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https://www.readbyqxmd.com/read/29218765/deregulation-of-autophagy-in-postmortem-brains-of-machado-joseph-disease-patients
#1
Annie Sittler, Marie-Paule Muriel, Martina Marinello, Alexis Brice, Wilfred den Dunnen, Sandro Alves
Autophagy, the major pathway for protein turnover, is critical to maintain cellular homeostasis and has been implicated in neurodegenerative diseases. The aim of this research was to analyze the expression of autophagy markers in postmortem brains from Machado-Joseph disease (MJD) patients. The expression of autophagy markers in the cerebellum and the oculomotor nucleus from MJD patients and age-matched controls with no signs of neuropathology was inspected postmortem by immunohistochemistry (IHC) and Western blot...
December 8, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/29158324/control-of-rab7-activity-and-localization-through-the-retromer-tbc1d5-complex-enables-rab7-dependent-mitophagy
#2
Ana Jimenez-Orgaz, Arunas Kvainickas, Heike Nägele, Justin Denner, Stefan Eimer, Jörn Dengjel, Florian Steinberg
Retromer is an endosomal multi-protein complex that organizes the endocytic recycling of a vast range of integral membrane proteins. Here, we establish an additional retromer function in controlling the activity and localization of the late endosomal small GTPase RAB7. Surprisingly, we found that RAB7 not only decorates late endosomes or lysosomes, but is also present on the endoplasmic reticulum, trans-Golgi network, and mitochondrial membranes, a localization that is maintained by retromer and the retromer-associated RAB7-specific GAP TBC1D5...
November 20, 2017: EMBO Journal
https://www.readbyqxmd.com/read/29146912/structural-insights-into-legionella-ridl-vps29-retromer-subunit-interaction-reveal-displacement-of-the-regulator-tbc1d5
#3
Kevin Bärlocher, Cedric A J Hutter, A Leoni Swart, Bernhard Steiner, Amanda Welin, Michael Hohl, François Letourneur, Markus A Seeger, Hubert Hilbi
Legionella pneumophila can cause Legionnaires' disease and replicates intracellularly in a distinct Legionella-containing vacuole (LCV). LCV formation is a complex process that involves a plethora of type IV-secreted effector proteins. The effector RidL binds the Vps29 retromer subunit, blocks retrograde vesicle trafficking, and promotes intracellular bacterial replication. Here, we reveal that the 29-kDa N-terminal domain of RidL (RidL2-281) adopts a "foot-like" fold comprising a protruding β-hairpin at its "heel"...
November 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/29138439/abma-a-small-molecule-that-inhibits-intracellular-toxins-and-pathogens-by-interfering-with-late-endosomal-compartments
#4
Yu Wu, Valérie Pons, Amélie Goudet, Laetitia Panigai, Annette Fischer, Jo-Ana Herweg, Sabrina Kali, Robert A Davey, Jérôme Laporte, Céline Bouclier, Rahima Yousfi, Céline Aubenque, Goulven Merer, Emilie Gobbo, Roman Lopez, Cynthia Gillet, Sandrine Cojean, Michel R Popoff, Pascal Clayette, Roger Le Grand, Claire Boulogne, Noël Tordo, Emmanuel Lemichez, Philippe M Loiseau, Thomas Rudel, Didier Sauvaire, Jean-Christophe Cintrat, Daniel Gillet, Julien Barbier
Intracellular pathogenic microorganisms and toxins exploit host cell mechanisms to enter, exert their deleterious effects as well as hijack host nutrition for their development. A potential approach to treat multiple pathogen infections and that should not induce drug resistance is the use of small molecules that target host components. We identified the compound 1-adamantyl (5-bromo-2-methoxybenzyl) amine (ABMA) from a cell-based high throughput screening for its capacity to protect human cells and mice against ricin toxin without toxicity...
November 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29135058/distinct-features-of-multivesicular-body-lysosome-fusion-revealed-by-a-new-cell-free-content-mixing-assay
#5
Mahmoud Abdul Karim, Dieter Ronny Samyn, Sevan Mattie, Christopher Leonard Brett
When marked for degradation, surface receptor and transporter proteins are internalized and delivered to endosomes where they are packaged into intralumenal vesicles (ILVs). Many rounds of ILV formation create multivesicular bodies (MVBs) that fuse with lysosomes exposing ILVs to hydrolases for catabolism. Despite being critical for protein degradation, the molecular underpinnings of MVB-lysosome fusion remain unclear, although machinery underlying other lysosome fusion events is implicated. But how then is specificity conferred? And how is MVB maturation and fusion coordinated for efficient protein degradation? To address these questions, we developed a cell-free MVB-lysosome fusion assay using S...
November 14, 2017: Traffic
https://www.readbyqxmd.com/read/29125872/impaired-placental-autophagy-in-placental-malaria
#6
Kris Genelyn Dimasuay, Lan Gong, Fredrick Rosario, Emma McBryde, Tim Spelman, Jocelyn Glazier, Stephen J Rogerson, James G Beeson, Thomas Jansson, Rodney J Devenish, Philippe Boeuf
BACKGROUND: Placental malaria is a major cause of low birthweight, principally due to impaired fetal growth. Intervillositis, a local inflammatory response to placental malaria, is central to the pathogenesis of poor fetal growth as it impairs transplacental amino acid transport. Given the link between inflammation and autophagy, we investigated whether placental malaria-associated intervillositis increased placental autophagy as a potential mechanism in impaired fetal growth. METHODS: We examined placental biopsies collected after delivery from uninfected women (n = 17) and from women with Plasmodium falciparum infection with (n = 14) and without (n = 7) intervillositis...
2017: PloS One
https://www.readbyqxmd.com/read/29124250/impaired-rab7-and-dynamin2-block-fat-turnover-by-autophagy-in-alcoholic-fatty-livers
#7
Yuan Li, Wen-Xing Ding
No abstract text is available yet for this article.
August 2017: Hepatology Communications
https://www.readbyqxmd.com/read/29117102/mechanisms-of-entry-and-endosomal-pathway-of-african-swine-fever-virus
#8
REVIEW
Elena G. Sánchez, Daniel Pérez-Núñez, Yolanda Revilla
African Swine Fever Virus (ASFV) causes a serious swine disease that is endemic in Africa and Sardinia and presently spreading in Russia and neighboring countries, including Poland and recently, the Czech Republic. This uncontrolled dissemination is a world-wide threat, as no specific protection or vaccine is available. ASFV is a very complex icosahedral, enveloped virus about 200 nm in diameter, which infects several members of pigs. The virus enters host cells by receptor-mediated endocytosis that depends on energy, vacuolar pH and temperature...
November 8, 2017: Vaccines
https://www.readbyqxmd.com/read/29099291/post-translational-modifications-how-to-modulate-rab7-functions
#9
Graziana Modica, Stephane Lefrancois
The small GTPase Rab7 is the main regulator of membrane trafficking at late endosomes. This small GTPase regulates endosome-to-trans Golgi Network trafficking of sorting receptors, membrane fusion of late endosomes to lysosomes, and autophagosomes to lysosomes during autophagy. Rab7, like all Rab GTPases, binds downstream effectors coordinating several divergent pathways. How cells regulate these interactions and downstream functions is not well understood. Recent evidence suggests that Rab7 function can be modulated by the combination of several post-translational modifications that facilitate interactions with one effector while preventing binding to another one...
November 3, 2017: Small GTPases
https://www.readbyqxmd.com/read/29066608/molecular-mechanisms-of-developmentally-programmed-crinophagy-in-drosophila
#10
Tamás Csizmadia, Péter Lőrincz, Krisztina Hegedűs, Szilvia Széplaki, Péter Lőw, Gábor Juhász
At the onset of metamorphosis, Drosophila salivary gland cells undergo a burst of glue granule secretion to attach the forming pupa to a solid surface. Here, we show that excess granules evading exocytosis are degraded via direct fusion with lysosomes, a secretory granule-specific autophagic process known as crinophagy. We find that the tethering complex HOPS (homotypic fusion and protein sorting); the small GTPases Rab2, Rab7, and its effector, PLEKHM1; and a SNAP receptor complex consisting of Syntaxin 13, Snap29, and Vamp7 are all required for the fusion of secretory granules with lysosomes...
October 24, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29051265/regulation-of-notch-signaling-by-rab7-and-rab8-requires-carboxyl-methylation-by-icmt
#11
Helen Court, Ian M Ahearn, Marc Amoyel, Erika A Bach, Mark R Philips
Isoprenylcysteine carboxyl methyltransferase (ICMT) methylesterifies C-terminal prenylcysteine residues of CaaX proteins and some RAB GTPases. Deficiency of either ICMT or NOTCH1 accelerates pancreatic neoplasia in Pdx1-Cre;LSL-Kras(G12D) mice, suggesting that ICMT is required for NOTCH signaling. We used Drosophila melanogaster wing vein and scutellar bristle development to screen Rab proteins predicted to be substrates for ICMT (ste14 in flies). We identified Rab7 and Rab8 as ICMT substrates that when silenced phenocopy ste14 deficiency...
October 19, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29046869/staphylococcus-aureus-alpha-toxin-induces-the-formation-of-dynamic-tubules-labeled-with-lc3-within-host-cells-in-a-rab7-and-rab1b-dependent-manner
#12
María M López de Armentia, María C Gauron, María I Colombo
Staphylococcus aureus is a pathogen that causes severe infectious diseases that eventually lead to septic and toxic shock. S. aureus infection is characterized by the production of virulence factors, including enzymes and toxins. After internalization S. aureus resides in a phagosome labeled with Rab7 protein. Here, we show that S. aureus generates tubular structures marked with the small GTPases Rab1b and Rab7 and by the autophagic protein LC3 at early times post-infection. As shown by live cell imaging these tubular structures are highly dynamic, extend, branch and grow in length...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/29038162/systematic-analysis-of-human-cells-lacking-atg8-proteins-uncovers-roles-for-gabaraps-and-the-ccz1-mon1-regulator-c18orf8-rmc1-in-macro-and-selective-autophagic-flux
#13
Laura Pontano Vaites, Joao A Paulo, Edward L Huttlin, J Wade Harper
Selective and macro autophagy sequester specific organelles/substrates or bulk cytoplasm, respectively, inside autophagosomes as cargo for delivery to lysosomes. The mammalian ATG8 orthologues (MAP1LC3A/B/C and GABARAP/L1/L2) are ubiquitin (UB)-like proteins conjugated to the autophagosome membrane and are thought to facilitate cargo receptor recruitment, vesicle maturation, and lysosomal fusion. To elucidate the molecular functions of the ATG8 proteins, we engineered cells lacking genes for each subfamily as well as all six mammalian ATG8s...
October 16, 2017: Molecular and Cellular Biology
https://www.readbyqxmd.com/read/29028801/docrl-maintains-immune-cell-quiescence-by-regulating-endosomal-traffic
#14
Steven J Del Signore, Sarah A Biber, Katherine S Lehmann, Stephanie R Heimler, Benjamin H Rosenfeld, Tania L Eskin, Sean T Sweeney, Avital A Rodal
Lowe Syndrome is a developmental disorder characterized by eye, kidney, and neurological pathologies, and is caused by mutations in the phosphatidylinositol-5-phosphatase OCRL. OCRL plays diverse roles in endocytic and endolysosomal trafficking, cytokinesis, and ciliogenesis, but it is unclear which of these cellular functions underlie specific patient symptoms. Here, we show that mutation of Drosophila OCRL causes cell-autonomous activation of hemocytes, which are macrophage-like cells of the innate immune system...
October 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29027991/n6-isopentenyladenosine-dual-targeting-of-ampk-and-rab7-prenylation-inhibits-melanoma-growth-through-the-impairment-of-autophagic-flux
#15
Roberta Ranieri, Elena Ciaglia, Giuseppina Amodio, Paola Picardi, Maria Chiara Proto, Patrizia Gazzerro, Chiara Laezza, Paolo Remondelli, Maurizio Bifulco, Simona Pisanti
Targeting the autophagic process is considered a promising therapeutic strategy in cancer since a great number of tumors, including melanoma, show high basal levels of protective autophagy that contributes to tumor progression and chemoresistance. Here, exploiting both in vitro and in vivo approaches, we identified N6-isopentenyladenosine (iPA), an end product of the mevalonate pathway, as a novel autophagy inhibitor with an interesting anti-melanoma activity. iPA, after being phosphorylated by adenosine kinase into 5'-iPA-monophosphate, induces autophagosome accumulation through AMPK activation, measured by increased fluorescent GFP-LC3 puncta and enhanced conversion into the lipidated autophagosome-associated LC3-II...
October 13, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28979185/the-membrane-glycoprotein-m6a-endocytic-recycling-pathway-involves-clathrin-mediated-endocytosis-and-affects-neuronal-synapses
#16
Micaela D Garcia, Karina Formoso, Gabriela I Aparicio, Alberto C C Frasch, Camila Scorticati
Single point mutations or variations in the expression of the gene encoding the neuronal glycoprotein M6a have been associated with psychiatric disorders such as Alzheimer's disease, depression and schizophrenia. In cultured neurons, M6a positively contributes to neurite extension, axon guidance, filopodia/spine outgrowth, and synapse formation. The endocytic processes of neuronal membrane proteins are linked to the differentiation, growth, signaling and plasticity of neurons. However, the roles of M6a and the precise mechanisms through which M6a internalizes and recycles back to the neuronal membrane are unknown...
2017: Frontiers in Molecular Neuroscience
https://www.readbyqxmd.com/read/28956766/porcine-hemagglutinating-encephalomyelitis-virus-enters-neuro-2a-cells-via-clathrin-mediated-endocytosis-in-a-rab5-cholesterol-and-ph-dependent-manner
#17
Zi Li, Kui Zhao, Yungang Lan, Xiaoling Lv, Shiyu Hu, Jiyu Guan, Huijun Lu, Jing Zhang, Junchao Shi, Yawen Yang, Deguang Song, Feng Gao, Wenqi He
Porcine hemagglutinating encephalomyelitis virus (PHEV) is a highly neurovirulent coronavirus that invades the central nervous system (CNS) in piglets. Although important progress has been made toward understanding the biology of PHEV, many aspects of its life cycle remain obscure. Here we dissected the molecular mechanism underlying cellular entry and intracellular trafficking of PHEV in mouse neuroblastoma (Neuro-2a) cells. We first performed a thin-section transmission electron microscopy (TEM) assay to characterize the kinetics of PHEV, and we found that viral entry and transfer occur via membranous coating-mediated endo- and exocytosis...
December 1, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28946560/disruption-of-endocytic-trafficking-protein-rab7-impairs-invasiveness-of-cholangiocarcinoma-cells
#18
Nantana Suwandittakul, Onrapak Reamtong, Pattamaporn Molee, Santi Maneewatchararangsri, Maleerat Sutherat, Urai Chaisri, Sopit Wongkham, Poom Adisakwattana
BACKGROUND: Alterations and mutations of endo-lysosomal trafficking proteins have been associated with cancer progression. Identification and characterization of endo-lysosomal trafficking proteins in invasive cholangiocarcinoma (CCA) cells may benefit prognosis and drug design for CCA. OBJECTIVE: To identify and characterize endo-lysosomal trafficking proteins in invasive CCA. METHODS: A lysosomal-enriched fraction was isolated from a TNF-α induced invasive CCA cell line (KKU-100) and uninduced control cells and protein identification was performed with nano-LC MS/MS...
September 7, 2017: Cancer Biomarkers: Section A of Disease Markers
https://www.readbyqxmd.com/read/28935975/tumor-necrosis-factor-inducible-gene-6-protein-ameliorates-chronic-liver-damage-by-promoting-autophagy-formation-in-mice
#19
Sihyung Wang, Chanbin Lee, Jieun Kim, Jeongeun Hyun, Minso Lim, Hyuk-Jin Cha, Seh-Hoon Oh, Yung Hyun Choi, Youngmi Jung
Tumor necrosis factor-inducible gene 6 protein (TSG-6) has recently been shown to protect the liver from acute damage. However, the mechanism underlying the effect of TSG-6 on the liver remains unclear. Autophagy is a catabolic process that targets cell components to lysosomes for degradation, and its functions are reported to be dysregulated in liver diseases. Here we investigate whether TSG-6 promotes liver regeneration by inducing autophagic clearance in damaged livers. Mice fed a methionine choline-deficient diet supplemented with 0...
September 22, 2017: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/28928133/a-new-rab7-effector-controls-phosphoinositide-conversion-in-endosome-maturation
#20
James E Casanova, Bettina Winckler
Endosome maturation requires a coordinated change in the Rab GTPase and phosphoinositide composition of the endosomal membrane. In this issue, Liu et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201705151) identify WDR91 as a ubiquitous Rab7 effector that inhibits phosphatidylinositol 3-kinase activity on endosomes and is critical for endosome maturation, viability, and dendrite growth of neurons in vivo.
October 2, 2017: Journal of Cell Biology
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