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Early endosome

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https://www.readbyqxmd.com/read/28090783/probing-the-druggability-of-membrane-bound-rab5-by-molecular-dynamics-simulations
#1
Eileen Edler, Matthias Stein
Rab5 is a small GTPase and a key regulator in early endosomal trafficking. Rab5 and its effectors are involved in a large number of infectious diseases and certain types of cancer. We performed µs atomistic molecular dynamics simulations of inactive and active full-length Rab5 anchored to a complex model bilayer with composition of the early endosome membrane. Direct interactions between the Rab5 G domain and the bilayer were observed. We found two dominant nucleotide-dependent orientations characterised by a different accessibility of the switch regions...
December 2017: Journal of Enzyme Inhibition and Medicinal Chemistry
https://www.readbyqxmd.com/read/28077878/pla2g16-represents-a-switch-between-entry-and-clearance-of-picornaviridae
#2
Jacqueline Staring, Eleonore von Castelmur, Vincent A Blomen, Lisa G van den Hengel, Markus Brockmann, Jim Baggen, Hendrik Jan Thibaut, Joppe Nieuwenhuis, Hans Janssen, Frank J M van Kuppeveld, Anastassis Perrakis, Jan E Carette, Thijn R Brummelkamp
Picornaviruses are a leading cause of human and veterinary infections that result in various diseases, including polio and the common cold. As archetypical non-enveloped viruses, their biology has been extensively studied. Although a range of different cell-surface receptors are bound by different picornaviruses, it is unclear whether common host factors are needed for them to reach the cytoplasm. Using genome-wide haploid genetic screens, here we identify the lipid-modifying enzyme PLA2G16 (refs 8, 9, 10, 11) as a picornavirus host factor that is required for a previously unknown event in the viral life cycle...
January 19, 2017: Nature
https://www.readbyqxmd.com/read/28077646/adenovirus-modulates-toll-like-receptor-4-signaling-by-reprogramming-orp1l-vap-protein-contacts-for-cholesterol-transport-from-endosomes-to-the-endoplasmic-reticulum
#3
Nicholas L Cianciola, Stacey Chung, Danny Manor, Cathleen R Carlin
: Human adenoviruses generally cause mild self-limiting infections but can lead to serious disease and even be fatal in high-risk individuals, underscoring the importance of understanding how the virus counteracts host defense mechanisms. This study had two goals. First, determine the molecular basis of cholesterol homeostatic responses induced by the early region 3 membrane protein RIDα via its direct interaction with the sterol-binding protein ORP1L. Second, determine how this interaction regulates innate immunity to adenovirus...
January 11, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28071667/photogate-microscopy-to-track-single-molecules-in-crowded-environments
#4
Vladislav Belyy, Sheng-Min Shih, Jigar Bandaria, Yongjian Huang, Rosalie E Lawrence, Roberto Zoncu, Ahmet Yildiz
Tracking single molecules inside cells reveals the dynamics of biological processes, including receptor trafficking, signalling and cargo transport. However, individual molecules often cannot be resolved inside cells due to their high density. Here we develop the PhotoGate technique that controls the number of fluorescent particles in a region of interest by repeatedly photobleaching its boundary. PhotoGate bypasses the requirement of photoactivation to track single particles at surface densities two orders of magnitude greater than the single-molecule detection limit...
January 10, 2017: Nature Communications
https://www.readbyqxmd.com/read/28067668/adaptor-proteins-numb-and-numbl-promote-cell-cycle-withdrawal-by-targeting-erbb2-for-degradation
#5
Maretoshi Hirai, Yoh Arita, C Jane McGlade, Kuo-Fen Lee, Ju Chen, Sylvia M Evans
Failure of trabecular myocytes to undergo appropriate cell cycle withdrawal leads to ventricular noncompaction and heart failure. Signaling of growth factor receptor ERBB2 is critical for myocyte proliferation and trabeculation. However, the mechanisms underlying appropriate downregulation of trabecular ERBB2 signaling are little understood. Here, we have found that the endocytic adaptor proteins NUMB and NUMBL were required for downregulation of ERBB2 signaling in maturing trabeculae. Loss of NUMB and NUMBL resulted in a partial block of late endosome formation, resulting in sustained ERBB2 signaling and STAT5 activation...
January 9, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28063015/innate-immunity-against-legionella-pneumophila-during-pulmonary-infections-in-mice
#6
REVIEW
Bonggoo Park, Gayoung Park, Jiyoung Kim, Seon Ah Lim, Kyung-Mi Lee
Legionella pneumophila is an etiological agent of the severe pneumonia known as Legionnaires' disease (LD). This gram-negative bacterium is thought to replicate naturally in various freshwater amoebae, but also replicates in human alveolar macrophages. Inside host cells, legionella induce the production of non-endosomal replicative phagosomes by injecting effector proteins into the cytosol. Innate immune responses are first line defenses against legionella during early phases of infection, and distinguish between legionella and host cells using germline-encoded pattern recognition receptors such as Toll-like receptors , NOD-like receptors, and RIG-I-like receptors, which sense pathogen-associated molecular patterns that are absent in host cells...
January 6, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28056926/edible-bird-s-nest-modulate-intracellular-molecular-pathways-of-influenza-a-virus-infected-cells
#7
Amin Haghani, Parvaneh Mehrbod, Nikoo Safi, Fadzilah A'ini Abd Kadir, Abdul Rahman Omar, Aini Ideris
BACKGROUND: Edible Bird's Nest (EBN) as a popular traditional Chinese medicine is believed to have health enhancing and antiviral activities against influenza A virus (IAV); however, the molecular mechanism behind therapeutic effects of EBN is not well characterized. METHODS: In this study, EBNs that underwent different enzymatic preparation were tested against IAV infected cells. 50% cytotoxic concentration (CC50) and 50% inhibitory concentration (IC50) of the EBNs against IAV strain A/Puerto Rico/8/1934(H1N1) were determined by HA and MTT assays...
January 5, 2017: BMC Complementary and Alternative Medicine
https://www.readbyqxmd.com/read/28043862/rapid-and-facile-quantitation-of-polyplex-endocytic-trafficking
#8
Mihael Lazebnik, Daniel W Pack
Design of safe and effective synthetic nucleic acid delivery vectors such as polycation/DNA or polycation/siRNA complexes (polyplexes) will be facilitated by quantitative understanding of the mechanisms by which such materials escort cargo from the cell surface to the nucleus. In particular, the mechanisms of cellular internalization by various endocytosis pathways and subsequent endocytic vesicle trafficking have been shown to strongly affect nucleic acid delivery efficiency. Fluorescence microscopy and subcellular fractionation methods are commonly employed to follow intracellular trafficking of biomolecules and nanoparticulate delivery systems such as polyplexes...
December 31, 2016: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/28034633/glycol-chitosan-a-stabilizer-of-lipid-rafts-in-the-intestinal-brush-border
#9
E Thomas Danielsen, E Michael Danielsen
Chitosan is a polycationic polysaccharide consisting of β-(1-4)-linked glucosamine units and due to its mucoadhesive properties, chemical derivatives of chitosan are potential candidates as enhancers for transmucosal drug delivery. Recently, glycol chitosan (GC), a soluble derivative of chitosan, was shown to bind specifically to lipid raft domains in model bilayers. The small intestinal brush border membrane has a unique lipid raft composition with high amounts of glycolipids cross-linked by lectins, and the aim of the present work therefore was to study the interaction of FITC-conjugated GC (FITC-GC) with the small intestinal epithelium...
December 27, 2016: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28013071/from-fat-to-fat-cd36-sr-b2-understanding-the-regulation-of-cellular-fatty-acid-uptake
#10
Jan F C Glatz, Joost J F P Luiken
The molecular mechanisms underlying the cellular uptake of long-chain fatty acids and the regulation of this process have been elucidated in appreciable detail in the last decades. Two main players in this field, each discovered in the early 1990s, are (i) a membrane-associated protein first identified in adipose ('fat') tissue and referred to as putative fatty acid translocase (FAT)/CD36 (now officially designated as SR-B2) which facilitates the transport of fatty acids across the plasma membrane, and (ii) the family of transcription factors designated peroxisome proliferator-activated receptors (PPARα, PPARγ, and PPARβ/δ) for which fatty acids and fatty acid metabolites are the preferred ligand...
December 21, 2016: Biochimie
https://www.readbyqxmd.com/read/28006827/an-automated-image-analysis-system-to-quantify-endosomal-tubulation
#11
Timothy M Newton, Evan Reid
Recycling of cargos from early endosomes requires regulation of endosomal tubule formation and fission. This regulation is disrupted in cells depleted of the microtubule severing enzyme spastin, causing elongation of endosomal tubules and mis-trafficking of recycling endosomal cargos such as the transferrin receptor. Spastin is encoded by SPAST, mutations in which are the most frequent cause of autosomal dominant hereditary spastic paraplegia, a condition characterised by a progressive loss of lower limb function resulting from upper motor neuron axonopathy...
2016: PloS One
https://www.readbyqxmd.com/read/28003861/rei-1-a-novel-rab11-gef-with-a-sh3bp5-domain
#12
Aisa Sakaguchi, Miyuki Sato, Ken Sato
The small GTPase Rab proteins are key regulators of membrane trafficking. Rab11 is one of the best-characterized molecules among the Rab family proteins and it plays multiple roles in endocytic recycling, exocytosis, and cytokinesis. However, it remains unclear how Rab11 is activated at a precise timing and location and regulates its diverse functions. Specifically, our knowledge of the upstream regulatory factors that activate Rab11 is limited. In this regard, we have identified the RAB-11-interacting protein-1 (REI-1) as a novel guanine nucleotide exchange factor (GEF) for RAB-11 in Caenorhabditis elegans (C...
2016: Communicative & Integrative Biology
https://www.readbyqxmd.com/read/28003220/recycling-of-apolipoprotein-a-after-plgrkt-mediated-endocytosis-of-lipoprotein-a
#13
Monika Sharma, Gregory M Redpath, Michael J Williams, Sally P McCormick
RATIONALE: Lipoprotein(a) [Lp(a)] is a low density lipoprotein (LDL)-like lipoprotein and important cardiovascular risk factor whose cognate receptor and intracellular fate remains unknown. OBJECTIVE: Our study aimed to determine the intracellular trafficking pathway for Lp(a) and the receptor responsible for its uptake in liver cells. METHODS AND RESULTS: Human hepatoma (HepG2) cells were treated with Lp(a) purified from human plasma and Lp(a) uptake studied using western blot analysis and intracellular localisation of Lp(a) by confocal microscopy...
December 21, 2016: Circulation Research
https://www.readbyqxmd.com/read/28000370/amyloid-precursor-protein-traffics-from-the-golgi-directly-to-early-endosomes-in-an-arl5b-and-ap4-dependent-pathway
#14
Wei Hong Toh, Jing Zhi A Tan, Khalisah L Zulkefli, Fiona J Houghton, Paul A Gleeson
The intracellular trafficking and proteolytic processing of the membrane-bound amyloid precursor protein (APP) are co-ordinated events leading to the generation of pathogenic amyloid-beta (Aβ) peptides. The membrane transport of newly synthesised APP from the Golgi to the endolysosomal system is not well defined, yet is likely to be critical for regulating its processing by β-secretase (BACE1) and γ-secretase. Here we show that the majority of newly synthesised APP is transported from the trans-Golgi network (TGN) directly to early endosomes and then subsequently to the late endosomes/lysosomes with very little transported to the cell surface...
December 20, 2016: Traffic
https://www.readbyqxmd.com/read/27999198/tumour-derived-exosomes-as-a-signature-of-pancreatic-cancer-liquid-biopsies-as-indicators-of-tumour-progression
#15
REVIEW
Zarin Nuzhat, Vyjayanthi Kinhal, Shayna Sharma, Gregory E Rice, Virendra Joshi, Carlos Salomon
Pancreatic cancer is the fourth most common cause of death due to cancer in the world. It is known to have a poor prognosis, mostly because early stages of the disease are generally asymptomatic. Progress in pancreatic cancer research has been slow, leaving several fundamental questions pertaining to diagnosis and treatment unanswered. Recent studies highlight the putative utility of tissue-specific vesicles (i.e. extracellular vesicles) in the diagnosis of disease onset and treatment monitoring in pancreatic cancer...
December 16, 2016: Oncotarget
https://www.readbyqxmd.com/read/27974503/traffic-through-the-trans-golgi-network-and-the-endosomal-system-requires-collaboration-between-exomer-and-clathrin-adaptors-in-fission-yeast
#16
Marta Hoya, Francisco Yanguas, Sandra Moro, Cristina Prescianotto-Baschong, Cristina Doncel, Nagore de León, M-Ángeles Curto, Anne Spang, M-Henar Valdivieso
Despite its biological and medical relevance, traffic from the Golgi to the plasma membrane is one of the least understood steps of secretion. Exomer is a protein complex that mediates the trafficking of certain cargoes from the trans-Golgi network/early endosomes to the plasma membrane in budding yeast. Here we show that in Schizosaccharomyces pombe the Cfr1 and Bch1 proteins constitute the simplest form of an exomer. Cfr1 co-immunoprecipitates with AP-1, AP-2 and GGA subunits, and cfr1(+) interacts genetically with AP-1 and GGA genes...
December 14, 2016: Genetics
https://www.readbyqxmd.com/read/27943194/analyzing-endosomal-docking-fusion-sorting-and-budding-mechanisms-in-isolated-organelles
#17
Sina V Barysch, Ioanna Bethani
Due to their central role in the reception and sorting of newly internalized material, early endosomes undergo extensive membrane remodeling. They dock and fuse with endocytic carrier vesicles originating from the plasma membrane, sort the internalized material in internal microdomains, and allow the budding of new carrier vesicles from their membrane, destined to fuse with the plasma membrane (recycling) or other organelles. Early endosomal compartments might also be involved in the recycling of synaptic vesicles in nerve terminals...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/27941024/endosomal-phosphatidylinositol-3-phosphate-promotes-gephyrin-clustering-and-gabaergic-neurotransmission-at-inhibitory-postsynapses
#18
Theofilos Papadopoulos, Hong Jun Rhee, Devaraj Subramanian, Foteini Paraskevopoulou, Rainer Mueller, Carsten Schultz, Nils Brose, Jeong-Seop Rhee, Heinrich Betz
The formation of neuronal synapses and the dynamic regulation of their efficacy depends on the proper assembly of the postsynaptic neurotransmitter receptor apparatus. Receptor recruitment to inhibitory GABAergic postsynapses requires the scaffold protein gephyrin and the guanine nucleotide exchange factor collybistin (Cb)2. In vitro, the pleckstrin homology (PH) domain of Cb binds phosphoinositides, specifically phosphatidylinositol-3-phosphate (PI3P). However, whether PI3P is required for inhibitory postsynapse formation is currently unknown...
December 9, 2016: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/27930836/hepatitis-c-virus-infection-propagates-through-interactions-between-syndecan-1-and-cd81-and-impacts-the-hepatocyte-glycocalyx
#19
Boyan Grigorov, Emma Reungoat, Alice Gentil Dit Maurin, Mihayl Varbanov, Julie Blaising, Maud Michelet, Rachel Manuel, Romain Parent, Birke Bartosch, Fabien Zoulim, Florence Ruggiero, Eve-Isabelle Pécheur
The hepatitis C virus (HCV) infects hepatocytes after binding to heparan sulfate proteoglycans, in particular Syndecan-1, followed by recognition of the tetraspanin CD81 and other receptors. Heparan sulfate proteoglycans are found in a specific microenvironment coating the hepatocyte surface called the glycocalyx and are receptors for extracellular matrix proteins, cytokines, growth factors, lipoproteins, and infectious agents. We investigated the mutual influence of HCV infection on the glycocalyx and revealed new links between Syndecan-1 and CD81...
December 8, 2016: Cellular Microbiology
https://www.readbyqxmd.com/read/27927957/the-proteome-of-bloc-1-genetic-defects-identifies-the-arp2-3-actin-polymerization-complex-to-function-downstream-of-the-schizophrenia-susceptibility-factor-dysbindin-at-the-synapse
#20
Avanti Gokhale, Cortnie Hartwig, Amanda H Freeman, Ravi Das, Stephanie A Zlatic, Rachel Vistein, Amelia Burch, Guillemette Carrot, Arielle F Lewis, Sheldon Nelms, Dion K Dickman, Manojkumar A Puthenveedu, Daniel N Cox, Victor Faundez
: Proteome modifications downstream of monogenic or polygenic disorders have the potential to uncover novel molecular mechanisms participating in pathogenesis and/or extragenic modification of phenotypic expression. We tested this idea by determining the proteome sensitive to genetic defects in a locus encoding dysbindin, a protein required for synapse biology and implicated in schizophrenia risk. We applied quantitative mass spectrometry to identify proteins expressed in neuronal cells the abundance of which was altered after downregulation of the schizophrenia susceptibility factor dysbindin (Bloc1s8) or two other dysbindin-interacting polypeptides, which assemble into the octameric biogenesis of lysosome-related organelles complex 1 (BLOC-1)...
December 7, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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