The retromer complex is a vital element of the endosomal protein sorting machinery that is conserved across all eukaryotes. Retromer is most closely associated with the endosome-to-Golgi retrieval ...pathway and is necessary to maintain an active pool of hydrolase receptors in the trans-Golgi network. Recent progress in studies of retromer have identified new retromer-interacting proteins, including the WASH complex and cargo such as the Wntless/MIG-14 protein, which now extends the role of retromer beyond the endosome-to-Golgi pathway and has revealed that retromer is required for aspects of endosome-to-plasma membrane sorting and regulation of signalling events. The interactions between the retromer complex and other macromolecular protein complexes now show how endosomal protein sorting is coordinated with actin assembly and movement along microtubules, and place retromer squarely at the centre of a complex set of protein machinery that governs endosomal protein sorting. Dysregulation of retromer-mediated endosomal protein sorting leads to various pathologies, including neurodegenerative diseases such as Alzheimer disease and spastic paraplegia and the mechanisms underlying these pathologies are starting to be understood. In this Commentary, I will highlight recent advances in the understanding of retromer-mediated endosomal protein sorting and discuss how retromer contributes to a diverse set of physiological processes.
The fifth adaptor protein complex Hirst, Jennifer; Barlow, Lael D; Francisco, Gabriel Casey ...
PLoS biology,
10/2011, Volume:
9, Issue:
10
Journal Article
Peer reviewed
Open access
Adaptor protein (AP) complexes sort cargo into vesicles for transport from one membrane compartment of the cell to another. Four distinct AP complexes have been identified, which are present in most ...eukaryotes. We report the existence of a fifth AP complex, AP-5. Tagged AP-5 localises to a late endosomal compartment in HeLa cells. AP-5 does not associate with clathrin and is insensitive to brefeldin A. Knocking down AP-5 subunits interferes with the trafficking of the cation-independent mannose 6-phosphate receptor and causes the cell to form swollen endosomal structures with emanating tubules. AP-5 subunits can be found in all five eukaryotic supergroups, but they have been co-ordinately lost in many organisms. Concatenated phylogenetic analysis provides robust resolution, for the first time, into the evolutionary order of emergence of the adaptor subunit families, showing AP-3 as the basal complex, followed by AP-5, AP-4, and AP-1 and AP-2. Thus, AP-5 is an evolutionarily ancient complex, which is involved in endosomal sorting, and which has links with hereditary spastic paraplegia.
The cation-independent mannose 6-phosphate receptor (CIMPR) cycles between the trans-Golgi network (TGN) and endosomes to mediate sorting of lysosomal hydrolases. The endosome-to-TGN retrieval of the ...CIMPR requires the retromer complex. Genetic, biochemical and structural data support the hypothesis that the retromer can directly bind to the tail of the CIMPR, to sort the CIMPR into vesicles and tubules for retrieval to the TGN. Presently, however, no known retromer sorting motif in the tail of the CIMPR has been identified. Using CD8-reporter proteins carrying the cytoplasmic tail of the CIMPR we have systematically dissected the CIMPR tail to identify a novel, conserved aromatic-containing sorting motif that is critical for the endosome-to-TGN retrieval of the CIMPR and for the interaction with retromer and the clathrin adaptor AP-1.
The retromer cargo‐selective complex (CSC) comprising Vps35, Vps29 and Vps26 mediates the endosome‐to‐Golgi retrieval of the cation‐independent mannose 6‐phosphate receptor (CIMPR). Or does it? ...Recently published data have questioned the validity of this long‐established theory. Here, the evidence for and against a role for the retromer CSC in CIMPR endosome‐to‐Golgi retrieval is examined in the light of the new data that the SNX‐BAR dimer is actually responsible for CIMPR retrieval.
The cation‐independent mannose 6‐phosphate receptor (CIMPR) has long been regarded as the archetypal cargo protein for the retromer complex and its retrieval to the Golgi was thought to be mediated by the cargo‐selective complex. But new data showing that the SNX‐BAR dimer associates with the CIMPR have questioned this view. Here, I discuss the recent findings in the context of several years of published data on retromer and propose a new model for retromer‐mediated CIMPR retrieval.
The retromer complex is a conserved endosomal protein sorting complex that sorts membrane proteins into nascent endosomal tubules. The recognition of membrane proteins is mediated by the ...cargo-selective retromer complex, a stable trimer of the Vps35 (vacuolar protein sorting 35), Vps29 and Vps26 proteins. We have recently reported that the cargo-selective retromer complex associates with the WASH (Wiskott-Aldrich syndrome homologue) complex, a multimeric protein complex that regulates tubule dynamics at endosomes. In the present study, we show that the retromer-WASH complex interaction occurs through the long unstructured 'tail' domain of the WASH complex-Fam21 protein binding to Vps35, an interaction that is necessary and sufficient to target the WASH complex to endosomes. The Fam21-tail also binds to FKBP15 (FK506-binding protein 15), a protein associated with ulcerative colitis, to mediate the membrane association of FKBP15. Elevated Fam21-tail expression inhibits the association of the WASH complex with retromer, resulting in increased cytoplasmic WASH complex. Additionally, overexpression of the Fam21-tail results in cell-spreading defects, implicating the activity of the WASH complex in regulating the mobilization of membrane into the endosome-to-cell surface pathway.
We report the first study to estimate the socioeconomic gap in period life expectancy (LE) and life years spent with and without complications in a national cohort of individuals with type 1 ...diabetes. This retrospective cohort study used linked healthcare records from SCI-Diabetes, the population-based diabetes register of Scotland. We studied all individuals aged 50 and older with a diagnosis of type 1 diabetes who were alive and residing in Scotland on 1 January 2013 (N = 8591). We used the Scottish Index of Multiple Deprivation (SIMD) 2016 as an area-based measure of socioeconomic deprivation. For each individual, we constructed a history of transitions by capturing whether individuals developed retinopathy/maculopathy, cardiovascular disease, chronic kidney disease, and diabetic foot, or died throughout the study period, which lasted until 31 December 2018. Using parametric multistate survival models, we estimated total and state-specific LE at an attained age of 50. At age 50, remaining LE was 22.2 years (95% confidence interval (95% CI): 21.6 - 22.8) for males and 25.1 years (95% CI: 24.4 - 25.9) for females. Remaining LE at age 50 was around 8 years lower among the most deprived SIMD quintile when compared with the least deprived SIMD quintile: 18.7 years (95% CI: 17.5 - 19.9) vs. 26.3 years (95% CI: 24.5 - 28.1) among males, and 21.2 years (95% CI: 19.7 - 22.7) vs. 29.3 years (95% CI: 27.5 - 31.1) among females. The gap in life years spent without complications was around 5 years between the most and the least deprived SIMD quintile: 4.9 years (95% CI: 3.6 - 6.1) vs. 9.3 years (95% CI: 7.5 - 11.1) among males, and 5.3 years (95% CI: 3.7 - 6.9) vs. 10.3 years (95% CI: 8.3 - 12.3) among females. SIMD differences in transition rates decreased marginally when controlling for time-updated information on risk factors such as HbA1c, blood pressure, BMI, or smoking. In addition to societal interventions, tailored support to reduce the impact of diabetes is needed for individuals from low socioeconomic backgrounds, including access to innovations in management of diabetes and the prevention of complications.
Zero‐deforestation commitments seek to decouple agricultural production and forest loss to improve prospects for biodiversity. However, the effectiveness of methods designed to meet these commitments ...is poorly understood. In a highly fragmented tropical landscape dominated by oil palm, we tested the capacity for the High Carbon Stock (HCS) Approach to prioritize forest remnants that sustain mammal diversity. Patches afforded high priority by HCS protocols (100 ha core area) provided important refuges for IUCN‐threatened species and megafauna. However, patch‐scale HCS area recommendations conserved only 35% of the mammal community. At least 3,000 ha would be required to retain intact mammal assemblages, with nearly 10 times this area needed if hunting pressure was high. While current HCS protocols will safeguard patches capable of sustaining biodiversity, highly fragmented tropical landscapes typical of zero‐deforestation pledges will require thinking beyond the patch toward strategically configured forest remnants at the landscape level and enforcing strict controls on hunting.
The retromer complex has a well-established role in endosomal protein sorting, being necessary for maintaining the dynamic localisation of hundreds of membrane proteins that traverse the endocytic ...system. Retromer function and dysfunction is linked with neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, and many pathogens, both viral and bacterial, exploit or interfere in retromer function for their own ends. In this review, the history of retromer is distilled into a concentrated form that spans the identification of retromer to recent discoveries that have shed new light on how retromer functions in endosomal protein sorting and why retromer is increasingly being viewed as a potential therapeutic target in neurodegenerative disease.
The retromer complex was first identified 22 years ago and is now known to be critical for endosomal protein sorting.Although conserved in evolution, there are important differences in the composition of retromer between simple and higher eukaryotes that impact on its respective roles in different organisms.New insights into how retromer is arranged on the membrane have prompted a re-assessment of how it functions in endosomal protein sorting.Recent biochemical and structural studies have revealed new mechanisms that govern how retromer and associated proteins sort membrane proteins at endosomes.Expanding studies of retromer have revealed that its function is often hijacked or subverted by pathogens – both bacterial or viral - and that retromer dysfunction is linked to several neurodegenerative diseases.Intriguingly, retromer is now being viewed as a potential therapeutic target in diseases such as Alzheimer’s disease where accumulated evidence shows it plays a key role.
Greenspace has the potential to be a vital resource for promoting healthy living for people in urban areas, offering both opportunities for physical activity and wellbeing. Much research has explored ...the objectively measurable factors within areas to the end of explaining the role of greenspace access in continuing health inequalities. This paper explores the subjective reasons why people in urban areas choose to use, or not use, local public greenspace.
In-depth interviews with 24 people living in two areas of Glasgow, United Kingdom were conducted, supplemented with participant photography and participatory methods. Data was thematically categorised to explore subjectively experienced facilitators and barriers to greenspace use in urban areas.
From the perspective of current and potential urban greenspace users, access is revealed to be about more than the physical characteristics of neighbourhoods, greenspace resources or objectively measurable features of walkability and connectivity. Subjectively, the idea of walkability includes perceptions of social cohesion at a community level and the level of felt integration and inclusion by individuals in their communities. Individual's feelings of integration and inclusion potentially mitigate the effects of experiential barriers to urban greenspace access, such as evidence of anti-social behaviour.
We conclude that improving access to greenspace for all in urban communities will require more than providing high quality resources such as parks, footpaths, activities and lighting. Physical availability interacts with community contexts already established and a holistic understanding of access is required. A key cultural component of areas and neighbourhoods is the level of social cohesion, a factor that has the potential to reinforce existing health inequalities through shaping differentiated greenspace access between subgroups of the local population.
Myosin VI is an actin-based retrograde motor protein that plays a crucial role in both endocytic and secretory membrane trafficking pathways. Myosin VI's targeting to and function in these ...intracellular pathways is mediated by a number of specific binding partners. In this paper we have identified a new myosin-VI-binding partner, lemur tyrosine kinase 2 (LMTK2), which is the first transmembrane protein and kinase that directly binds to myosin VI. LMTK2 binds to the WWY site in the C-terminal myosin VI tail, the same site as the endocytic adaptor protein Dab2. When either myosin VI or LMTK2 is depleted by siRNAs, the transferrin receptor (TfR) is trapped in swollen endosomes and tubule formation in the endocytic recycling pathway is dramatically reduced, showing that both proteins are required for the transport of cargo, such as the TfR, from early endosomes to the endocytic recycling compartment.
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