Retromer is a heteropentameric complex that is composed of a less defined membrane-associated sorting nexin dimer (SNX1, SNX2, SNX5, SNX6), and a vacuolar protein sorting (Vps) trimer containing Vps26, Vps29, Vps35. Although the SNX dimer is required for the recruitment of retromer to the endosomal membrane, the cargo binding function of this complex is contributed by the core trimer through the binding of Vps35 subunit to various cargo molecules3 including M6PR4 wntless5and sortilin.6 Early study on sorting of acid hydrolases such as carboxypeptidase Y (CPY) in S. cerevisiae mutants has led to the identification of retromer in mediating the retrograde trafficking of the pro-CPY receptor (Vps10) from the endosomes to the TGN.7
The retromer complex is highly conserved: homologs have been found in C. elegans, mouse and human. The retromer complex consists of 5 proteins in yeast: Vps35p, Vps26p, Vps29p, Vps17p, Vps5p. The mammalian retromer consists of Vps26, Vps29, Vps35, SNX1 and SNX2, and possibly SNX5 and SNX6.8 It is proposed to act in two subcomplexes: (1) Cargo recognition complex that consist of Vps35, Vps29 and Vps26 (Vps trimer), and (2) SNX-BAR dimers which consist of SNX1 and SNX2 or SNX5 and SNX6 that facilitates endosomal membrane remodulation and curvature resulting in the formation of tubules/vesicles which transports cargo molecules to the trans-golgi network (TGN).
The retromer complex has been shown to mediate retrieval of various transmembrane receptors, such as the cation-independent mannose 6-phosphate receptor, the functional mammalian counterpart of Vps10, and the Wnt receptor Wntless.9 Retromer is required for the recycling of Kex2p and DPAP-A which also cycle between the trans-Golgi network and a pre-vacuolar (yeast endosome equivalent) compartment in yeast. It is also required for the recycling of the cell surface receptor CED-1, which is necessary for phagocytosis of apoptotic cells.10
Retromer plays a central role in the retrieval of several different cargo proteins from the endosome to the trans-Golgi network. However, it is clear that there are other complexes and proteins that act in this retrieval process. So far it is not clear whether other components that have been identified in the retrieval pathway act with retromer in the same pathway or are involved in alternative pathways. Recent studies have implicated retromer sorting defects in Alzheimer's disease11 and late-onset Parkinson disease 12
The association of the Vps35-Vps29-Vps26 complex to the cytosolic domains of cargo molecules endosomal membranes initiates the activation of retrograde trafficking and cargo capture.13 The nucleation complex was formed through the interaction of VPS complex with GTP-activated Rab7 with clathrin, clathrin-adaptors and various binding proteins.14
The SNX-BAR dimer enters the nucleation complex via direct binding or lateral movement on endosomal surface. The increased level of Retromer SNX-BARs causes a conformational switch to a curvature-inducing mode which initiates membrane tubule formation.1516 Once the cargo carriers are matured, the carrier scission is then catalyzed by dynamin-II or EHD1,17 together with the mechanical forces generated by actin polymerization and motor activity.
The cargo carrier is transported to the TGN by motor proteins such as dynein. Tethering of the cargo carrier to the recipient compartment will lead to the uncoating of the carrier which is driven by ATP-hydrolysis and Rab7-GTP hydrolysis. Once released from the carrier, the Vps35-Vps29-Vps26 complex and the SNX-BAR dimers get recycled back onto the endosomal membranes.
- Seaman MN (February 2005). "Recycle your receptors with retromer". Trends Cell Biol. 15 (2): 68–75. doi:10.1016/j.tcb.2004.12.004. PMID 15695093.
- Pfeffer SR (February 2001). "Membrane transport: retromer to the rescue". Curr. Biol. 11 (3): R109–11. doi:10.1016/S0960-9822(01)00042-2. PMID 11231171.
- Seaman MN (April 2004). "Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer". J. Cell Biol. 165 (1): 111–22. doi:10.1083/jcb.200312034. PMC 2172078. PMID 15078902.
- Arighi CN, Hartnell LM, Aguilar RC, Haft CR, Bonifacino JS (April 2004). "Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor". J. Cell Biol. 165 (1): 123–33. doi:10.1083/jcb.200312055. PMC 2172094. PMID 15078903.
- Belenkaya TY, Wu Y, Tang X, Zhou B, Cheng L, Sharma YV, Yan D, Selva EM, Lin X (January 2008). "The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network". Dev. Cell 14 (1): 120–31. doi:10.1016/j.devcel.2007.12.003. PMID 18160348.
- Canuel M, Korkidakis A, Konnyu K, Morales CR (August 2008). "Sortilin mediates the lysosomal targeting of cathepsins D and H". Biochem. Biophys. Res. Commun. 373 (2): 292–7. doi:10.1016/j.bbrc.2008.06.021. PMID 18559255.
- Seaman MN, McCaffery JM, Emr SD (August 1998). "A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast". J. Cell Biol. 142 (3): 665–81. doi:10.1083/jcb.142.3.665. PMC 2148169. PMID 9700157.
- Wassmer T, Attar N, Bujny MV, Oakley J, Traer CJ, Cullen PJ (January 2007). "A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer". J. Cell. Sci. 120 (Pt 1): 45–54. doi:10.1242/jcs.03302. PMID 17148574.
- Eaton S (January 2008). "Retromer retrieves wntless". Dev. Cell. 14 (1): 4–6. doi:10.1016/j.devcel.2007.12.014. PMID 18194646.
- Chen D, Xiao H, Zhang K, Gao Z, Jian Y, Qi X, Sun J, Miao L, Yang C (March 2010). "Retromer is required for apoptotic cell clearance by phagocytic receptor recycling". Science 327 (5970): 1261–4. doi:10.1126/science.1184840. PMID 20133524.
- Muhammad A, Flores I, Zhang H, Yu R, Staniszewski A, Planel E, Herman M, Ho L, Kreber R, Honig LS, Ganetzky B, Duff K, Arancio O, Small SA (May 2008). "Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Aβ accumulation". Proc. Natl. Acad. Sci. U.S.A. 105 (20): 7327–32. doi:10.1073/pnas.0802545105. PMC 2386077. PMID 18480253.
- Zimprich Alexander, Benet-Pages A, Struhal W, Graf E, Eck SH, Offman MN, Haubenberger D, Spielberger S, Schulte EC, Lichtner P, Rossle SC, Klopp N, Wolf E, Seppi K, Pirker W, Presslauer S, Mollenhauer B, Katzenschlager R, Foki T, Hotzy C, Reinthaler E, Harutyunyan A, Kralovics R, Peters A, Zimprich F, Brucke T, Poewe W, Auff E, Trenkwalder C, Rost B, Ransmayr G, Winkelmann J, Meitinger T, Strom TM (July 2011). "A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease". American journal of human genetics 89 (1): 168–75. doi:10.1016/j.ajhg.2011.06.008. PMC 3135812.
- Nothwehr SF, Ha SA, Bruinsma P (October 2000). "Sorting of yeast membrane proteins into an endosome-to-Golgi pathway involves direct interaction of their cytosolic domains with Vps35p". J. Cell Biol. 151 (2): 297–310. doi:10.1083/jcb.151.2.297. PMC 2192648. PMID 11038177.
- McGough IJ, Cullen PJ (August 2011). "Recent advances in retromer biology". Traffic 12 (8): 963–71. doi:10.1111/j.1600-0854.2011.01201.x. PMID 21463457.
- Shimada A, Niwa H, Tsujita K, Suetsugu S, Nitta K, Hanawa-Suetsugu K, Akasaka R, Nishino Y, Toyama M, Chen L, Liu ZJ, Wang BC, Yamamoto M, Terada T, Miyazawa A, Tanaka A, Sugano S, Shirouzu M, Nagayama K, Takenawa T, Yokoyama S (May 2007). "Curved EFC/F-BAR-domain dimers are joined end to end into a filament for membrane invagination in endocytosis". Cell 129 (4): 761–72. doi:10.1016/j.cell.2007.03.040. PMID 17512409.
- Bhatia VK, Madsen KL, Bolinger PY, Kunding A, Hedegård P, Gether U, Stamou D (November 2009). "Amphipathic motifs in BAR domains are essential for membrane curvature sensing". EMBO J. 28 (21): 3303–14. doi:10.1038/emboj.2009.261. PMC 2776096. PMID 19816406.
- Walseng E, Bakke O, Roche PA (May 2008). "Major histocompatibility complex class II-peptide complexes internalize using a clathrin- and dynamin-independent endocytosis pathway". J. Biol. Chem. 283 (21): 14717–27. doi:10.1074/jbc.M801070200. PMC 2386912. PMID 18378669.