multiple endosomal cargo export pathways (2,3). Hence, elucidating the molecular mechanisms that underlie retromer function is key for understanding the endosomal system.…”

WASH drives early recycling from macropinosomes and phagosomes to maintain surface phagocytic receptors

“…In the pH neutral Golgi, the CI-M6PR binds mannose-6-phosphate-tagged hydrolases to extract and deliver them to the lysosome. The acidic pH of the lysosome then causes the hydrolases to dissociate from the receptor, whereupon the retromer mediates CI-M6PR retrieval and return to the TGN (39,60,61). As the Dictyostelium postlysosomal transition is precipitated by neutralization, we hypothesize that the hydrolases will reassociate with their M6PR for retromer-mediated extraction before exocytosis.…”

Prolonged Insulin Stimulation Down-regulates GLUT4 through Oxidative Stress-mediated Retromer Inhibition by a Protein Kinase CK2-dependent Mechanism in 3T3-L1 Adipocytes

“…The reason for this discrepancy is unknown, but it may reflect the absence of PI 3-phosphate or the presence of as yet unidentified SNX protein(s) in the GSC fraction. In light of recent studies showing that non-prototypical retromer is involved in the endosome-to-plasma membrane traffic of G-protein-coupled receptors (14,15), it would be intriguing to investigate the role of GSC-associated retromer components in the physiological action of insulin on subcellular trafficking of GLUT4. Figure 5B …”

“…Retromer is a key component of the endosomal protein sorting machinery that mediates the endosometo-TGN retrieval of diverse functional transmembrane proteins (cargos) such as the cation-independent mannose 6-phosphate receptor, the Wnt-binding protein Wntless, and the sortilin family proteins (for reviews, see Refs. [12][13][14][15]. The prototypical mammalian retromer (sorting nexin (SNX)-BAR retromer) is a heteropentameric complex comprising two functionally separate subcomplexes: the cargo-selective subcomplex composed of Vps26, Vps29, and Vps35 that recruits cargos via an association between Vps35 and a sorting motif within the cytoplasmic tail of cargo and the SNX-BAR dimer subcomplex composed of SNX1 and SNX2 or of SNX5 and SNX6 that drives membrane curvature by binding to the early endosomal phosphatidylinositol (PI) 3-phosphate resulting in the formation of membrane tubules.…”