Retromer Explained

Retromer is a complex of proteins that has been shown to be important in recycling transmembrane receptors from endosomes to the trans-Golgi network (TGN) and directly back to the plasma membrane. Mutations in retromer and its associated proteins have been linked to Alzheimer's and Parkinson's diseases.[1] [2] [3] [4]

Retromer is a heteropentameric complex, which in humans is composed of a less defined membrane-associated sorting nexin dimer (SNX1, SNX2, SNX5, SNX6), and a vacuolar protein sorting (Vps) heterotrimer containing Vps26, Vps29, and 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 heterotrimer through the binding of Vps26 and Vps35 subunits to various cargo molecules[5] including M6PR,[6] wntless,[7] SORL1 (which is also a receptor for other cargo proteins such as APP), and sortilin.[8] 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.[9] Age-related loss of OXR1 causes retromer decline.[10]

Structure

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.[11] It is proposed to act in two subcomplexes: (1) A cargo recognition heterotrimeric complex that consist of Vps35, Vps29 and Vps26, and (2) SNX-BAR dimers, which consist of SNX1 or SNX2 and SNX5 or SNX6 that facilitate endosomal membrane remodulation and curvature, resulting in the formation of tubules/vesicles that transport cargo molecules to the trans-golgi network (TGN). Humans have two orthologs of VPS26: VPS26A, which is ubiquitous, and VPS26B, which is found in the central nervous system, where it forms a unique retromer that is dedicated to direct recycling of neuronal cell surface proteins such as APP back to the plasma membrane with the assistance of the cargo receptor SORL1. [12]

Function

The retromer complex has been shown to mediate retrieval of various transmembrane receptors, such as the cation-independent mannose 6-phosphate receptor, functional mammalian counterparts of Vps10 such as SORL1, and the Wnt receptor Wntless.[13] 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.[14]

Retromer plays a central role in the retrieval of several different cargo proteins from the endosome to the trans-Golgi network, or for direct recycling back to the cell surface. However, it is clear that there are other complexes and proteins that act in this retrieval process. So far it is not clear whether some of the 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 disease[15] [16] and late-onset Parkinson disease[17]

Retromer also seems to play a role in Hepatitis C Virus replication.[18]

Retrograde trafficking and direct recycling

Retrograde trafficking to the trans-Golgi network

The association of the Vps35-Vps29-Vps26 complex with the cytosolic domains of cargo molecules on endosomal membranes initiates the activation of retrograde trafficking and cargo capture.[19] The nucleation complex is formed through the interaction of VPS complex with GTP-activated Rab7[20] with clathrin, clathrin-adaptors and various binding proteins.[21]

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.[22] [23] Once the cargo carriers are matured, the carrier scission is then catalyzed by dynamin-II or EHD1,[24] 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 is thought to 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.

Direct recycling back to the cell surface

The other function of retromer is the recycling of protein cargo directly back to the plasma membrane. Dysfunction of this branch of the retromer recycling pathway causes endosomal protein traffic jams [25] that are linked to Alzheimer’s disease. [26] [27] It has been suggested that recycling dysfunction is the “fire” that drives the common form of Alzheimer’s, leading to the production of amyloid and tau tangle “smoke”. [28]

See also

Notes and References

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  2. Seaman MN . Recycle your receptors with retromer . Trends in Cell Biology . 15 . 2 . 68–75 . February 2005 . 15695093 . 10.1016/j.tcb.2004.12.004 .
  3. Pfeffer SR . Membrane transport: retromer to the rescue . Current Biology . 11 . 3 . R109-R111 . February 2001 . 11231171 . 10.1016/S0960-9822(01)00042-2 . free .
  4. Small SA, Petsko GA . Retromer in Alzheimer disease, Parkinson disease and other neurological disorders . Nature Reviews. Neuroscience . 16 . 3 . 126–132 . March 2015 . 25669742 . 10.1038/nrn3896 . 5166260 .
  5. Seaman MN . Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer . The Journal of Cell Biology . 165 . 1 . 111–122 . April 2004 . 15078902 . 2172078 . 10.1083/jcb.200312034 .
  6. Arighi CN, Hartnell LM, Aguilar RC, Haft CR, Bonifacino JS . Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor . The Journal of Cell Biology . 165 . 1 . 123–133 . April 2004 . 15078903 . 2172094 . 10.1083/jcb.200312055 .
  7. Belenkaya TY, Wu Y, Tang X, Zhou B, Cheng L, Sharma YV, Yan D, Selva EM, Lin X . The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network . Developmental Cell . 14 . 1 . 120–131 . January 2008 . 18160348 . 10.1016/j.devcel.2007.12.003 . free .
  8. Canuel M, Korkidakis A, Konnyu K, Morales CR . Sortilin mediates the lysosomal targeting of cathepsins D and H . Biochemical and Biophysical Research Communications . 373 . 2 . 292–297 . August 2008 . 18559255 . 10.1016/j.bbrc.2008.06.021 .
  9. Seaman MN, McCaffery JM, Emr SD . A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast . The Journal of Cell Biology . 142 . 3 . 665–681 . August 1998 . 9700157 . 2148169 . 10.1083/jcb.142.3.665 .
  10. Wilson KA, Bar S, Dammer EB, Carrera EM, Hodge BA, Hilsabeck TA, Bons J, Brownridge GW, Beck JN, Rose J, Granath-Panelo M, Nelson CS, Qi G, Gerencser AA, Lan J, Afenjar A, Chawla G, Brem RB, Campeau PM, Bellen HJ, Schilling B, Seyfried NT, Ellerby LM, Kapahi P . OXR1 maintains the retromer to delay brain aging under dietary restriction . Nature Communications . 15 . 1 . 467 . January 2024 . 38212606 . 10784588 . 10.1038/s41467-023-44343-3 . free .
  11. Wassmer T, Attar N, Bujny MV, Oakley J, Traer CJ, Cullen PJ . A loss-of-function screen reveals SNX5 and SNX6 as potential components of the mammalian retromer . Journal of Cell Science . 120 . Pt 1 . 45–54 . January 2007 . 17148574 . 10.1242/jcs.03302 . free .
  12. Simoes S, Guo J, Buitrago L, Qureshi YH, Feng X, Kothiya M, Cortes E, Patel V, Kannan S, Kim YH, Chang KT, Hussaini SA, Moreno H, Di Paolo G, Andersen OM, Small SA . Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling . Cell Reports . 37 . 13 . 110182 . December 2021 . 34965419 . 8792909 . 10.1016/j.celrep.2021.110182 .
  13. Eaton S . Retromer retrieves wntless . Developmental Cell . 14 . 1 . 4–6 . January 2008 . 18194646 . 10.1016/j.devcel.2007.12.014 . free .
  14. Chen D, Xiao H, Zhang K, Wang B, Gao Z, Jian Y, Qi X, Sun J, Miao L, Yang C . Retromer is required for apoptotic cell clearance by phagocytic receptor recycling . Science . 327 . 5970 . 1261–1264 . March 2010 . 20133524 . 10.1126/science.1184840 . 6923948 . free . 2010Sci...327.1261C .
  15. Sadigh-Eteghad S, Askari-Nejad MS, Mahmoudi J, Majdi A . Cargo trafficking in Alzheimer’s disease: the possible role of retromer . Neurological Sciences . 37 . 1 . 17–22 . January 2016 . 26482054 . 10.1007/s10072-015-2399-3 . 20019740 .
  16. 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 . Retromer deficiency observed in Alzheimer's disease causes hippocampal dysfunction, neurodegeneration, and Abeta accumulation . Proceedings of the National Academy of Sciences of the United States of America . 105 . 20 . 7327–7332 . May 2008 . 18480253 . 2386077 . 10.1073/pnas.0802545105 . free . 2008PNAS..105.7327M .
  17. Zimprich A, Benet-Pagès 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, Brücke T, Poewe W, Auff E, Trenkwalder C, Rost B, Ransmayr G, Winkelmann J, Meitinger T, Strom TM . A mutation in VPS35, encoding a subunit of the retromer complex, causes late-onset Parkinson disease . American Journal of Human Genetics . 89 . 1 . 168–175 . July 2011 . 21763483 . 3135812 . 10.1016/j.ajhg.2011.06.008 .
  18. Yin P, Hong Z, Yang X, Chung RT, Zhang L . A role for retromer in hepatitis C virus replication . Cellular and Molecular Life Sciences . 73 . 4 . 869–881 . February 2016 . 26298293 . 10.1007/s00018-015-2027-7 . 3617566 . 11108358 .
  19. Nothwehr SF, Ha SA, Bruinsma P . Sorting of yeast membrane proteins into an endosome-to-Golgi pathway involves direct interaction of their cytosolic domains with Vps35p . The Journal of Cell Biology . 151 . 2 . 297–310 . October 2000 . 11038177 . 2192648 . 10.1083/jcb.151.2.297 .
  20. Rojas R, van Vlijmen T, Mardones GA, Prabhu Y, Rojas AL, Mohammed S, Heck AJ, Raposo G, van der Sluijs P, Bonifacino JS . Regulation of retromer recruitment to endosomes by sequential action of Rab5 and Rab7 . The Journal of Cell Biology . 183 . 3 . 513–526 . November 2008 . 18981234 . 2575791 . 10.1083/jcb.200804048 .
  21. McGough IJ, Cullen PJ . Recent advances in retromer biology . Traffic . 12 . 8 . 963–971 . August 2011 . 21463457 . 10.1111/j.1600-0854.2011.01201.x . 22729583 . free .
  22. 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 . Curved EFC/F-BAR-domain dimers are joined end to end into a filament for membrane invagination in endocytosis . Cell . 129 . 4 . 761–772 . May 2007 . 17512409 . 10.1016/j.cell.2007.03.040 . free .
  23. Bhatia VK, Madsen KL, Bolinger PY, Kunding A, Hedegård P, Gether U, Stamou D . Amphipathic motifs in BAR domains are essential for membrane curvature sensing . The EMBO Journal . 28 . 21 . 3303–3314 . November 2009 . 19816406 . 2776096 . 10.1038/emboj.2009.261 .
  24. Walseng E, Bakke O, Roche PA . Major histocompatibility complex class II-peptide complexes internalize using a clathrin- and dynamin-independent endocytosis pathway . The Journal of Biological Chemistry . 283 . 21 . 14717–14727 . May 2008 . 18378669 . 2386912 . 10.1074/jbc.M801070200 . free .
  25. Small SA, Simoes-Spassov S, Mayeux R, Petsko GA . Endosomal Traffic Jams Represent a Pathogenic Hub and Therapeutic Target in Alzheimer's Disease . Trends in Neurosciences . 40 . 10 . 592–602 . October 2017 . 28962801 . 5654621 . 10.1016/j.tins.2017.08.003 .
  26. Cataldo AM, Peterhoff CM, Troncoso JC, Gomez-Isla T, Hyman BT, Nixon RA . Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations . The American Journal of Pathology . 157 . 1 . 277–286 . July 2000 . 10880397 . 1850219 . 10.1016/s0002-9440(10)64538-5 .
  27. Simoes S, Guo J, Buitrago L, Qureshi YH, Feng X, Kothiya M, Cortes E, Patel V, Kannan S, Kim YH, Chang KT, Hussaini SA, Moreno H, Di Paolo G, Andersen OM, Small SA . Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling . Cell Reports . 37 . 13 . 110182 . December 2021 . 34965419 . 8792909 . 10.1016/j.celrep.2021.110182 .
  28. Small SA, Petsko GA . Endosomal recycling reconciles the Alzheimer's disease paradox . Science Translational Medicine . 12 . 572 . eabb1717 . December 2020 . 33268506 . 8025181 . 10.1126/scitranslmed.abb1717 .

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