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Retromer

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https://www.readbyqxmd.com/read/28179995/caspase-mediated-proteolysis-of-the-sorting-nexin-2-disrupts-retromer-assembly-and-potentiates-met-hepatocyte-growth-factor-receptor-signaling
#1
Catherine M Duclos, Audrey Champagne, Julie C Carrier, Caroline Saucier, Christine L Lavoie, Jean-Bernard Denault
The unfolding of apoptosis involves the cleavage of hundreds of proteins by the caspase family of cysteinyl peptidases. Among those substrates are proteins involved in intracellular vesicle trafficking with a net outcome of shutting down the crucial processes governing protein transport to organelles and to the plasma membrane. However, because of the intertwining of receptor trafficking and signaling, cleavage of specific proteins may lead to unintended consequences. Here we show that in apoptosis, sorting nexin 1 and 2 (SNX1 and SNX2), two proteins involved in endosomal sorting, are cleaved by initiator caspases and also by executioner caspase-6 in the case of SNX2...
2017: Cell Death Discovery
https://www.readbyqxmd.com/read/28134614/ablation-of-snx6-leads-to-defects-in-synaptic-function-of-ca1-pyramidal-neurons-and-spatial-memory
#2
Yang Niu, Zhonghua Dai, Wenxue Liu, Cheng Zhang, Yanrui Yang, Zhenzhen Guo, Xiaoyu Li, Chenchang Xu, Xiahe Huang, Yingchun Wang, Yun S Shi, Jia-Jia Liu
SNX6 is a ubiquitously expressed PX-BAR protein that plays important roles in retromer-mediated retrograde vesicular transport from endosomes. Here we report that CNS-specific Snx6 knockout mice exhibit deficits in spatial learning and memory, accompanied with loss of spines from distal dendrites of hippocampal CA1 pyramidal cells. SNX6 interacts with Homer1b/c, a postsynaptic scaffold protein crucial for synaptic distribution of other postsynaptic density (PSD) proteins and structural integrity of dendritic spines...
January 30, 2017: ELife
https://www.readbyqxmd.com/read/28131823/in-situ-peroxidase-labeling-and-mass-spectrometry-connects-alpha-synuclein-directly-to-endocytic-trafficking-and-mrna-metabolism-in-neurons
#3
Chee Yeun Chung, Vikram Khurana, Song Yi, Nidhi Sahni, Ken H Loh, Pavan K Auluck, Valeriya Baru, Namrata D Udeshi, Yelena Freyzon, Steven A Carr, David E Hill, Marc Vidal, Alice Y Ting, Susan Lindquist
Synucleinopathies, including Parkinson's disease (PD), are associated with the misfolding and mistrafficking of alpha-synuclein (α-syn). Here, using an ascorbate peroxidase (APEX)-based labeling method combined with mass spectrometry, we defined a network of proteins in the immediate vicinity of α-syn in living neurons to shed light on α-syn function. This approach identified 225 proteins, including synaptic proteins, proteins involved in endocytic vesicle trafficking, the retromer complex, phosphatases and mRNA binding proteins...
January 25, 2017: Cell Systems
https://www.readbyqxmd.com/read/28129035/where-no-ras-has-gone-before-vps35-steers-n-ras-through-the-cytosol
#4
Mo Zhou, Mark R Philips
Ras is the best-studied member of the superfamily of small GTPases because of its role in cancer. Ras proteins transmit signals for proliferation, differentiation and survival. Three RAS genes encode 4 isoforms. All Ras isoforms have long been considered membrane bound, a localization required for function. Our recent study revealed that N-Ras differs from all other isoforms in being largely cytosolic even following modification with a prenyl lipid. Endogenous, cytosolic N-Ras chromatographed in both high and low molecular weight pools, a pattern that required prenylation, suggesting prenyl-dependent interaction with other proteins...
January 27, 2017: Small GTPases
https://www.readbyqxmd.com/read/28115417/the-parkinson-s-disease-linked-protein-tmem230-is-required-for-rab8a-mediated-secretory-vesicle-trafficking-and-retromer-trafficking
#5
Myung Jong Kim, Han-Xiang Deng, Yvette C Wong, Teepu Siddique, Dimitri Krainc
TMEM230 is a newly identified Parkinson's disease (PD) gene encoding a transmembrane protein whose cellular and pathogenic roles remain largely unknown. Here, we demonstrate that loss of TMEM230 disrupts retromer cargo CI-M6PR (cation-independent mannose 6-phosphate receptor) trafficking and autophagic cargo degradation rates. TMEM230 depletion further inhibits extracellular secretion of the autophagic cargo p62 and immature lysosomal hydrolases in Golgi-derived vesicles leading to their intracellular accumulation, and is specifically mediated by loss of the small GTPase Rab8a...
January 22, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28110103/the-retromer-complex-system-in-a-transgenic-mouse-model-of-ad-influence-of-age
#6
Jin Chu, Domenico Praticò
Deficiencies of the retrograde transport mediated by the retromer complex have been described in Alzheimer's disease (AD). Genetic manipulation of retromer modulates brain amyloidosis in Tg2576 mice. However, whether the complex is altered during the development of the AD-like phenotype remains unknown. In this study we assayed the expression levels of the vacuolar sorting protein 35 (VPS35), VPS26, VPS29, and its cargo proteins, cation independent mannose 6-phosphate receptor, sortilin-related receptor in brains of Tg2576 and controls at the ages of 3, 8, and 14 months...
January 3, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/28100638/retromer-driven-membrane-tubulation-separates-endosomal-recycling-from-rab7-ypt7-dependent-fusion
#7
Latha Kallur Purushothaman, Henning Arlt, Anne Kuhlee, Stefan Raunser, Christian Ungermann
Endosomes are the major protein sorting hubs of the endocytic pathway. They sort proteins destined for degradation into internal vesicles, while in parallel recycling receptors via tubular carriers back to the Golgi. Tubule formation depends on the Rab7/Ypt7-interacting retromer complex, consisting of the sorting nexin dimer (SNX-BAR) and the trimeric cargo selection complex (CSC). Fusion of mature endosomes with the lysosome-like vacuole also requires Rab7/Ypt7. Here, we now solved a major problem in understanding this dual function of endosomal Rab7/Ypt7 using a fully reconstituted system, including purified, full-length yeast SNX-BAR and CSC, whose overall structure we present...
January 18, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/28053230/snx-1-and-rme-8-oppose-the-assembly-of-hgrs-1-escrt-0-degradative-microdomains-on-endosomes
#8
Anne Norris, Prasad Tammineni, Simon Wang, Julianne Gerdes, Alexandra Murr, Kelvin Y Kwan, Qian Cai, Barth D Grant
After endocytosis, transmembrane cargo reaches endosomes, where it encounters complexes dedicated to opposing functions: recycling and degradation. Microdomains containing endosomal sorting complexes required for transport (ESCRT)-0 component Hrs [hepatocyte growth factor-regulated tyrosine kinase substrate (HGRS-1) in Caenorhabditis elegans] mediate cargo degradation, concentrating ubiquitinated cargo and organizing the activities of ESCRT. At the same time, retromer associated sorting nexin one (SNX-1) and its binding partner, J-domain protein RME-8, sort cargo away from degradation, promoting cargo recycling to the Golgi...
January 17, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28040727/a-conserved-retromer-sorting-motif-is-essential-for-mitochondrial-dlp1-recycling-by-vps35-in-parkinson-s-disease-model
#9
Wenzhang Wang, Xiaopin Ma, Leping Zhou, Jun Liu, Xiongwei Zhu
Impaired mitochondria dynamics and quality control are involved in mitochondrial dysfunction and pathogenesis of Parkinson's disease (PD). VPS35 mutations cause autosomal dominant PD and we recently demonstrated that fPD-associated VPS35 mutants can cause mitochondrial fragmentation through enhanced VPS35-DLP1 interaction. In this study, we focused on the specific sites on DLP1 responsible for the VPS35-DLP1 interaction. A highly conserved FLV motif was identified in the C-terminus of DLP1, mutation of which significantly reduced VPS35-DLP1 interaction...
December 30, 2016: Human Molecular Genetics
https://www.readbyqxmd.com/read/28026081/distinct-complexes-of-yeast-snx4-family-snx-bars-mediate-retrograde-trafficking-of-snc1-and-atg27
#10
Mengxiao Ma, Christopher G Burd, Richard J Chi
The yeast SNX4 sub-family of sorting nexin containing a Bin-Amphiphysin-Rvs domain (SNX-BAR) proteins, Snx4/Atg24, Snx41 and Atg20/Snx42, are required for endocytic recycling and selective autophagy. Here, we show that Snx4 forms 2 functionally distinct heterodimers: Snx4-Atg20 and Snx4-Snx41. Each heterodimer coats an endosome-derived tubule that mediates retrograde sorting of distinct cargo; the v-SNARE, Snc1, is a cargo of the Snx4-Atg20 pathway, and Snx4-Snx41 mediates retrograde sorting of Atg27, an integral membrane protein implicated in selective autophagy...
February 2017: Traffic
https://www.readbyqxmd.com/read/27984059/cruising-the-cellular-highways-how-human-papillomavirus-travels-from-the-surface-to-the-nucleus
#11
REVIEW
Stephen DiGiuseppe, Malgorzata Bienkowska-Haba, Lucile G Guion, Martin Sapp
The non-enveloped human papillomaviruses (HPVs) specifically target epithelial cells of the skin and mucosa. Successful infection requires a lesion in the stratified tissue for access to the basal cells. Herein, we discuss our recent progress in understanding binding, internalization, uncoating, and intracellular trafficking of HPV particles. Our focus will be on HPV type 16, which is the most common HPV type associated with various anogenital and oropharyngeal carcinomas. The study of HPV entry has revealed a number of novel cellular pathways utilized during infection...
October 28, 2016: Virus Research
https://www.readbyqxmd.com/read/27964832/role-of-the-vps35-d620n-mutation-in-parkinson-s-disease
#12
REVIEW
Megha Mohan, George D Mellick
Parkinson's disease (PD) is a neurodegenerative disorder involving the loss of dopaminergic neurons in the brain. Following the discovery of the PD-causing D620N mutation in the VPS35 (Vacuolar sorting protein 35) gene, dysfunction in the subcellular retromer complex has been strongly implicated in pathogenesis of PD. Although the function and dysfunction of the retromer has been a focus of study for some time, the role of this complex in the development of PD is not fully understood. Investigating cellular alterations that occur when the retromer is rendered dysfunctional, such as when the D620N disease-causing mutation is introduced into various model systems, shows that endosomal processing defects are major contributors to the disease phenotype...
December 5, 2016: Parkinsonism & related Disorders
https://www.readbyqxmd.com/read/27942972/the-influenza-a-virus-matrix-protein-2-undergoes-retrograde-transport-from-the-endoplasmic-reticulum-into-the-cytoplasm-and-bypasses-cytoplasmic-proteasomal-degradation
#13
Sanchari Bhowmick, Chandrani Chakravarty, Shanmugaapriya Sellathamby, Sunil K Lal
The matrix protein 2 (M2) is a spliced product of segment 7 genome of influenza A virus. Previous studies indicate its role in uncoating of the viral ribonucleoprotein complex during viral entry and in membrane scission while budding. Despite its crucial role in the viral life cycle, little is known about its subcellular distribution and dynamics. In this study, we have shown that the M2 protein is translocated from the membrane to the cytoplasm by a retrograde route via endosomes and the Golgi network. It utilizes retromer cargo while moving from the endosome to the trans-Golgi network and prevents endosome fusion with the lysosome...
December 9, 2016: Archives of Virology
https://www.readbyqxmd.com/read/27932943/vacuolar-protein-sorting-genes-in-parkinson-s-disease-a-re-appraisal-of-mutations-detection-rate-and-neurobiology-of-disease
#14
REVIEW
Stefano Gambardella, Francesca Biagioni, Rosangela Ferese, Carla L Busceti, Alessandro Frati, Giuseppe Novelli, Stefano Ruggieri, Francesco Fornai
Mammalian retromers play a critical role in protein trans-membrane sorting from endosome to the trans-Golgi network (TGN). Recently, retromer alterations have been related to the onset of Parkinson's Disease (PD) since the variant p.Asp620Asn in VPS35 (Vacuolar Protein Sorting 35) was identified as a cause of late onset PD. This variant causes a primary defect in endosomal trafficking and retromers formation. Other mutations in VPS genes have been reported in both sporadic and familial PD. These mutations are less defined...
2016: Frontiers in Neuroscience
https://www.readbyqxmd.com/read/27929418/yeast-reporter-assay-to-identify-cellular-components-of-ricin-toxin-a-chain-trafficking
#15
Björn Becker, Tina Schnöder, Manfred J Schmitt
RTA, the catalytic A-subunit of the ribosome inactivating A/B toxin ricin, inhibits eukaryotic protein biosynthesis by depurination of 28S rRNA. Although cell surface binding of ricin holotoxin is mainly mediated through its B-subunit (RTB), sole application of RTA is also toxic, albeit to a significantly lower extent, suggesting alternative pathways for toxin uptake and transport. Since ricin toxin trafficking in mammalian cells is still not fully understood, we developed a GFP-based reporter assay in yeast that allows rapid identification of cellular components required for RTA uptake and subsequent transport through a target cell...
December 6, 2016: Toxins
https://www.readbyqxmd.com/read/27924069/retrograde-trafficking-of-vmat2-and-its-role-in-protein-stability-in-non-neuronal-cells
#16
Qiuzi Wu, Hongfei Xu, Wei Wang, Fei Chang, Yu Jiang, Yongjian Liu
Increasing evidence suggests that the impaired neuroprotection of vesicular monoamine transporter 2 (VMAT2) contributes to the pathogenesis of Parkinson's disease. That has been linked to aberrant subcellular retrograde trafficking as strongly indicated by recent genomic studies on familial Parkinson's diseases. However, whether VMAT2 function is regulated by retrograde trafficking is unknown. By using biochemistry and cell biology approaches, we have shown that VMAT2 was stringently localized to the trans-Golgi network and underwent retrograde trafficking in non-neuronal cells...
November 2016: Journal of Biomedical Research
https://www.readbyqxmd.com/read/27917878/spatiotemporal-control-of-interferon-induced-jak-stat-signalling-and-gene-transcription-by-the-retromer-complex
#17
Daniela Chmiest, Nanaocha Sharma, Natacha Zanin, Christine Viaris de Lesegno, Massiullah Shafaq-Zadah, Vonick Sibut, Florent Dingli, Philippe Hupé, Stephan Wilmes, Jacob Piehler, Damarys Loew, Ludger Johannes, Gideon Schreiber, Christophe Lamaze
Type-I interferons (IFNs) play a key role in the immune defences against viral and bacterial infections, and in cancer immunosurveillance. We have established that clathrin-dependent endocytosis of the type-I interferon (IFN-α/β) receptor (IFNAR) is required for JAK/STAT signalling. Here we show that the internalized IFNAR1 and IFNAR2 subunits of the IFNAR complex are differentially sorted by the retromer at the early endosome. Binding of the retromer VPS35 subunit to IFNAR2 results in IFNAR2 recycling to the plasma membrane, whereas IFNAR1 is sorted to the lysosome for degradation...
December 5, 2016: Nature Communications
https://www.readbyqxmd.com/read/27912055/retromer-sets-a-trap-for-endosomal-cargo-sorting
#18
Ludger Johannes, Christian Wunder
Membrane trafficking from endosomes to the trans-Golgi network or the plasma membrane is driven by the retromer complex. Through structural analysis of the cargo-bound complex, Lucas et al. describe a mechanism by which endosomal membrane recruitment and cargo recognition are integrated through cooperative interactions between retromer subunits.
December 1, 2016: Cell
https://www.readbyqxmd.com/read/27909246/retromer-wash-dependent-sorting-of-nutrient-transporters-requires-a-multivalent-interaction-network-with-ankrd50
#19
Arunas Kvainickas, Ana Jimenez Orgaz, Heike Nägele, Britta Diedrich, Kate J Heesom, Jörn Dengjel, Peter J Cullen, Florian Steinberg
Retromer and the associated actin polymerizing WASH-complex are essential for the endocytic recycling of a wide range of integral membrane proteins. A hereditary Parkinson's disease causing point mutation (D620N) in the retromer subunit VPS35 perturbs retromer's association with the WASH-complex and also with the uncharacterized protein Ankyrin Repeat Domain Containing Protein 50 (ANKRD50). Here, we firmly establish ANKRD50 as a novel and essential component of the SNX27-retromer-WASH supercomplex. Depletion of ANKRD50 in HeLa or U2OS cells phenocopied the loss of endosome to cell surface recycling of multiple transmembrane proteins seen upon suppression of SNX27, retromer or WASH-complex components...
December 1, 2016: Journal of Cell Science
https://www.readbyqxmd.com/read/27894086/the-anti-tumor-drug-2-hydroxyoleic-acid-minerval-stimulates-signaling-and-retrograde-transport
#20
Maria L Torgersen, Tove Irene Klokk, Simona Kavaliauskiene, Christian Klose, Kai Simons, Tore Skotland, Kirsten Sandvig
2-hydroxyoleic acid (OHOA, Minerval®) is an example of a substance used for membrane lipid therapy, where the cellular membranes rather than specific proteins constitute the therapeutical target. OHOA is thought to mediate its anti-tumor effect by affecting the biophysical properties of membranes, which leads to altered recruitment and activation of amphitropic proteins, altered cellular signaling, and eventual cell death. Little is known about the initial signaling events upon treatment with OHOA, and whether the altered membrane properties would have any impact on the dynamic intracellular transport system...
November 22, 2016: Oncotarget
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