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Review
. 2018 Aug;19(8):578-590.
doi: 10.1111/tra.12574. Epub 2018 May 21.

Endosomal receptor trafficking: Retromer and beyond

Jing Wang  1 , Alina Fedoseienko  2   3 , Baoyu Chen  4 , Ezra Burstein  5   6 , Da Jia  1 , Daniel D Billadeau  2   3
Affiliations
Review

Endosomal receptor trafficking: Retromer and beyond

Jing Wang et al. Traffic. 2018 Aug.

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.

Keywords: WASH; endosome; receptor trafficking; retriever; retromer; sorting nexin.

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Figures

Figure 1
Figure 1
Representative trafficking pathways of transmembrane receptors. Transmembrane proteins are internalized into early endosomes via endocytosis. Maturation of early endosomes into late endosomes leads to protein degradation via lysosome. Some proteins are delivered to the plasma membrane or to the TGN with the assistance of retromer, retriever, WASH, CCC, and a variety of SNX proteins, thus escaping lysosomal degradation. At the TGN, TBC1d23 and associated proteins are responsible for receiving endosomal vesicles.
Figure 2
Figure 2
Domain organization and functional modes of select SNXs. (A) Domain structures of retromer and retriever-associated SNXs. All SNXs share a conserved PX domain. SNX-BAR and SNX-FERM subfamilies possess a BAR or FERM domain, respectively, C-terminal to the PX domain. Within the SNX-FERM subfamily, SNX27 features a unique N-terminal PDZ domain whereas SNX17 has a unique C-terminal tail. (B) Distinct cargo recognition modes of SNXs. Representative cargo proteins are listed under the cartoon. SNX3 interacts with both VPS35 and VPS26 subunits of retromer, and cargo recognition is achieved through cooperative action of SNX3 and VPS26. SNX-BAR may directly bind to cargo such as CI-MPR and IGF1R. The PDZ domain of SNX27 recognizes a subset of cargo proteins independent of retromer; however, interaction with VPS26 enhances the affinity of SNX27 for cargo. SNX17 may bridge cargo with retriever through simultaneous interaction with cargo and DSCR3.
Figure 3
Figure 3
Function of the WASH complex in retromer- and retriever-mediated trafficking. (A) Organization of the WASH complex and some of its associated proteins. Whereas CCC and CapZ interact with FAM21 fragments containing amino acids 448-631 and 1010-1067 (as indicated), respectively, other proteins either bind to multiple regions of FAM21 or the exact interacting regions are not fully defined. For instance, VPS35 binds to many LFa repeats of FAM21, with highest affinity toward those at the C-terminal end of the tail. (B) A model depicting the role of WASH complex in regulating retromer-mediating trafficking. Increasing concentration of cargo (step I) leads to membrane recruitment of the retromer-SNX27 complex (step II), which, in turn, recruits the WASH complex (step III). WASH-mediated actin polymerization could promote the organization of retromer endosomal subdomains (step IV), and formation of retromer tubules (step V). WASH could also function to assist the scission of tubular structures together with other proteins, such as Dynamin II (step VI). (C) A model depicting the role of WASH complex in regulating retriever-mediating trafficking. SNX17 binds to cargo protein on the membrane, and WASH is recruited to membrane in a retromer-dependent manner (steps I and II). WASH and SNX17 in turn recruit CCC (step III), and retriever complexes (step IV). Similar to its role in retromer trafficking, WASH-mediated actin polymerization could promote the formation of SNX17/cargo/CCC/retriever endosomal subdomains (step V), vesicle budding (step VI), and vesicle scission (step VII). (D) A mutation in VPS35 (D620N) diminishes the interaction of the WASH1 complex with the retromer, and impairs retromer-mediated cargo trafficking.
Figure 4
Figure 4
Function of TBC1d23 in endosomal sorting. (A) Domain organization of TBC1d23 and TBC1d5. Although both proteins possess a TBC domain, TBC1d5, but not TBC1d5, is catalytically active. (B) A model depicting the function of TBC1d23 in tethering endosomal vesicles with TGN. Left: The WASH and WDR11 complexes decorate endosome-derived vesicles, and TBC1d23 is localized at the TGN through its interaction with Goglin-97/245. Right: Interaction between TBC1d23 and FAM21 or the WDR11 complex allows tethering and subsequent fusion of endosomal vesicles with the TGN.
Figure 5
Figure 5
Mechanisms of interference of endosomal trafficking by bacterial effector proteins RidL and IncE. (A) Model showing how RidL subverts retromer-dependent transport. Left: TBC1d5 is required for retromer-dependent endosomal trafficking. TBC1d5 interacts with both VPS35 and VPS29. Right: During L. pneumophila infection, RidL replaces TBC1d5, and likely VARP (not shown), to block retromer-mediated trafficking. In contrast with TBC1d5, RidL interacts only with VPS29. (B) Model showing how IncE inhibits SNX-BAR-dependent transport. Left: SNX-BAR complex mediates endosome-to-TGN transport of certain proteins, such as CI-MPR. Right: Bacterial effector protein IncE interacts with the PX domain of SNX5/SNX6, and may inhibit their association with cargo proteins.
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References

    1. Burd C, Cullen PJ. Retromer: A Master Conductor of Endosome Sorting. Csh Perspect Biol. 2014;6(2) - PMC - PubMed
    1. Guo Y, Sirkis DW, Schekman R. Protein sorting at the trans-Golgi network. Annu Rev Cell Dev Biol. 2014;30:169–206. - PubMed
    1. Bonifacino JS, Hurley JH. Retromer. Curr Opin Cell Biol. 2008;20(4):427–436. - PMC - PubMed
    1. McMillan KJ, Korswagen HC, Cullen PJ. The emerging role of retromer in neuroprotection. Curr Opin Cell Biol. 2017;47:72–82. - PMC - PubMed
    1. Lucas M, Hierro A. Retromer. Curr Biol. 2017;27(14):R687–R689. - PubMed

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