Biology:Retromer

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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]

Background

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]

Structure

Ribbon diagram of the retromer heterotrimeric complex comprising the proteins VPS26 (green), VPS35 (orange) and VPS29 (red). On the endosomal membrane, this heterotrimer forms an arch-shaped dimer via interaction of two VPS35 molecules (see next image). Structure data from PDB fie 6H7W by Brett Collins et al.
The retromer arch forms a polymeric network on the outside (cytoplasmic side) of the endosome tubule (VPS26 in green; VPS35 in orange, and VPS29 in red). Inside the tubule, the cargo receptor SORL1, some mutations in which are causal in Alzheimer's disease, forms its own network and binds protein cargo such as APP for trafficking. SORL1 connects to retromer on the outside via a transmembrane helix and a short C-terminal tail that binds VPS26. Model built based on structural data by Brett Collins and Yu Kitago.

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.[10] 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. [11]

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.[12] 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.[13]

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[14][15] and late-onset Parkinson disease[16]

Retromer also seems to play a role in Hepatitis C Virus replication.[17]

Retromer-mediated 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.[18] The nucleation complex is formed through the interaction of VPS complex with GTP-activated Rab7[19] with clathrin, clathrin-adaptors and various binding proteins.[20]

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.[21][22] Once the cargo carriers are matured, the carrier scission is then catalyzed by dynamin-II or EHD1,[23] 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. [4] Dysfunction of this branch of the retromer recycling pathway causes endosomal protein traffic jams [24] that are linked to Alzheimer’s disease. [25][26] 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”. [27]

See also

  • SORL1
  • VPS26B
  • VPS26A
  • VPS35
  • VPS29

References

  1. ↑ "Retromer: a master conductor of endosome sorting". Cold Spring Harbor Perspectives in Biology 6 (2): a016774. February 2014. doi:10.1101/cshperspect.a016774. PMID 24492709. 
  2. ↑ "Recycle your receptors with retromer". Trends in Cell Biology 15 (2): 68–75. February 2005. doi:10.1016/j.tcb.2004.12.004. PMID 15695093. 
  3. ↑ "Membrane transport: retromer to the rescue". Current Biology 11 (3): R109–11. February 2001. doi:10.1016/S0960-9822(01)00042-2. PMID 11231171. 
  4. ↑ 4.0 4.1 Small, Scott A.; Petsko, Gregory A. (2015). "Retromer in Alzheimer disease, Parkinson disease and other neurological disorders" (in en). Nature Reviews Neuroscience 16 (3): 126–132. doi:10.1038/nrn3896. ISSN 1471-0048. PMID 25669742. https://www.nature.com/articles/nrn3896. 
  5. ↑ "Cargo-selective endosomal sorting for retrieval to the Golgi requires retromer". The Journal of Cell Biology 165 (1): 111–22. April 2004. doi:10.1083/jcb.200312034. PMID 15078902. 
  6. ↑ "Role of the mammalian retromer in sorting of the cation-independent mannose 6-phosphate receptor". The Journal of Cell Biology 165 (1): 123–33. April 2004. doi:10.1083/jcb.200312055. PMID 15078903. 
  7. ↑ "The retromer complex influences Wnt secretion by recycling wntless from endosomes to the trans-Golgi network". Developmental Cell 14 (1): 120–31. January 2008. doi:10.1016/j.devcel.2007.12.003. PMID 18160348. 
  8. ↑ "Sortilin mediates the lysosomal targeting of cathepsins D and H". Biochemical and Biophysical Research Communications 373 (2): 292–7. August 2008. doi:10.1016/j.bbrc.2008.06.021. PMID 18559255. 
  9. ↑ "A membrane coat complex essential for endosome-to-Golgi retrograde transport in yeast". The Journal of Cell Biology 142 (3): 665–81. August 1998. doi:10.1083/jcb.142.3.665. PMID 9700157. 
  10. ↑ "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. doi:10.1242/jcs.03302. PMID 17148574. 
  11. ↑ Simoes, Sabrina; Guo, Jia; Buitrago, Luna; Qureshi, Yasir H.; Feng, Xinyang; Kothiya, Milankumar; Cortes, Etty; Patel, Vivek et al. (2021). "Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling". Cell Reports 37 (13): 110182. doi:10.1016/j.celrep.2021.110182. ISSN 2211-1247. PMID 34965419. 
  12. ↑ "Retromer retrieves wntless". Developmental Cell 14 (1): 4–6. January 2008. doi:10.1016/j.devcel.2007.12.014. PMID 18194646. 
  13. ↑ "Retromer is required for apoptotic cell clearance by phagocytic receptor recycling". Science 327 (5970): 1261–4. March 2010. doi:10.1126/science.1184840. PMID 20133524. Bibcode: 2010Sci...327.1261C. 
  14. ↑ "Cargo trafficking in Alzheimer's disease: the possible role of retromer". Neurological Sciences 37 (1): 17–22. January 2016. doi:10.1007/s10072-015-2399-3. PMID 26482054. 
  15. ↑ "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): 7327–32. May 2008. doi:10.1073/pnas.0802545105. PMID 18480253. Bibcode: 2008PNAS..105.7327M. 
  16. ↑ "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. July 2011. doi:10.1016/j.ajhg.2011.06.008. PMID 21763483. 
  17. ↑ "A role for retromer in hepatitis C virus replication". Cellular and Molecular Life Sciences 73 (4): 869–81. February 2016. doi:10.1007/s00018-015-2027-7. PMID 26298293. 
  18. ↑ "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. doi:10.1083/jcb.151.2.297. PMID 11038177. 
  19. ↑ "Regulation of retromer recruitment to endosomes by sequential action of Rab5 and Rab7". The Journal of Cell Biology 183 (3): 513–26. November 2008. doi:10.1083/jcb.200804048. PMID 18981234. 
  20. ↑ "Recent advances in retromer biology". Traffic 12 (8): 963–71. August 2011. doi:10.1111/j.1600-0854.2011.01201.x. PMID 21463457. 
  21. ↑ "Curved EFC/F-BAR-domain dimers are joined end to end into a filament for membrane invagination in endocytosis". Cell 129 (4): 761–72. May 2007. doi:10.1016/j.cell.2007.03.040. PMID 17512409. 
  22. ↑ "Amphipathic motifs in BAR domains are essential for membrane curvature sensing". The EMBO Journal 28 (21): 3303–14. November 2009. doi:10.1038/emboj.2009.261. PMID 19816406. 
  23. ↑ "Major histocompatibility complex class II-peptide complexes internalize using a clathrin- and dynamin-independent endocytosis pathway". The Journal of Biological Chemistry 283 (21): 14717–27. May 2008. doi:10.1074/jbc.M801070200. PMID 18378669. 
  24. ↑ Small, Scott A.; Simoes-Spassov, Sabrina; Mayeux, Richard; Petsko, Gregory A. (2017). "Endosomal traffic jams represent a pathogenic hub and therapeutic target in Alzheimer's disease". Trends in Neurosciences 40 (10): 592–602. doi:10.1016/j.tins.2017.08.003. ISSN 0166-2236. PMID 28962801. 
  25. ↑ Cataldo, Anne M.; Peterhoff, Corrinne M.; Troncoso, Juan C.; Gomez-Isla, Teresa; Hyman, Bradley T.; Nixon, Ralph A. (2000). "Endocytic Pathway Abnormalities Precede Amyloid β Deposition in Sporadic Alzheimer's Disease and Down Syndrome". The American Journal of Pathology 157 (1): 277–286. doi:10.1016/s0002-9440(10)64538-5. ISSN 0002-9440. PMID 10880397. 
  26. ↑ Simoes, Sabrina; Guo, Jia; Buitrago, Luna; Qureshi, Yasir H.; Feng, Xinyang; Kothiya, Milankumar; Cortes, Etty; Patel, Vivek et al. (2021). "Alzheimer's vulnerable brain region relies on a distinct retromer core dedicated to endosomal recycling". Cell Reports 37 (13): 110182. doi:10.1016/j.celrep.2021.110182. ISSN 2211-1247. PMID 34965419. 
  27. ↑ Small, Scott A.; Petsko, Gregory A. (2020). "Endosomal Recycling Reconciles the Alzheimer's Paradox". Science Translational Medicine 12 (572): eabb1717. doi:10.1126/scitranslmed.abb1717. ISSN 1946-6234. PMID 33268506. 



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