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https://www.readbyqxmd.com/read/29446751/molecular-mechanism-to-target-the-endosomal-mon1-ccz1-gef-complex-to-the-pre-autophagosomal-structure
#1
Jieqiong Gao, Lars Langemeyer, Daniel Kuemmel, Fulvio Reggiori, Christian Ungermann
During autophagy, a newly formed double membrane surrounds its cargo to generate the so-called autophagosome, which then fuses with a lysosome after closure. Previous work implicated that endosomal Rab7/Ypt7 associates to autophagosomes prior to their fusion with lysosomes. Here, we unravel how the Mon1-Ccz1 guanosine exchange factor (GEF) acting upstream of Ypt7 is specifically recruited to the pre-autophagosomal structure under starvation conditions. We find that Mon1-Ccz1 directly binds to Atg8, the yeast homolog of the members of the mammalian LC3 protein family...
February 15, 2018: ELife
https://www.readbyqxmd.com/read/29425100/the-rab-effector-protein-rabep2-regulates-endosomal-trafficking-to-mediate-vascular-endothelial-growth-factor-receptor-2-vegfr2-dependent-signaling
#2
Natalie Kofler, Federico Corti, Felix Rivera-Molina, Yong Deng, Derek Toomre, Michael Simons
As a master regulator of endothelial cell function, vascular endothelial growth factor receptor-2 (VEGFR2) activates multiple downstream signaling pathways that are critical for vascular development and normal vessel function. VEGFR2 trafficking through various endosomal compartments modulates its signaling output. Accordingly, proteins that regulate the speed and direction by which VEGFR2 traffics through endosomes have been demonstrated to be particularly important for arteriogenesis. However, little is known about how these proteins control VEGFR2 trafficking and about the implications of this control for endothelial cell function...
February 7, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29408503/common-traffic-routes-for-imported-spermine-and-endosomal-glypican-1-derived-heparan-sulfate-in-fibroblasts
#3
Fang Cheng, Lars-Åke Fransson, Katrin Mani
Import of the polyamine spermine from the extracellular environment depends on the presence of cell surface heparan sulfate proteoglycans, such as glypican-1. This proteoglycan is internalized by endocytosis, releases its heparan sulfate chains in endosomes by a nitric oxide-, copper- and amyloid precursor protein-dependent mechanism, then penetrates the membrane and is transported to the nucleus and then to autophagosomes. This process is spontaneous or induced by ascorbate depending on the growth-state of the cell...
February 2, 2018: Experimental Cell Research
https://www.readbyqxmd.com/read/29404450/ethanol-exposure-inhibits-hepatocyte-lipophagy-by-inactivating-the-small-guanosine-triphosphatase-rab7
#4
Ryan J Schulze, Karuna Rasineni, Shaun G Weller, Micah B Schott, Barbara Schroeder, Carol A Casey, Mark A McNiven
Alcohol consumption is a well-established risk factor for the onset and progression of fatty liver disease. An estimated 90% of heavy drinkers are thought to develop significant liver steatosis. For these reasons, an increased understanding of the molecular basis for alcohol-induced hepatic steatosis is important. It has become clear that autophagy, a catabolic process of intracellular degradation and recycling, plays a key role in hepatic lipid metabolism. We have shown that Rab7, a small guanosine triphosphatase known to regulate membrane trafficking, acts as a key orchestrator of hepatocellular lipophagy, a selective form of autophagy in which lipid droplets (LDs) are specifically targeted for turnover by the autophagic machinery...
April 2017: Hepatology Communications
https://www.readbyqxmd.com/read/29382080/structural-studies-of-predicted-ligand-binding-sites-and-molecular-docking-analysis-of-slc2a4-as-a-therapeutic-target-for-the-treatment-of-cancer
#5
Raphael Taiwo Aruleba, Tayo Alex Adekiya, Babatunji Emmanuel Oyinloye, Abidemi Paul Kappo
Presently, many studies have focused on exploring in silico approaches in the identification and development of alternative therapy for the treatment and management of cancer. Solute carrier family-2-member-4-gene (Slc2a4) which encodes glucose transporter 4 protein (GLUT4), has been identified as a promising therapeutic target for cancer. Though Slc2a4 is known to play a major regulatory role in the pathophysiology of type 2 diabetes, emerging evidence suggests that successful pharmacological inhibition of this protein may lead to the development of a novel drug candidate for the treatment of cancer...
January 28, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29364868/mitochondria-lysosome-contacts-regulate-mitochondrial-fission-via-rab7-gtp-hydrolysis
#6
Yvette C Wong, Daniel Ysselstein, Dimitri Krainc
Both mitochondria and lysosomes are essential for maintaining cellular homeostasis, and dysfunction of both organelles has been observed in multiple diseases. Mitochondria are highly dynamic and undergo fission and fusion to maintain a functional mitochondrial network, which drives cellular metabolism. Lysosomes similarly undergo constant dynamic regulation by the RAB7 GTPase, which cycles from an active GTP-bound state into an inactive GDP-bound state upon GTP hydrolysis. Here we have identified the formation and regulation of mitochondria-lysosome membrane contact sites using electron microscopy, structured illumination microscopy and high spatial and temporal resolution confocal live cell imaging...
January 24, 2018: Nature
https://www.readbyqxmd.com/read/29355788/the-kinetics-of-autophagy-in-the-lung-following-acute-spinal-cord-injury-in-rats
#7
Ruiliang Chu, Jiuling Wang, Yang Bi, Guoxin Nan
BACKGROUND CONTEXT: Lung injury is a major cause of respiratory complications following an acute spinal cord injury (ASCI), which are associated with a high mortality rate. Autophagy has been shown to be involved in a variety of lung diseases; however, Whether autophaphy is activated in the lung following ASCI remains unknown. PURPOSE: The objective of this study was to investigate the induction of autophagy in the lung after ASCI. STUDY DESIGN: This is an experimental animal study of ASCI investigating kinetics of autophagy in the lung following ASCI...
January 17, 2018: Spine Journal: Official Journal of the North American Spine Society
https://www.readbyqxmd.com/read/29336362/screening-for-sh3tc2-pmp2-and-bscl2-variants-in-a-cohort-of-chinese-patients-with-charcot-marie-tooth
#8
Xin Zhao, Ming-Ming Jiang, Yi-Zhou Yan, Lei Liu, Yong-Zhi Xie, Xiao-Bo Li, Zheng-Mao Hu, Xiao-Hong Zi, Kun Xia, Bei-Sha Tang, Ru-Xu Zhang
BACKGROUND: SH3TC2, PMP2, and BSCL2 genes are related to autosomal recessive (AR) Charcot-Marie-Tooth (CMT) disease type 1, autosomal dominant (AD)-CMT1, and AD-CMT2, respectively. Pathogenic variants in these three genes were not well documented in Chinese CMT patients. Therefore, this study aims to detect SH3TC2, PMP2, and BSCL2 pathogenic variants in a cohort of 315 unrelated Chinese CMT families. METHODS: A total of 315 probands from 315 unrelated Chinese CMT families were recruited from the Department of Neurology of Third Xiangya Hospital and Xiangya Hospital...
January 20, 2018: Chinese Medical Journal
https://www.readbyqxmd.com/read/29331581/identification-and-characterization-of-arginine-finger-like-motifs-and-endosome-lysosome-basolateral-sorting-signals-within-ectopically-expressed-cira-a-coxiella-burnetii-type-iv-secreted-effector-protein
#9
Mary M Weber, Robert Faris, Erin J van Schaik, James E Samuel
Coxiella burnetii is an obligate intracellular pathogen that replicates in an endolysosome-like compartment termed the Coxiella-containing vacuole (CCV). Formation of this unique replicative niche requires delivery of bacterial effector proteins into the host cytosol where they mediate crucial interactions with the host. We previously identified an essential Dot/Icm effector, CirA that is required for intracellular replication and CCV formation. Furthermore, CirA was shown to stimulate the GTPase activity of RhoA in vitro...
January 10, 2018: Microbes and Infection
https://www.readbyqxmd.com/read/29284148/itraq-based-comparative-proteome-analysis-for-molecular-mechanism-of-defense-against-acute-ammonia-toxicity-in-pacific-white-shrimp-litopenaeus-vannamei
#10
Xia Lu, Sheng Luan, Ping Dai, Xianhong Meng, Baoxiang Cao, Kun Luo, Jie Kong
In the practical farming of Litopenaeus vannamei, the intensive culture system and environmental pollution usually results in a high concentration of ammonia, which brings large detrimental effects to shrimp, such as increasing the susceptibility to pathogens and even causing high mortality. We have revealed that the survival time under acute ammonia stress varied substantially among different families and obtained ammonia-tolerant (LV_T) and ammonia-sensitive (LV_S) families. In order to understand the molecular mechanism of defense against ammonia toxicity in shrimp, we performed iTRAQ LC-MS/MS proteomic analysis between LV_T and LV_S groups of L...
December 25, 2017: Fish & Shellfish Immunology
https://www.readbyqxmd.com/read/29241549/trafficking-mediated-sting-degradation-requires-sorting-to-acidified-endolysosomes-and-can-be-targeted-to-enhance-anti-tumor-response
#11
Vijay K Gonugunta, Tomomi Sakai, Vladislav Pokatayev, Kun Yang, Jianjun Wu, Nicole Dobbs, Nan Yan
STING is an endoplasmic reticulum (ER)-associated transmembrane protein that turns on and quickly turns off downstream signaling as it translocates from the ER to vesicles. How STING signaling is attenuated during trafficking remains poorly understood. Here, we show that trafficking-mediated STING degradation requires ER exit and function of vacuolar ATPase complex. Late-stage STING vesicles are sorted to Rab7-positive endolysosomes for degradation. Based on analysis of existing structures, we also identified the helix amino acid 281 (aa281)-297 as a motif required for trafficking-mediated STING degradation...
December 12, 2017: Cell Reports
https://www.readbyqxmd.com/read/29237927/distinct-rab7-related-endosomal-autophagic-lysosomal-dysregulation-observed-in-cortex-and-hippocampus-in-appswe-psen1de9-mouse-model-of-alzheimer-s-disease
#12
Li Ba, Xiao-Hua Chen, Yan-Lin Chen, Qing Nie, Zhi-Jun Li, Feng-Fei Ding, Min Zhang
BACKGROUND: Amyloid-β deposition and accumulation of autophagic vacuoles are pathologic features of Alzheimer's disease (AD). Dysregulation of the endosomal-autophagic-lysosomal (EAL) pathway, which impairs amyloid precursor protein processing, is one of the earliest changes in AD. However, the precise role of EAL pathway in neurodegeneration remains unclear. This study aimed to investigate the role of EAL pathway in AD and further study the mechanism of EAL dysfunction. METHODS: We used 3-, 7-, and 12-month-old APPswe/PSEN1dE9 (APP/PS1) mice to model different stages of AD with age- and gender-matched wild-type littermates as controls (4-7 mice per group) and detected the changes of EAL markers, endosomal organizers Rab5 and Rab7, autophagosome marker LC3B, and lysosomal proteins Lamp1/2 in cortex and hippocampus by immunohistochemistry and Western blotting analysis...
December 20, 2017: Chinese Medical Journal
https://www.readbyqxmd.com/read/29237845/human-cytomegalovirus-replication-is-inhibited-by-the-autophagy-inducing-compounds-trehalose-and-smer28-through-distinctively-different-mechanisms
#13
Alex E Clark, Maite Sabalza, Philip L S M Gordts, Deborah H Spector
Human Cytomegalovirus (HCMV) is the top viral cause of birth defects worldwide, and current therapies have high toxicity. We previously published that the mTOR-independent autophagy-inducing disaccharide trehalose inhibits HCMV replication in multiple cell types. Here, we examine the mechanism of inhibition and introduce the autophagy inducer SMER28 as an additional inhibitor of HCMV acting through a different mechanism. We find that trehalose induces vacuolation and acidification of vacuoles, and that debris, including debris consistent in appearance with abnormal virions, is present in multivesicular bodies...
December 13, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29218765/deregulation-of-autophagy-in-postmortem-brains-of-machado-joseph-disease-patients
#14
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
#15
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
#16
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
#17
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
#18
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
#19
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
#20
Yuan Li, Wen-Xing Ding
No abstract text is available yet for this article.
August 2017: Hepatology Communications
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