Molecular Insights into Rab7‐Mediated Endosomal Recruitment of Core Retromer: Deciphering the Role of Vps26 and Vps35

Priya, Amulya; Kalaidzidis, Inna V; Kalaidzidis, Yannis; Lambright, David G.; Datta, Soma

doi:10.1111/tra.12237

Cited by 65 publications

(59 citation statements)

References 63 publications

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“…Our data show that although the core complex remains unaffected by the P316S, the R524W mutation partially disrupts this formation and also negatively impacts the association with regulatory molecules needed for cargo sorting. Previously, Vps35-Rab7a-SNX3 interaction studies demonstrated that binding of Rab7a and SNX3 is within the first 300 amino acids of Vps35 and immediately adjacent to the Vps26-Vps35 interface (41). Despite this, we showed that R524W, but not the P316S mutation within Vps35, severely impacts the retromerRab7a interaction and Vps35 R524W-retromer membrane association, coupled with reduced interactions with the WASH complex subunit FAM21, the RabGAP TBC1D5, and PDZ motif cargo adaptor SNX27.…”

Section: Vps35 R524w Mutation Impairs the Function Of Retromercontrasting

confidence: 48%

Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation

Follett

Bugarčić

Yang

et al. 2016

Journal of Biological Chemistry

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Endosomal sorting is a highly orchestrated cellular process. Retromer is a heterotrimeric complex that associates with endosomal membranes and facilitates the retrograde sorting of multiple receptors, including the cation-independent mannose 6-phosphate receptor for lysosomal enzymes. The cycling of retromer on and off the endosomal membrane is regulated by a network of retromer-interacting proteins. Here, we find that Parkinson disease-associated Vps35 variant, R524W, but not P316S, is a loss-of-function mutation as marked by a reduced association with this regulatory network and dysregulation of endosomal receptor sorting. Expression of Vps35 R524W-containing retromer results in the accumulation of intracellular ␣-synuclein-positive aggregates, a hallmark of Parkinson disease. Overall, the Vps35 R524W-containing retromer has a decreased endosomal association, which can be partially rescued by R55, a small molecule previously shown to stabilize the retromer complex, supporting the potential for future targeting of the retromer complex in the treatment of Parkinson disease.

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Section: Vps35 R524w Mutation Impairs the Function Of Retromercontrasting

confidence: 48%

Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation

Follett

Bugarčić

Yang

et al. 2016

Journal of Biological Chemistry

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“…Rab7 is known to recruit the retromer on endosomal membrane, and it is required for the transfer of cargo from the late endosomes to the lysosome (Priya et al, 2015;Pryor and Luzio, 2009). A conserved function of WASH in retromer-dependent endocytic recycling of the luminal protein Serpentine has already been found during Drosophila trachea development (Dong et al, 2013).…”

Section: Research Articlementioning

confidence: 99%

Drosophila WASH is required for integrin-mediated cell adhesion, cell motility and lysosomal neutralization

Nagel

Bechtold

Rodríguez

et al. 2017

Journal of Cell Science

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The Wiskott-Aldrich syndrome protein and SCAR homolog (WASH; also known as Washout in flies) is a conserved actin-nucleationpromoting factor controlling Arp2/3 complex activity in endosomal sorting and recycling. Previous studies have identified WASH as an essential regulator in Drosophila development. Here, we show that homozygous wash mutant flies are viable and fertile. We demonstrate that Drosophila WASH has conserved functions in integrin receptor recycling and lysosome neutralization. WASH generates actin patches on endosomes and lysosomes, thereby mediating both aforementioned functions. Consistently, loss of WASH function results in cell spreading and cell migration defects of macrophages, and an increased lysosomal acidification that affects efficient phagocytic and autophagic clearance. WASH physically interacts with the vacuolar (V)-ATPase subunit Vha55 that is crucial to establish and maintain lysosome acidification. As a consequence, starved flies that lack WASH function show a dramatic increase in acidic autolysosomes, causing a reduced lifespan. Thus, our data highlight a conserved role for WASH in the endocytic sorting and recycling of membrane proteins, such as integrins and the V-ATPase, that increase the likelihood of survival under nutrient deprivation.

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“…Our data shows that although the core complex remains unaffected by the P316S and R524W mutations, the association with regulatory molecules is significantly altered in the presence of Vps35 R524W mutation. Previously, Vps35-Rab7a-SNX3 interaction interface studies demonstrated that binding of Rab7a and SNX3 is within the first 300 amino acids of Vps35 and immediately adjacent to the Vps26-Vps35 interface [101]. Despite this, we showed that R524W but not the P316S mutation within Vps35 severely impacts the retromer-Rab7a interaction and Vps35 R524W-retromer membrane association, coupled with reduced interactions with the WASH complex subunit FAM21, the RabGAP TBC1D5 and PDZ motif cargo adaptor SNX27.…”

Section: Discussionmentioning

confidence: 46%

“…Consistent with this study, this thesis shows that use of R55 increased the total Vps35 protein level and limited the formation of α-synuclein inclusions, even following the stable loss of retromer using a shRNA system (See section Though the underlying mechanism as to why Vps35 R524W does not interact with most of the known interacting partners was not described in this thesis, the loss of Vps35 R524W-retromer's membrane association may be explained by the previous in vitro study which characterized a conformational shift within the complex at the initial stages of the trimer formation [277]. Given that the formation of the retromer trimer is a prerequisite for its interaction with both Rab7A and the endosomal membrane [101,276], one explanation for the observations reported here could be influenced by the capacity of the Vps35 R524W-retromer to undergo this conformational change, rather than impacting on the binding Additionally, whether the trafficking defect observed following the expression of Vps35 D620N could be rescued following incubation with R55 is currently unknown.…”

Section: Pharmacological Modulators Of Retromermentioning

confidence: 95%

“…Amongst these regulatory proteins are the membrane tubulating SNX-BAR proteins, the PX-domain only protein SNX3 [82], and the small GTPase Rab7A [18,[99][100][101][102]. Simplified sorting of single and multi-pass transmembrane receptors back to the cell surface via a SNX27-retromer dependent pathway (top) or, to the TGN via either a SNX-BARretromer or SNX3/Rab7-retromer complex (bottom).…”

Section: Recruitment Of Retromer To the Endosomal Membranementioning

confidence: 99%

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The role of retromer in Parkinson's disease

Follett¹

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Abstract:Parkinson's disease (PD) is an irreversible neurological disorder characterized by protein aggregate accumulation, endo-lysosomal dysfunction and neuronal cell death.Recently, several novel point mutations linked to late onset PD were identified in the retromer subunit; Vps35. Retromer is a highly conserved protein sorting complex that governs the endosome-to-Trans Golgi Network (TGN) trafficking pathway (hereafter referred to as retrograde sorting). While a great deal of evidence currently exists detailing the mechanisms of retromer in the retrograde sorting process, very little information conclusively highlights how sorting is misguided by retromer in PD. Secondly, I identified several novel shortfalls of retromer in the various point mutations that are linked to PD and additionally, expanded on how retromer plays a fundamental role in preservation of the endo-lysosomal network. This thesis demonstrates that Vps35 D620N, Vps35 P316S or Vps35 R524W do not disrupt the overall formation of the retromer complex, but functionally demonstrates incorrect sorting of specific cargo to the TGN. The failed sorting observed by Vps35 D620N containing retromer results in vacuolization of the late endosome, and large disruptions to the overall localization of endocytic compartments. As a result, the lysosomal hydrolase, Cathepsin D, an enzyme needed for the degradation of α-synuclein, is not transported to the late endocytic network and can be detected in the extracellular medium. Subsequent investigation into additional point mutations (Vps35 P316S and Vps35 R524W) highlighted the inability for Vps35 R524W containing retromer to correctly associate with the endosome compartment. While Vps35 P316S containing retromer appears to function identical to that of the wild type retromer, Vps35 R524W negatively regulates retromer-dependent machinery at the endosome surface, leads to the mislocalization of receptors and delays the ability of α-synuclein to be cleared from the cell. Collectively, it is clear that the findings presented here ii strongly implicate the PD-linked Vps35 variants as loss-of-function mutations and lead to the presence of cellular phenotypes witnessed in PD.Lastly, I investigated the use of a pharmacological agent to enhance retromer's function that consequently, aided in significant clearance of α-synuclein inclusions that were observed following the depletion of Vps35 or expression of PD linked mutations Vps35 P316S and Vps35 R524W. These findings support the notion that therapeutic intervention against retromer may aid in delaying the cellular phenotypes observed in PD tissue and subsequently, bridge the gap between the mammalian retromer complex, the lysosome and human disease.iii

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Molecular Insights into Rab7‐Mediated Endosomal Recruitment of Core Retromer: Deciphering the Role of Vps26 and Vps35

Cited by 65 publications

References 63 publications

Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation

Parkinson Disease-linked Vps35 R524W Mutation Impairs the Endosomal Association of Retromer and Induces α-Synuclein Aggregation

Drosophila WASH is required for integrin-mediated cell adhesion, cell motility and lysosomal neutralization

The role of retromer in Parkinson's disease

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