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https://www.readbyqxmd.com/read/29452354/alpha-synuclein-inhibits-snx3-retromer-mediated-retrograde-recycling-of-iron-transporters-in-s-cerevisiae-and-c-elegans-models-of-parkinson-s-disease
#1
Dhaval Patel, Chuan Xu, Sureshbabu Nagarajan, Zhengchang Liu, Wayne O Hemphill, Runhua Shi, Vladimir N Uversky, Guy A Caldwell, Kim A Caldwell, Stephan N Witt
We probed the role of alpha-synuclein (α-syn) in modulating sorting nexin 3 (Snx3)-retromer-mediated recycling of iron transporters in Saccharomyces cerevisiae and Caenorhabditis elegans. In yeast, the membrane-bound heterodimer Fet3/Ftr1 is the high affinity iron importer. Fet3 is a membrane-bound multicopper ferroxidase, whose ferroxidase domain is orthologous to human ceruloplasmin (Cp), that oxidizes external Fe+2 to Fe+3; the Fe+3 ions then channel through the Ftr1 permease into the cell. When the concentration of external iron is low (< 1 µM), Fet3/Ftr1 is maintained on the plasma membrane by retrograde endocytic-recycling; whereas, when the concentration of external iron is high (> 10 µM), Fet3/Ftr1 is endocytosed and shunted to the vacuole for degradation...
February 14, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29444958/cdc48-and-ubiquilins-confer-selective-anterograde-protein-sorting-and-entry-into-the-multivesicular-body-in-yeast
#2
Rachel Kama, Galina Gabriely, Vydehi Kanneganti, Jeffrey E Gerst
Cdc48/p97 is known primarily for the retro-translocation of misfolded proteins in ER-associated protein degradation (ERAD). Here, we uncover a novel function for both Cdc48 and the conserved UBA-UBL ubiquitin receptor (ubiquilin) proteins in yeast ( e.g. Ddi1, Dsk2, Rad23), which deliver ubiquitinated proteins to the proteasome for degradation. We show that Cdc48, its core adaptors Npl4 and Ufd1, and the ubiquilins confer the constitutive anterograde delivery of carboxypeptidase S (Cps1), a membranal hydrolase, to the multivesicular body (MVB) and vacuolar lumen...
February 14, 2018: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29436780/autosomal-tubulointerstitial-kidney-disease-muc1-type-differential-proteomics-suggests-that-mutated-muc1-insc-affects-vesicular-transport-in-renal-epithelial-cells
#3
Simon Staubach, Andrea Wenzel, Bodo B Beck, Markus M Rinschen, Stefan Müller, Franz-Georg Hanisch
Autosomal dominant tubulointerstitial kidney disease associated to the MUC1 gene (ADTKD-MUC1; formerly MCKD1) belongs to a heterogenous group of rare hereditary kidney diseases that is prototypically caused by frameshift mutations in the MUC1 repeat domain. The mutant MUC1(insC) lacks the transmembrane domaine, exhibits aberant cellular topology and hence might gain a function during the pathological process. To get insight into potential pathomechanisms we performed differential proteomics of extracellular vesicles shed by renal epithelia into the urine of patients...
February 13, 2018: Proteomics
https://www.readbyqxmd.com/read/29427073/dissecting-the-biochemical-architecture-and-morphological-release-pathways-of-the-human-platelet-extracellular-vesiculome
#4
Silvia H De Paoli, Tseday Z Tegegn, Oumsalama K Elhelu, Michael B Strader, Mehulkumar Patel, Lukas L Diduch, Ivan D Tarandovskiy, Yong Wu, Jiwen Zheng, Mikhail V Ovanesov, Abdu Alayash, Jan Simak
Platelet extracellular vesicles (PEVs) have emerged as potential mediators in intercellular communication. PEVs exhibit several activities with pathophysiological importance and may serve as diagnostic biomarkers. Here, imaging and analytical techniques were employed to unveil morphological pathways of the release, structure, composition, and surface properties of PEVs derived from human platelets (PLTs) activated with the thrombin receptor activating peptide (TRAP). Based on extensive electron microscopy analysis, we propose four morphological pathways for PEVs release from TRAP-activated PLTs: (1) plasma membrane budding, (2) extrusion of multivesicular α-granules and cytoplasmic vacuoles, (3) plasma membrane blistering and (4) "pearling" of PLT pseudopodia...
February 9, 2018: Cellular and Molecular Life Sciences: CMLS
https://www.readbyqxmd.com/read/29410228/facile-metabolic-glycan-labeling-strategy-for-exosome-tracking
#5
Tae Sup Lee, Young Kim, Weiqi Zhang, In Ho Song, Ching-Hsuan Tung
BACKGROUND: Exosomes are nano-sized vesicles derived from the fusion of multivesicular bodies with the surrounding plasma membrane. Exosomes have various diagnostic and therapeutic potentials in cancer and other diseases, thus tracking exosomes is an important issue. METHODS: Here, we report a facile exosome labeling strategy using a natural metabolic incorporation of an azido-sugar into the glycan, and a strain-promoted azide-alkyne click reaction. In culture, tetra-acetylated N-azidoacetyl-D-mannosamine (Ac4ManNAz) was spontaneously incorporated into glycans within the cells and later redistributed onto their exosomes...
February 2, 2018: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/29403276/characterization-of-exosomes-derived-from-toxoplasma-gondii-and-their-functions-in-modulating-immune-responses
#6
Yawen Li, Yuan Liu, Fangming Xiu, Jianing Wang, Hua Cong, Shenyi He, Yongyu Shi, Xiaoyan Wang, Xun Li, Huaiyu Zhou
Introduction: Exosomes are nanograde membrane-bound vesicles secreted from most cell types through the fusion of multivesicular bodies with plasma membranes. Some of these exosomes are well defined, and are known to have immunomodulatory properties as well as play critical roles in intercellular communications. In this study, we characterized the exosomes derived from Toxoplasma gondii and their functions in aspect of immune responses. Methods: T. gondii exosomes were isolated and identified using electron microscopy, nanoparticle tracking analysis, and Western blotting...
2018: International Journal of Nanomedicine
https://www.readbyqxmd.com/read/29400984/antigen-presentation-by-extracellular-vesicles-from-professional-antigen-presenting-cells
#7
Marthe F S Lindenbergh, Willem Stoorvogel
The initiation and maintenance of adaptive immunity require multifaceted modes of communication between different types of immune cells, including direct intercellular contact, secreted soluble signaling molecules, and extracellular vesicles (EVs). EVs can be formed as microvesicles directly pinched off from the plasma membrane or as exosomes secreted by multivesicular endosomes. Membrane receptors guide EVs to specific target cells, allowing directional transfer of specific and complex signaling cues. EVs are released by most, if not all, immune cells...
January 31, 2018: Annual Review of Immunology
https://www.readbyqxmd.com/read/29386126/unconventional-trafficking-of-mammalian-phospholipase-d3-to-lysosomes
#8
Adriana Carolina Gonzalez, Michaela Schweizer, Sebastian Jagdmann, Christian Bernreuther, Thomas Reinheckel, Paul Saftig, Markus Damme
Variants in the phospholipase D3 (PLD3) gene have genetically been linked to late-onset Alzheimer's disease. We present a detailed biochemical analysis of PLD3 and reveal its endogenous localization in endosomes and lysosomes. PLD3 reaches lysosomes as a type II transmembrane protein via a (for mammalian cells) uncommon intracellular biosynthetic route that depends on the ESCRT (endosomal sorting complex required for transport) machinery. PLD3 is sorted into intraluminal vesicles of multivesicular endosomes, and ESCRT-dependent sorting correlates with ubiquitination...
January 23, 2018: Cell Reports
https://www.readbyqxmd.com/read/29385717/rhob-team-oncogene-or-team-tumor-suppressor
#9
REVIEW
Julia A Ju, Daniele M Gilkes
Although Rho GTPases RhoA, RhoB, and RhoC share more than 85% amino acid sequence identity, they play very distinct roles in tumor progression. RhoA and RhoC have been suggested in many studies to contribute positively to tumor development, but the role of RhoB in cancer remains elusive. RhoB contains a unique C-terminal region that undergoes specific post-translational modifications affecting its localization and function. In contrast to RhoA and RhoC, RhoB not only localizes at the plasma membrane, but also on endosomes, multivesicular bodies and has even been identified in the nucleus...
January 30, 2018: Genes
https://www.readbyqxmd.com/read/29381137/multivesicular-bodies-mediate-long-range-retrograde-ngf-trka-signaling
#10
Mengchen Ye, Kathryn M Lehigh, David D Ginty
The development of neurons in the peripheral nervous system is dependent on target-derived, long-range retrograde neurotrophic factor signals. The prevailing view is that target-derived nerve growth factor (NGF), the prototypical neurotrophin, and its receptor TrkA are carried retrogradely by early endosomes, which serve as TrkA signaling platforms in cell bodies. Here, we report that the majority of retrograde TrkA signaling endosomes in mouse sympathetic neurons are ultrastructurally- and molecularly-defined multivesicular bodies (MVBs)...
January 30, 2018: ELife
https://www.readbyqxmd.com/read/29376493/placental-exosomes-during-gestation-liquid-biopsies-carrying-signals-for-the-regulation-of-human-parturition
#11
Carlos Salomon, Zarin Nuzhat, Christopher L Dixon, Ramkumar Menon
Parturition is defined as the action or process of giving birth to offspring. Normal term human parturition ensues following the maturation of fetal organ systems typically between 37 and 40 weeks of gestation. Our conventional understanding of how parturition initiation is signaled revolves around feto-maternal immune and endocrine changes occurring in the intrauterine cavity. These changes in turn correlate with the sequence of fetal growth and development. These important physiological changes also result in homeostatic imbalances which result in heightened inflammatory signaling...
January 25, 2018: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29372401/exosomes-in-extracellular-matrix-bone-biology
#12
REVIEW
Adrienn Pethő, Yinghua Chen, Anne George
PURPOSE OF REVIEW: Exosomes are membrane vesicles that are released by most cell types into the extracellular environment. The purpose of this article is to discuss the main morphological features and contents of bone-derived exosomes, as well as their major isolation and physical characterization techniques. Furthermore, we present various scenarios and discuss potential clinical applications of bone-derived exosomes in bone repair and regeneration. RECENT FINDINGS: Exosomes were believed to be nanosized vesicles derived from the multivesicular body...
January 25, 2018: Current Osteoporosis Reports
https://www.readbyqxmd.com/read/29368980/tp53-is-required-for-becn1-and-atg5-dependent-cell-death-induced-by-sphingosine-kinase-1-inhibition
#13
Santiago Lima, Kazuaki Takabe, Jason Newton, Kumar Saurabh, Megan M Young, Andreia Machado Leopoldino, Nitai C Hait, Jane L Roberts, Hong-Gang Wang, Paul Dent, Sheldon Milstien, Laurence Booth, Sarah Spiegel
The bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) and the enzyme that produces it, SPHK1 (sphingosine kinase 1), regulate many processes important for the etiology of cancer. It has been suggested that SPHK1 levels are regulated by the tumor suppressor protein TP53, a key regulator of cell cycle arrest, apoptosis, and macroautophagy/autophagy. However, little is still known of the relationship between TP53 and SPHK1 activity in the regulation of these processes. To explore this link, we examined the effects of inhibiting SPHK1 in wild-type and TP53 null cancer cell lines...
January 25, 2018: Autophagy
https://www.readbyqxmd.com/read/29339438/quantifying-exosome-secretion-from-single-cells-reveals-a-modulatory-role-for-gpcr-signaling
#14
Frederik Johannes Verweij, Maarten P Bebelman, Connie R Jimenez, Juan J Garcia-Vallejo, Hans Janssen, Jacques Neefjes, Jaco C Knol, Richard de Goeij-de Haas, Sander R Piersma, S Rubina Baglio, Matthijs Verhage, Jaap M Middeldorp, Anoek Zomer, Jacco van Rheenen, Marc G Coppolino, Ilse Hurbain, Graça Raposo, Martine J Smit, Ruud F G Toonen, Guillaume van Niel, D Michiel Pegtel
Exosomes are small endosome-derived extracellular vesicles implicated in cell-cell communication and are secreted by living cells when multivesicular bodies (MVBs) fuse with the plasma membrane (PM). Current techniques to study exosome physiology are based on isolation procedures after secretion, precluding direct and dynamic insight into the mechanics of exosome biogenesis and the regulation of their release. In this study, we propose real-time visualization of MVB-PM fusion to overcome these limitations. We designed tetraspanin-based pH-sensitive optical reporters that detect MVB-PM fusion using live total internal reflection fluorescence and dynamic correlative light-electron microscopy...
January 16, 2018: Journal of Cell Biology
https://www.readbyqxmd.com/read/29331069/cellular-membrane-trafficking-machineries-utilized-by-the-hepatitis-viruses
#15
REVIEW
Jun Inoue, Masashi Ninomiya, Tooru Shimosegawa, Mark A McNiven
While the life cycles of hepatitis viruses (hepatitis A, B, C, D, and E viruses) have been modestly characterized, recent intensive studies have provided new insights. Because these viruses 'hijack' the membrane trafficking of the host cell machinery during replicative propagation, it is essential to determine and understand these specific cellular pathways. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are well known as a leading cause of liver cirrhosis and hepatocellular carcinoma. While substantial inroads toward treating HCV patients have recently been made, patients with HBV continue to require life-long treatment, which makes a thorough understanding of the HBV life cycle essential...
January 13, 2018: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/29237845/human-cytomegalovirus-replication-is-inhibited-by-the-autophagy-inducing-compounds-trehalose-and-smer28-through-distinctively-different-mechanisms
#16
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/29229612/targeting-tmbim1-alleviates-pathological-cardiac-hypertrophy
#17
Ke-Qiong Deng, Guang-Nian Zhao, Zhihua Wang, Jing Fang, Zhou Jiang, Jun Gong, Feng-Juan Yan, Xue-Yong Zhu, Peng Zhang, Zhi-Gang She, Hongliang Li
Background -Cardiac hypertrophy and its resultant heart failure are among the most common causes of mortality worldwide. Abnormal protein degradation, especially the impaired lysosomal degradation of large organelles and membrane proteins, is involved in the progression of cardiac hypertrophy. However, the underlying mechanisms have not been fully elucidated. Methods -We investigated cardiac TMBIM1 mRNA and protein expression levels in samples from patients with heart failure and mice with aortic banding (AB)-induced cardiac hypertrophy...
December 11, 2017: Circulation
https://www.readbyqxmd.com/read/29212874/the-na-k-h-exchanger-nhx1-controls-multivesicular-body-vacuolar-lysosome-fusion
#18
Mahmoud Abdul Karim, Christopher Leonard Brett
Loss-of-function mutations in human endosomal Na+(K+)/H+ Exchangers (NHEs) NHE6 and NHE9 are implicated in neurological disorders including Christianson Syndrome, autism and attention deficit and hyperactivity disorder (ADHD). These mutations disrupt retention of surface receptors within neurons and glial cells by affecting their delivery to lysosomes for degradation. However, the molecular basis of how these endosomal NHEs control endocytic trafficking is unclear. Using Saccharomyces cerevisiae as a model, we conducted cell-free organelle fusion assays to show that transport activity of the orthologous endosomal NHE Nhx1 is important for multivesicular body (MVB)-vacuolar lysosome fusion, the last step of endocytosis required for surface protein degradation...
December 6, 2017: Molecular Biology of the Cell
https://www.readbyqxmd.com/read/29212659/unconventional-secretion-of-fabp4-by-endosomes-and-secretory-lysosomes
#19
Julien Villeneuve, Laia Bassaganyas, Sebastien Lepreux, Marioara Chiritoiu, Pierre Costet, Jean Ripoche, Vivek Malhotra, Randy Schekman
An appreciation of the functional properties of the cytoplasmic fatty acid binding protein 4 (FABP4) has advanced with the recent demonstration that an extracellular form secreted by adipocytes regulates a wide range of physiological functions. Little, however, is known about the mechanisms that mediate the unconventional secretion of FABP4. Here, we demonstrate that FABP4 secretion is mediated by a membrane-bounded compartment, independent of the conventional endoplasmic reticulum-Golgi secretory pathway. We show that FABP4 secretion is also independent of GRASP proteins, autophagy, and multivesicular bodies but involves enclosure within endosomes and secretory lysosomes...
December 6, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29210491/multicompartment-vesicles-formation-by-emulsification-induced-assembly-of-poly-ethylene-oxide-block-poly-%C3%AE%C2%B5-caprolactone-and-their-dual-loading-capability
#20
Seon-Mi Jin, Jongseol Jeon, Mi-Kyoung Park, Geon Hee Kim, Eunji Lee
Emulsification-induced assembly is employed to allow structural diversity in nanoaggregates of a biocompatible amphiphilic polymer, poly(ethylene oxide)-block-poly(ε-caprolactone). Onion-like vesicles are efficiently produced by tuning the interfacial instability of the oil-in-water emulsion. The increase in the polymer concentration and use of the organic solvents with a low interfacial tension between water and the oil phase lead to a strong tendency of emulsion droplets to generate the onion-like vesicles...
December 6, 2017: Macromolecular Rapid Communications
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