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https://www.readbyqxmd.com/read/29334397/recombinant-phosphatidylserine-binding-nanobodies-for-targeting-of-extracellular-vesicles-to-tumor-cells-a-plug-and-play-approach
#1
Sander A A Kooijmans, Jerney J J M Gitz-Francois, Raymond M Schiffelers, Pieter Vader
Extracellular vesicles (EVs) are increasingly being recognized as candidate drug delivery systems due to their ability to functionally transfer biological cargo between cells. However, manipulation of targeting properties of EVs through engineering of the producer cells can be challenging and time-consuming. As a novel approach to confer tumor targeting properties to isolated EVs, we generated recombinant fusion proteins of nanobodies against the epidermal growth factor receptor (EGFR) fused to phosphatidylserine (PS)-binding domains of lactadherin (C1C2)...
January 15, 2018: Nanoscale
https://www.readbyqxmd.com/read/29328651/enzymatic-cleavage-of-branched-peptides-for-targeting-mitochondria
#2
Hongjian He, Jiaqing Wang, Huaimin Wang, Ning Zhou, Dongsik Yang, Douglas R Green, Bing Xu
Most of the reported mitochondria targeting molecules are lipophilic and cationic, which may become cytotoxic with accumulation. Here we show enzymatic cleavage of branched peptides that carry negative charges for targeting mitochondria. Conjugating a well-established protein tag (i.e., FLAG-tag) to self-assembling motifs affords the pre-cursors that form micelles. Enzymatic cleavage of the hydrophilic FLAG motif (DDDDK) by enterokinase (ENTK) turns the micelles to nanofibers. After being taken up by cells, the micelles, upon the action of intracellular ENTK, turns into nanofibers to locate mainly at mitochondria...
January 12, 2018: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/29321591/respiratory-syncytial-virus-infection-changes-cargo-composition-of-exosome-released-from-airway-epithelial-cells
#3
Harendra Singh Chahar, Tiziana Corsello, Andrzej S Kudlicki, Narayana Komaravelli, Antonella Casola
Exosomes are microvesicles known to carry biologically active molecules, including RNA, DNA and proteins. Viral infections can induce profound changes in exosome composition, and exosomes have been implicated in viral transmission and pathogenesis. No information is current available regarding exosome composition and function during infection with Respiratory Syncytial Virus (RSV), the most important cause of lower respiratory tract infections in children. In this study, we characterized exosomes released from RSV-infected lung carcinoma-derived A549 cells...
January 10, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29321502/the-peroxisomal-aaa-atpase-pex1-pex6-unfolds-substrates-by-processive-threading
#4
Brooke M Gardner, Dominic T Castanzo, Saikat Chowdhury, Goran Stjepanovic, Matthew S Stefely, James H Hurley, Gabriel C Lander, Andreas Martin
Pex1 and Pex6 form a heterohexameric motor essential for peroxisome biogenesis and function, and mutations in these AAA-ATPases cause most peroxisome-biogenesis disorders in humans. The tail-anchored protein Pex15 recruits Pex1/Pex6 to the peroxisomal membrane, where it performs an unknown function required for matrix-protein import. Here we determine that Pex1/Pex6 from S. cerevisiae is a protein translocase that unfolds Pex15 in a pore-loop-dependent and ATP-hydrolysis-dependent manner. Our structural studies of Pex15 in isolation and in complex with Pex1/Pex6 illustrate that Pex15 binds the N-terminal domains of Pex6, before its C-terminal disordered region engages with the pore loops of the motor, which then processively threads Pex15 through the central pore...
January 10, 2018: Nature Communications
https://www.readbyqxmd.com/read/29321391/-prothymosin%C3%AE-as-a-neuroprotective-damps-alarmins-molecule
#5
Hiroshi Ueda, Shiori Maeda
Prothymosin alpha (ProTα) has been identified as an anti-necrotic factor from the conditioned medium of primary cultured of rat cortical neurons under the serum-free starving condition. ProTα is released in a non-vesicular manner from neurons or astrocytes by the help of cargo protein S100A13. Thus released ProTα is found to have robustness roles in the brain under the condition of neuronal necrosis or apoptosis. ProTα inhibits necrosis by plasma membrane-translocation of glucose transporters endocytosed by ischemia/starving stress, through an activation of unidentified G protein-coupled receptor and protein kinase Cβ...
2018: Nihon Yakurigaku Zasshi. Folia Pharmacologica Japonica
https://www.readbyqxmd.com/read/29321327/human-papillomavirus-16-infection-induces-vap-dependent-endosomal-tubulation
#6
Abida Siddiqa, Paola Massimi, David Pim, Justyna Broniarczyk, Lawrence Banks
Human Papillomavirus (HPV) infection involves complex interactions with the endocytic transport machinery, which ultimately facilitates the entry of the incoming viral genomes into the trans-Golgi network and their subsequent nuclear entry during mitosis. The endosomal pathway is a highly dynamic intracellular transport system, which consists of vesicular compartments and tubular extensions, although it is currently unclear whether incoming viruses specifically alter the endocytic machinery. In this study, using MICAL-L1 as a marker for tubulating endosomes, we show that incoming HPV-16 virions induce a profound alteration in global levels of endocytic tubulation...
January 10, 2018: Journal of Virology
https://www.readbyqxmd.com/read/29320704/extracellular-vesicles-provide-a-means-for-tissue-crosstalk-during-exercise
#7
Martin Whitham, Benjamin L Parker, Martin Friedrichsen, Janne R Hingst, Marit Hjorth, William E Hughes, Casey L Egan, Lena Cron, Kevin I Watt, Rhiannon P Kuchel, Navind Jayasooriah, Emma Estevez, Tim Petzold, Catherine M Suter, Paul Gregorevic, Bente Kiens, Erik A Richter, David E James, Jørgen F P Wojtaszewski, Mark A Febbraio
Exercise stimulates the release of molecules into the circulation, supporting the concept that inter-tissue signaling proteins are important mediators of adaptations to exercise. Recognizing that many circulating proteins are packaged in extracellular vesicles (EVs), we employed quantitative proteomic techniques to characterize the exercise-induced secretion of EV-contained proteins. Following a 1-hr bout of cycling exercise in healthy humans, we observed an increase in the circulation of over 300 proteins, with a notable enrichment of several classes of proteins that compose exosomes and small vesicles...
January 9, 2018: Cell Metabolism
https://www.readbyqxmd.com/read/29317286/the-a-enth-domain-containing-protein-ateca4-is-an-adaptor-protein-involved-in-cargo-recycling-from-the-trans-golgi-network-early-endosome-to-the-plasma-membrane
#8
Hong Hanh Nguyen, Myoung Hui Lee, Kyungyoung Song, Gyeongik Ahn, Jihyeong Lee, Inhwan Hwang
Endocytosis and subsequent trafficking pathways are crucial for regulating the activity of plasma membrane-localized proteins. Depending on cellular and physiological conditions, the internalized cargoes are sorted at (and transported from) the trans-Golgi network/early endosome (TGN/EE) to the vacuole for degradation or recycled back to the plasma membrane. How this occurs at the molecular level remains largely elusive. Here we provide evidence that the ENTH domain-containing protein AtECA4 plays a crucial role in recycling cargoes from the TGN/EE to the plasma membrane...
January 6, 2018: Molecular Plant
https://www.readbyqxmd.com/read/29313416/dicot-specific-atg8-interacting-ati3-proteins-interact-with-conserved-ubac2-proteins-and-play-critical-roles-in-plant-stress-responses
#9
Jie Zhou, Zhe Wang, Xiaoting Wang, Xifeng Li, Zhenchao Zhang, Baofang Fan, Cheng Zhu, Zhixiang Chen
Selective macroautophagy/autophagy targets specific cargo by autophagy receptors through interaction with ATG8 (autophagy-related protein 8)/MAP1LC3 (microtubule associated protein 1 light chain 3) for degradation in the vacuole. Here, we report the identification and characterization of 3 related ATG8-interacting proteins (AT1G17780/ATI3A, AT2G16575/ATI3B and AT1G73130/ATI3C) from Arabidopsis. ATI3 proteins contain a WxxL LC3-interacting region (LIR) motif at the C terminus required for interaction with ATG8...
January 9, 2018: Autophagy
https://www.readbyqxmd.com/read/29313356/sub-cellular-nanorheology-reveals-lysosomal-viscosity-as-a-reporter-for-lysosomal-storage-diseases
#10
John Devany, Kasturi Chakraborty, Yamuna Krishnan
We describe a new method to measure viscosity within sub-cellular organelles of a living cell using nanorheology. We demonstrate proof of concept by measuring viscosity in lysosomes in multiple cell types and disease models. The lysosome is an organelle, which is responsible for the breakdown of complex biomolecules. When different lysosomal proteins are defective, they are unable to breakdown specific biological substrates, that get stored within the lysosome, causing about 70 fatal diseases called lysosomal storage disorders (LSDs)...
January 9, 2018: Nano Letters
https://www.readbyqxmd.com/read/29313030/poly-2-propylacrylic-acid-poly-lactic-co-glycolic-acid-blend-microparticles-as-a-targeted-antigen-delivery-system-to-direct-either-cd4-or-cd8-t-cell-activation
#11
Lirong Yang, Evelyn Bracho-Sanchez, Lawrence P Fernando, Jamal S Lewis, Matthew R Carstens, Craig L Duvall, Benjamin G Keselowsky
Poly(lactic-co-glycolic acid) (PLGA) based microparticles (MPs) are widely investigated for their ability to load a range of molecules with high efficiency, including antigenic proteins, and release them in a controlled manner. Micron-sized PLGA MPs are readily phagocytosed by antigen presenting cells, and localized to endosomes. Due to low pH and digestive enzymes, encapsulated protein cargo is largely degraded and processed in endosomes for MHC-II loading and presentation to CD4+ T cells, with very little antigen delivered into the cytosol, limiting MHC-I antigenic loading and presentation to CD8+ T cells...
June 2017: Bioengineering & Translational Medicine
https://www.readbyqxmd.com/read/29313023/virus-like-particles-next-generation-nanoparticles-for-targeted-therapeutic-delivery
#12
REVIEW
Marcus J Rohovie, Maya Nagasawa, James R Swartz
Most drug therapies distribute the agents throughout the entire body, even though the drugs are typically only needed at specific tissues. This often limits dosage and causes discomfort and harmful side-effects. Significant research has examined nanoparticles (NPs) for use as targeted delivery vehicles for therapeutic cargo, however, major clinical success has been limited. Current work focuses mainly on liposomal and polymer-based NPs, but emerging research is exploring the engineering of viral capsids as noninfectious protein-based NPs-termed virus-like particles (VLPs)...
March 2017: Bioengineering & Translational Medicine
https://www.readbyqxmd.com/read/29311697/mechanistic-insights-into-the-role-of-prenyl-binding-protein-prbp-%C3%AE-in-membrane-dissociation-of-phosphodiesterase-6
#13
Bilal M Qureshi, Andrea Schmidt, Elmar Behrmann, Jörg Bürger, Thorsten Mielke, Christian M T Spahn, Martin Heck, Patrick Scheerer
Isoprenylated proteins are associated with membranes and their inter-compartmental distribution is regulated by solubilization factors, which incorporate lipid moieties in hydrophobic cavities and thereby facilitate free diffusion during trafficking. Here we report the crystal structure of a solubilization factor, the prenyl-binding protein (PrBP/δ), at 1.81 Å resolution in its ligand-free apo-form. Apo-PrBP/δ harbors a preshaped, deep hydrophobic cavity, capacitating apo-PrBP/δ to readily bind its prenylated cargo...
January 8, 2018: Nature Communications
https://www.readbyqxmd.com/read/29305420/in-vitro-reconstitution-functional-dissection-and-mutational-analysis-of-metal-ion-transport-by-mitoferrin-1
#14
Eric T Christenson, Austin S Gallegos, Anirban Banerjee
Iron is universally important to cellular metabolism and mitoferrins-1 and -2 have been proposed to be the iron importers of mitochondria, the cell's assembly plant of heme and iron-sulfur clusters. These iron-containing prosthetic groups are critical for a host of physiological processes ranging from oxygen transport and energy consumption to maintaining protein structural integrity. Mitoferrin-1 (Mfrn1) belongs to the mitochondrial carrier (MC) family and is atypical given its putative metallic cargo; most MCs transport nucleotides, amino acids, or other small to medium-size metabolites...
January 5, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29305410/evolution-of-tools-and-methods-for-monitoring-autophagic-flux-in-mammalian-cells
#15
REVIEW
Kevin C Yang, Paalini Sathiyaseelan, Cally Ho, Sharon M Gorski
Autophagy is an evolutionarily conserved lysosome-mediated degradation and recycling process, which functions in cellular homeostasis and stress adaptation. The process is highly dynamic and involves autophagosome synthesis, cargo recognition and transport, autophagosome-lysosome fusion, and cargo degradation. The multistep nature of autophagy makes it challenging to quantify, and it is important to consider not only the number of autophagosomes within a cell but also the autophagic degradative activity. The rate at which cargos are recognized, segregated, and degraded through the autophagy pathway is defined as autophagic flux...
January 5, 2018: Biochemical Society Transactions
https://www.readbyqxmd.com/read/29304346/nrf2-mediates-the-expression-of-bag3-and-autophagy-cargo-adaptor-proteins-and-tau-clearance-in-an-age-dependent-manner
#16
Maoping Tang, Changyi Ji, Susanne Pallo, Irfan Rahman, Gail V W Johnson
During aging, decreased efficiency of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activation and autophagic processes in the brain may be a contributing factor in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease. Therefore, we analyzed the expression of Bcl-2-associated athanogene 3, a cochaperone that mediates autophagy, and the autophagy adaptors NBR1, NDP52, and sequestosome 1/p62 in the brains of 4-, 8-, and 12-month-old wild-type and Nrf2 knockout (-/-) mice. We also analyzed the levels of total tau and phospho-tau species...
December 9, 2017: Neurobiology of Aging
https://www.readbyqxmd.com/read/29304174/importin-%C3%AE-1-is-required-for-nuclear-import-of-herpes-simplex-virus-proteins-and-capsid-assembly-in-fibroblasts-and-neurons
#17
Katinka Döhner, Ana Ramos-Nascimento, Dagmara Bialy, Fenja Anderson, Ana Hickford-Martinez, Franziska Rother, Thalea Koithan, Kathrin Rudolph, Anna Buch, Ute Prank, Anne Binz, Stefanie Hügel, Robert Jan Lebbink, Rob C Hoeben, Enno Hartmann, Michael Bader, Rudolf Bauerfeind, Beate Sodeik
Herpesviruses are large DNA viruses which depend on many nuclear functions, and therefore on host transport factors to ensure specific nuclear import of viral and host components. While some import cargoes bind directly to certain transport factors, most recruit importin β1 via importin α. We identified importin α1 in a small targeted siRNA screen to be important for herpes simplex virus (HSV-1) gene expression. Production of infectious virions was delayed in the absence of importin α1, but not in cells lacking importin α3 or importin α4...
January 5, 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29302779/glia-to-neuron-transfer-of-mirnas-via-extracellular-vesicles-a-new-mechanism-underlying-inflammation-induced-synaptic-alterations
#18
Ilaria Prada, Martina Gabrielli, Elena Turola, Alessia Iorio, Giulia D'Arrigo, Roberta Parolisi, Mariacristina De Luca, Marco Pacifici, Mattia Bastoni, Marta Lombardi, Giuseppe Legname, Dan Cojoc, Annalisa Buffo, Roberto Furlan, Francesca Peruzzi, Claudia Verderio
Recent evidence indicates synaptic dysfunction as an early mechanism affected in neuroinflammatory diseases, such as multiple sclerosis, which are characterized by chronic microglia activation. However, the mode(s) of action of reactive microglia in causing synaptic defects are not fully understood. In this study, we show that inflammatory microglia produce extracellular vesicles (EVs) which are enriched in a set of miRNAs that regulate the expression of key synaptic proteins. Among them, miR-146a-5p, a microglia-specific miRNA not present in hippocampal neurons, controls the expression of presynaptic synaptotagmin1 (Syt1) and postsynaptic neuroligin1 (Nlg1), an adhesion protein which play a crucial role in dendritic spine formation and synaptic stability...
January 4, 2018: Acta Neuropathologica
https://www.readbyqxmd.com/read/29299530/evidence-that-the-plasmodium-falciparum-protein-sortilin-potentially-acts-as-an-escorter-for-the-trafficking-of-the-rhoptry-associated-membrane-antigen-to-the-rhoptries
#19
Stéphanie Hallée, Justin A Boddey, Alan F Cowman, Dave Richard
The rhoptry organelle is critical for the invasion of an erythrocyte by the malaria parasite Plasmodium falciparum. Despite their critical roles, the mechanisms behind their biogenesis are still poorly defined. Our earlier work had suggested that the interaction between the glycosylphosphatidylinositol (GPI)-anchored rhoptry-associated membrane antigen (RAMA) and the soluble rhoptry-associated protein 1 was involved in the transport of the latter from the Golgi apparatus to the rhoptry. However, how this protein complex could interact with the intracellular trafficking machinery was unknown at this stage...
January 2018: MSphere
https://www.readbyqxmd.com/read/29299164/xpo1-target-occupancy-measurements-confirm-the-selinexor-recommended-phase-2-dose
#20
Marsha L Crochiere, Stefan Hannus, Kerrin Hansen, Frank Becker, Erkan Baloglu, Margaret Lee, Michael Kauffman, Sharon Shacham, Yosef Landesman
XPO1 (exportin 1) is the main nuclear export protein with over 200 different protein cargos. XPO1 is overexpressed in tumor cells and high levels are correlated with poor prognosis. Selective Inhibitor of Nuclear Export (SINE) compounds block nuclear export by inhibiting XPO1. The first SINE compound, selinexor, shows promising anti-cancer activity across hematological and solid tumors in Phase 2 and 3 clinical trials. The 2nd generation SINE compound KPT-8602 is being evaluated as an anti-cancer agent in a Phase 1 clinical trial...
December 15, 2017: Oncotarget
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