The retromer complex

Attar, Naomi; Cullen, Peter J.

doi:10.1016/j.advenzreg.2009.10.002

Cited by 77 publications

(73 citation statements)

References 183 publications

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“…Retromers are heteropentameric protein complexes composed mainly of 2 components: 1) a structural component made of a dimer of sorting nexins (SNX), which mediates the binding to lipids in the endosomal membrane; and 2) a core cargo recognition element, a heterotrimer comprised of 'vacuolar protein sorting' (VPS) proteins Vps35-Vps29-Vps26. Vps35 is the core component of the complex, which then binds Vps26 (there are 2 isoforms: Vps26a and Vps26b), Vps29, and the SNX proteins [13,14]. This core trimeric complex binds to be-transported transmembrane proteins while they reside in endosomal membranes.…”

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The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

et al. 2015

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The retromer is an evolutionary conserved multiprotein complex involved in the sorting and retrograde trafficking of cargo from endosomal compartments to the Golgi network and to the cell surface. The neuronal retromer traffics the amyloid precursor protein away from the endosomes, a site where amyloid precursor protein is enzymatically cleaved into pathogenic fragments in Alzheimer's disease. In recent years, deficiencies in retromer-mediated transport have been implicated in several neurological and non-neurological diseases, including Parkinson's disease, suggesting that improving the efficacy of the retromer trafficking pathway would result in decreased pathology. We recently identified a new family of small molecules that appear to stabilize the interaction between members of the retromer complex and enhance its function in neurons: the retromer pharmacological chaperones. Here we discuss the role of these molecules in the improvement of retromer trafficking and endosomal dysfunction, as well as their potential as therapeutics for neurological and non-neurological disorders.

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The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

et al. 2015

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“…Much of the core machinery that carries out endosomal protein sorting is conserved in evolution, for example, the retromer complex (for reviews, see Attar and Cullen, 2009;Verges, 2008;Collins, 2008;Bonifacino and Hurley, 2008). Retromer mediates endosometo-Golgi retrieval of lysosomal and vacuolar hydrolase receptors (e.g.…”

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confidence: 99%

“…There is a striking localisation of many of the HSP-encoded proteins to the endosome, including the microtubule-severing protein spastin, the ubiquitin-ligase-interacting protein spartin, and NIPA1, a membrane protein that mediates bone morphogenic protein signaling at the endosome (Tsang et al, 2009; for a review, see Salinas et al, 2008). Despite this concentration of HSP proteins at endosomes, in most cases their function is unknown.Much of the core machinery that carries out endosomal protein sorting is conserved in evolution, for example, the retromer complex (for reviews, see Attar and Cullen, 2009;Verges, 2008;Collins, 2008;Bonifacino and Hurley, 2008). Retromer mediates endosometo-Golgi retrieval of lysosomal and vacuolar hydrolase receptors (e.g.…”

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The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics

Harbour

Breusegem

Antrobus³

et al. 2010

Journal of Cell Science

233

339

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Research Article 3703 IntroductionEndosomal protein sorting has a vital role in a number of physiologically important processes including antigen presentation, macromolecular nutrient uptake, growth factor receptor signaling and downregulation, autophagy and lysosome biogenesis (for reviews, see Sadowski et al., 2009;Saksena and Emr, 2009;Sann et al., 2009;Seaman, 2008;Lee et al., 2008). Recent studies of inherited diseases have identified several examples of genes encoding proteins that function in endosomal protein sorting that, when mutated, result in a range of pathologies. A notable example is hereditary spastic paraplegias (HSP), the hallmark of which is a selective distal axonopathy. There is a striking localisation of many of the HSP-encoded proteins to the endosome, including the microtubule-severing protein spastin, the ubiquitin-ligase-interacting protein spartin, and NIPA1, a membrane protein that mediates bone morphogenic protein signaling at the endosome (Tsang et al., 2009; for a review, see Salinas et al., 2008). Despite this concentration of HSP proteins at endosomes, in most cases their function is unknown.Much of the core machinery that carries out endosomal protein sorting is conserved in evolution, for example, the retromer complex (for reviews, see Attar and Cullen, 2009;Verges, 2008;Collins, 2008;Bonifacino and Hurley, 2008). Retromer mediates endosometo-Golgi retrieval of lysosomal and vacuolar hydrolase receptors (e.g. the cation-independent mannose 6 phosphate receptor, CIMPR) along with other physiologically significant membrane proteins including wntless, which functions in WNT secretion, and SORL1, a protein that is genetically linked to late-onset Alzheimer's disease (Arighi et al., 2004;Seaman, 2004;Eaton, 2008;Nielsen et al., 2007;Rogaeva et al., 2007).The retromer complex was first identified in yeast where it comprises five proteins encoded by vacuolar protein sorting (VPS) genes. The heteropentameric retromer complex can be functionally dissected into two subcomplexes: a cargo-selective complex formed from a conserved trimer of Vps35p, Vps29p and Vps26p and a 'structural complex' formed from a dimer of the sorting nexin (SNX) proteins Vps5p and Vps17p (Seaman et al., 1998). In mammals, SNX1, SNX2 with SNX5 and SNX6 provide the 'structural' role and can tubulate membranes through the C-terminal Bin, amphiphysin and Rvs (BAR) domains present in these proteins (Carlton et al., 2004;Wassmer et al., 2007). Additionally, SNX5 and SNX6 interact with the microtubule cytoskeleton via the p150glued protein that binds to dynein, thereby linking endosomal protein sorting to microtubules (Wassmer et al., 2009;Hong et al., 2009).The interaction between the SNX component of retromer and p150glued is an example of how retromer-interacting proteins facilitate retromer in mediating endosome-to-Golgi retrieval. In yeast, the SNX3 homologue Grd19p binds to Ftr1p to sort Ftr1p into the retromer pathway (Strochlic et al., 2008). In mammalian cells, the EPS15 homology domain protein, EHD1, interacts ...

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“…Interestingly, A. thaliana mutants impaired in retromer functions exhibit severe defects in seed and plant development, including alteration in the maturation of seed storage proteins and the presence of small OBs (11,12). The retromer is a multiprotein complex, conserved among eukaryotes, that is involved in the recycling of transmembrane receptors and retrograde transport of cargo proteins from endosomes to the trans-Golgi network (13). In mammals, the retromer consists of two distinct subcomplexes: one composed of a dimer of Sorting Nexins (SNXs) and the other, known as the core retromer, consisting of a trimer of vacuolar protein sorting (VPS) 26, VPS29, and VPS35 proteins (13,14).…”

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confidence: 99%

“…The retromer is a multiprotein complex, conserved among eukaryotes, that is involved in the recycling of transmembrane receptors and retrograde transport of cargo proteins from endosomes to the trans-Golgi network (13). In mammals, the retromer consists of two distinct subcomplexes: one composed of a dimer of Sorting Nexins (SNXs) and the other, known as the core retromer, consisting of a trimer of vacuolar protein sorting (VPS) 26, VPS29, and VPS35 proteins (13,14). The Arabidopsis genome contains genes encoding all components of the retromer complex, including three SNX genesdesignated SNX1, SNX2a, and SNX2b-three genes coding for VPS35 isoforms (VPS35a, VPS35b, and VPS35c), two genes encoding VPS26 isoforms (VPS26a and VPS26b), and a single gene encoding VPS29 (12,(15)(16)(17).…”

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Peroxisome extensions deliver the Arabidopsis SDP1 lipase to oil bodies

Thazar-Poulot

Miquel

Fobis-Loisy

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

153

135

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Lipid droplets/oil bodies (OBs) are lipid-storage organelles that play a crucial role as an energy resource in a variety of eukaryotic cells. Lipid stores are mobilized in the case of food deprivation or high energy demands-for example, during certain developmental processes in animals and plants. OB degradation is achieved by lipases that hydrolyze triacylglycerols (TAGs) into free fatty acids and glycerol. In the model plant Arabidopsis thaliana, Sugar-Dependent 1 (SDP1) was identified as the major TAG lipase involved in lipid reserve mobilization during seedling establishment. Although the enzymatic activity of SDP1 is associated with the membrane of OBs, its targeting to the OB surface remains uncharacterized. Here we demonstrate that the core retromer, a complex involved in protein trafficking, participates in OB biogenesis, lipid store degradation, and SDP1 localization to OBs. We also report an as-yet-undescribed mechanism for lipase transport in eukaryotic cells, with SDP1 being first localized to the peroxisome membrane at early stages of seedling growth and then possibly moving to the OB surface through peroxisome tubulations. Finally, we show that the timely transfer of SDP1 to the OB membrane requires a functional core retromer. In addition to revealing previously unidentified functions of the retromer complex in plant cells, our work provides unanticipated evidence for the role of peroxisome dynamics in interorganelle communication and protein transport.oil bodies | retromer | SDP1 lipase | peroxisome | protein trafficking

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The retromer complex

Cited by 77 publications

References 183 publications

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

The Use of Pharmacological Retromer Chaperones in Alzheimer's Disease and other Endosomal-related Disorders

The cargo-selective retromer complex is a recruiting hub for protein complexes that regulate endosomal tubule dynamics

Peroxisome extensions deliver the Arabidopsis SDP1 lipase to oil bodies

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