Retromer-mediated endosomal protein sorting: all WASHed up!

Abstract

Endosomal protein sorting governs the fate of many physiologically important proteins involved in a panoply of cellular functions. Recent discoveries have revealed a vital role for endosomally localised branched actin patches in facilitating protein sorting. The formation of the actin patches has been shown to require the function of the WASH complex - the major endosomal actin polymerisation-promoting complex - which stimulates the activity of the ubiquitously expressed Arp2/3 complex. Another key component of the endosomal protein-sorting machinery is the retromer complex. Studies now show that retromer mediates the recruitment of the WASH complex and its regulators to endosomes. In this review, recent progress in understanding the role of the WASH complex along with retromer in endosomal protein sorting is discussed.

Keywords: Fam21; WASH complex; actin; endosome; retromer; sorting.

Figure 1. The role of actin patches on endosomes

Schematic diagram of a sorting/recycling endosome where retromer and the WASH complex operate. Branched actin patches formed by the action of the WASH complex demarcate discrete domains into which specific proteins are sorted for transport to their respective destinations, for example, sorting for recycling to the cell surface of proteins such as the β2-adrenergic receptor requires the WASH complex along with SNX27 and retromer. The FERM domain of SNX27 can bind to Ras potentially linking sorting to signalling [47]. Actin patches close to sites where membrane tubules are formed may contribute to scission of tubules. Additionally, myosin motors could employ the actin filaments to facilitate short-range movement and possibly tubule elongation.

Figure 2. The key role of the Fam21 protein in linking the WASH complex to retromer

A. Cartoon diagram of the retromer and WASH complexes. The retromer cargo-selective complex (CSC) comprising VPS35, VPS29 and VPS26 function as a unit that is recruited to endosomes by RAB7a and SNX3 [14]. The TBC1D5 protein acts antagonistically to RAB7a to downregulate recruitment of the retromer CSC [32]. Through an interaction between VPS35 and FAM21 mediated by numerous LFa motifs within the long unstructured tail of FAM21, the retromer CSC recruits the WASH complex to endosomes to drive formation of branched actin patches. Additionally, MAGE-L2 connects VPS35 to TRIM27 which polyubiquitinates WASH1 and activates its NPF activity toward Arp2/3. B. Alignment of human and chicken FAM21 sequences and also human and Dictyostelium (Dicty.) FAM21 sequences showing the position of the globular head and unstructured tail domains which contain the CP-binding region and the LFa motifs (black triangles). This graphically demonstrates the evolutionary divergence of the FAM21 protein resulting in a lack of homology between human and Dictyostelium FAM21 proteins. The alignment was performed using the SIM alignment tool (http://web.expasy.org/sim/).

Figure 2. The key role of the Fam21 protein in linking the WASH complex to retromer

A. Cartoon diagram of the retromer and WASH complexes. The retromer cargo-selective complex (CSC) comprising VPS35, VPS29 and VPS26 function as a unit that is recruited to endosomes by RAB7a and SNX3 [14]. The TBC1D5 protein acts antagonistically to RAB7a to downregulate recruitment of the retromer CSC [32]. Through an interaction between VPS35 and FAM21 mediated by numerous LFa motifs within the long unstructured tail of FAM21, the retromer CSC recruits the WASH complex to endosomes to drive formation of branched actin patches. Additionally, MAGE-L2 connects VPS35 to TRIM27 which polyubiquitinates WASH1 and activates its NPF activity toward Arp2/3. B. Alignment of human and chicken FAM21 sequences and also human and Dictyostelium (Dicty.) FAM21 sequences showing the position of the globular head and unstructured tail domains which contain the CP-binding region and the LFa motifs (black triangles). This graphically demonstrates the evolutionary divergence of the FAM21 protein resulting in a lack of homology between human and Dictyostelium FAM21 proteins. The alignment was performed using the SIM alignment tool (http://web.expasy.org/sim/).