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The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics
Abstract
The retromer complex is required for the efficient endosome-to-Golgi retrieval of the CIMPR, sortilin, SORL1, wntless and other physiologically important membrane proteins. Retromer comprises two protein complexes that act together in endosome-to-Golgi retrieval; the cargo-selective complex is a trimer of VPS35, VPS29 and VPS26 that sorts cargo into tubules for retrieval to the Golgi. Tubules are produced by the oligomerization of sorting nexin dimers. Here, we report the identification of five endosomally-localised proteins that modulate tubule formation and are recruited to the membrane via interactions with the cargo-selective retromer complex. One of the retromer-interacting proteins, strumpellin, is mutated in hereditary spastic paraplegia, a progressive length-dependent axonopathy. Here, we show that strumpellin regulates endosomal tubules as part of a protein complex with three other proteins that include WASH1, an actin-nucleating promoting factor. Therefore, in addition to a direct role in endosome-to-Golgi retrieval, the cargo-selective retromer complex also acts as a platform for recruiting physiologically important proteins to endosomal membranes that regulate membrane tubule dynamics.
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The WASH complex is recruited to endosomes by interactions with the retromer complex.
“Strumpellin is a component of the WASH complex, an actin-regulating complex that is recruited to endosomes by interactions with the retromer complex.”
Strumpellin participates in the WASH complex via interactions with KIAA1033.
“Strumpellin participates in the complex via interactions with KIAA1033 (Fig. 1) [13].”
Cells lacking components of the WASH complex, including strumpellin, have increased endosomal tubulation.
“Thus cells lacking components of the WASH complex, including strumpellin, have increased endosomal tubulation, consistent with a defect in tubule fission from the endosome [9,10,13].”
Knockdown of strumpellin causes mislocalisation and perinuclear clustering of other members of the WASH complex, notably WASH.
“Knockdown of strumpellin causes mislocalisation and perinuclear clustering of other members of the WASH complex, notably WASH [13].”
Mammalian cells lacking strumpellin have an increased number of SNX1- and VPS26-positive endosomal tubules.
“Mammalian cells lacking strumpellin have an increased number of SNX1- and VPS26-positive endosomal tubules [9,10,13].”
HeLa cells lacking strumpellin have increased tubulation of the SNX1 and retromer endosomal compartment.
“HeLa cells lacking strumpellin have increased tubulation of the SNX1 and retromer endosomal compartment [10,13].”
The interaction between Wash1 and strumpellin occurs through at least one additional WASH complex component, KIAA1033.
“As the interaction between Wash1 and strumpellin occurs through at least one additional WASH complex component, KIAA1033, the demonstration of this interaction strongly suggests that the core WASH complex assembles in the brain.”
Direct binding of FAM21 to VPS35 is a major mechanism for the retromer-dependent association of the WASH complex to endosomes.
“Direct binding of FAM21 to VPS35 is a major mechanism for the retromer-dependent association of the WASH complex to endosomes (Gomez and Billadeau, 2009; Harbour et al., 2010; Jia et al., 2012).”
From Acute inactivation of retromer and ESCPE-1 leads to time-resolved defects in endosomal cargo sorting (2020) · cites this paper as Harbour et al., 2010
The common labelling of the WASH complex by both Retromer and Retriever is consistent with their known biochemical association and physical co-localisation to the retrieval sub-domain and the central role of actin polymerisation and actin turnover in Retromer- and Retriever-dependent cargo sorting.
“Building on this, the common labelling of the WASH complex by both Retromer and Retriever (Fig. 2E) is entirely consistent with their known biochemical association and physical co-localisation to the retrieval sub-domain and the central role of actin polymerisation and actin turnover in Retromer- and Retriever-dependent cargo sorting17,19,24,56–58.”
From Mapping of endosomal proximity proteomes reveals Retromer as a hub for RAB GTPase regulation (2025) · cites this paper as [56]
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Metadata
- Authors
- Harbour, M. E., Breusegem, S. Y. A., Antrobus, R., Freeman, C., Reid, E., & Seaman, M. N. J.
- Affiliations
- Department of Clinical Biochemistry, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrookes Hospital, Cambridge CB2 0XY, UK
- Department of Medical Genetics, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrookes Hospital, Cambridge CB2 0XY, UK
- Venue
- Journal of Cell Science
- Publisher
- The Company of Biologists
- Published
- 2010-11-01
- Volume
- 123
- Issue
- 21
- Pages
- 3703-3717
- ISSN
- 1477-9137
- 0021-9533
- Cited by
- 246
- References
- 1
- Language
- en
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