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Yasir Mohamud, Junyan Shi, Junyan Qu, Tak Poon, Yuan Chao Xue, Haoyu Deng, Jingchun Zhang, Honglin Luo
Picornaviruses have evolved to hijack host cellular machinery, including the autophagic pathway. However, the mechanisms remain largely unclear. We use coxsackievirus B3 (CVB3) as a model organism to explore the possible role of picornavirus subversion of the autophagic pathway in viral infection. Our in vivo and in vitro experiments demonstrate that CVB3 infection causes a significant, albeit incomplete, inhibition of autophagic flux by limiting the fusion of autophagosomes with lysosomes and/or late endosomes...
March 20, 2018: Cell Reports
Julius A Edson, Dominique Ingato, Shirley Wu, Bianca Lee, Young Jik Kwon
Despite its promises for biomedical applications, the lack of solubility in a physiological solution, the limited molecular interactions with nucleic acids due to the rigid backbone, and the inefficient intracellular release limits the use of chitosan, a natural cationic polysaccharide, for gene delivery. In this study, a flexible, aqueous-soluble aminoethoxy branch was conjugated to the primary hydroxyl group of chitosan via an acid-cleavable ketal linkage, resulting in acid-transforming chitosan (ATC) with greatly increased aqueous solubility, improved siRNA complexation, and degradability in response to an acidic pH...
March 21, 2018: Biomacromolecules
Jie Han, Leslie A Goldstein, Wen Hou, Suman Chatterjee, Timothy F Burns, Hannah Rabinowich
Macroautophagy/autophagy has emerged as a resistance mechanism to anticancer drug treatments that induce metabolic stress. Certain tumors, including a subset of KRAS-mutant NSCLCs have been shown to be addicted to autophagy, and potentially vulnerable to autophagy inhibition. Currently, autophagy inhibition is being tested in the clinic as a therapeutic component for tumors that utilize this degradation process as a drug resistance mechanism. The current study provides evidence that HSP90 (heat shock protein 90) inhibition diminishes the expression of ATG7, thereby impeding the cellular capability of mounting an effective autophagic response in NSCLC cells...
March 21, 2018: Autophagy
Shufang He, Weiwei Fan, Na Wu, Jingjing Zhu, Yunqiu Miao, Xiaran Miao, Feifei Li, Xinxin Zhang, Yong Gan
RNA interference (RNAi) technology has shown great promise for the treatment of cancer and other genetic disorders. Despite the efforts to increase the target tissue distribution, the safe and effective delivery of siRNA to the diseased cells with sufficient cytosolic transport is another critical factor for successful RNAi clinical application. Here, the constructed lipid-based liquid crystalline nanoparticles, called nano-Transformers, can transform the structure in the intracellular acidic environment, and perform high-efficient siRNA delivery for cancer treatment...
March 21, 2018: Nano Letters
Andrea E Toth, Piotr Siupka, Thomas J P Augustine, Susanne T Venø, Louiza B Thomsen, Torben Moos, Hannes T Lohi, Peder Madsen, Karin Lykke-Hartmann, Morten S Nielsen
Receptor- and adsorptive-mediated transport through brain endothelial cells (BEC) of the blood-brain barrier (BBB) involves a complex array of subcellular vesicular structures, the endo-lysosomal system. It consists of several types of vesicles, such as early, recycling, and late endosomes, retromer-positive structures, and lysosomes. Since this system is important for receptor-mediated transcytosis of drugs across brain capillaries, our aim was to characterise the endo-lysosomal system in BEC with emphasis on their interactions with astrocytes...
March 20, 2018: Molecular Neurobiology
Anish Sharda, Robert Flaumenhaft
Platelet granules are unique among secretory vesicles in both their content and their life cycle. Platelets contain three major granule types-dense granules, α-granules, and lysosomes-although other granule types have been reported. Dense granules and α-granules are the most well-studied and the most physiologically important. Platelet granules are formed in large, multilobulated cells, termed megakaryocytes, prior to transport into platelets. The biogenesis of dense granules and α-granules involves common but also distinct pathways...
2018: F1000Research
Indranil Sarkar, Ravendra Garg, Sylvia van Drunen Littel-van den Hurk
Respiratory syncytial virus (RSV) causes acute respiratory tract infections in infants, the elderly and immunocompromised individuals. No licensed vaccine is available against RSV. We previously reported that intranasal immunization of rodents and lambs with a RSV vaccine candidate (ΔF/TriAdj) induces protective immunity with a good safety profile. ΔF/TriAdj promoted innate immune responses in respiratory mucosal tissues in vivo, by local chemokine and cytokine production, as well as infiltration and activation of immune cells including macrophages...
March 17, 2018: Vaccine
Jeanne M Sisk, Matthew B Frieman, Carolyn E Machamer
Enveloped viruses gain entry into host cells by fusing with cellular membranes, a step that is required for virus replication. Coronaviruses, including the severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV) and infectious bronchitis virus (IBV), fuse at the plasma membrane or use receptor-mediated endocytosis and fuse with endosomes, depending on the cell or tissue type. The virus spike (S) protein mediates fusion with the host cell membrane. We have shown previously that an Abelson (Abl) kinase inhibitor, imatinib, significantly reduces SARS-CoV and MERS-CoV viral titres and prevents endosomal entry by HIV SARS S and MERS S pseudotyped virions...
March 20, 2018: Journal of General Virology
Qiaoxian Huang, Shengke Li, Yuan-Fu Ding, Hang Yin, Lian-Hui Wang, Ruibing Wang
Due to its outstanding capability to facilitate DNA condensation, transportation and endosomal escape, polyethylenimine (PEI) has been frequently studied for gene delivery. However, its molecular weight (M.W.) dependent transfection efficiency and cytotoxicity has severely limited its clinical application. To resolve this dilemma, a supramolecular strategy was developed for the first time, in which PEI with large M.W. (branched, 25 kDa) that has a satisfactory transfection efficiency, yet high non-specific cytotoxicity for gene delivery was wrapped with macrocyclic cucurbit[7]uril (CB[7])...
March 20, 2018: Biomaterials Science
Zeanap A Mabruk, Samrein B M Ahmed, Asha Caroline Thomas, Sally A Prigent
Preliminary screening data showed that the ShcD adaptor protein associates with the proto-oncogene RET receptor tyrosine kinase. In the present study, we aimed to investigate the molecular interaction between ShcD and RET in human neuroblastoma cells and study the functional impact of this interaction. We were able to show that ShcD immunoprecipitated with RET from SK-N-AS neuroblastoma cell lysates upon GDNF treatment. This result was validated by ShcD-RET co-localization, which was visualized using a fluorescence microscope...
March 2018: Biochemistry and Biophysics Reports
Juan F Aranda, Stefan Rathjen, Ludger Johannes, Carlos Fernández-Hernando
Retrograde transport (RT) allows cells the retrieval of receptors and other cellular cargoes to the Golgi contributing to the maintenance of cellular homeostasis. This transport route is also commonly used by several bacterial toxins to exert their deleterious actions on eukaryotic cells. While the retrograde transport process has been well characterized, the contribution of microRNAs (miRNAs) in regulating this cellular transport mechanism remains unknown. Here, we identified that the intronic miRNA family, miR-199a/b , coordinate genes regulating RT and endosome trafficking...
March 19, 2018: Molecular and Cellular Biology
Yaron Caspi, Cees Dekker
Cell division in most prokaryotes is mediated by the well-studied fts genes, with FtsZ as the principal player. In many archaeal species, however, division is orchestrated differently. The Crenarchaeota phylum of archaea features the action of the three proteins, CdvABC. This Cdv system is a unique and less-well-studied division mechanism that merits closer inspection. In vivo , the three Cdv proteins form a composite band that contracts concomitantly with the septum formation. Of the three Cdv proteins, CdvA is the first to be recruited to the division site, while CdvB and CdvC are thought to participate in the active part of the Cdv division machinery...
2018: Frontiers in Microbiology
Kelly Barford, Austin Keeler, Lloyd McMahon, Kathryn McDaniel, Chan Choo Yap, Christopher D Deppmann, Bettina Winckler
The development of the peripheral nervous system relies on long-distance signaling from target organs back to the soma. In sympathetic neurons, this long-distance signaling is mediated by target derived Nerve Growth Factor (NGF) interacting with its axonal receptor, TrkA. This ligand receptor complex internalizes into what is commonly referred to as the signaling endosome which is transported retrogradely to the soma and dendrites to mediate survival signaling and synapse formation, respectively. The molecular identity of signaling endosomes in dendrites has not yet been determined...
March 16, 2018: Scientific Reports
Yihong Ye
Secretion of proteins lacking leader sequence was deemed rare and unconventional, only accountable for the export of a limited number of clients by mechanisms that are poorly defined. However, recent studies have shown that many leaderless proteins misfolded in the cytoplasm can be selectively exported to extracellular milieu via an unconventional secretory path termed Misfolding-Associated Protein Secretion (MAPS). This process uses the surface of the endoplasmic reticulum (ER) as a platform to enrich abnormally folded polypeptides, and then transport them into the lumen of ER-associated late endosomes for subsequent secretion...
March 13, 2018: Seminars in Cell & Developmental Biology
Andrea K H Stavoe, Erika L F Holzbaur
Neurons are long-lived and highly polarized cells that depend on autophagy to maintain cellular homeostasis. The robust, constitutive biogenesis of autophagosomes in the distal axon occurs via a conserved pathway that is required to maintain functional synapses and prevent axon degeneration. Autophagosomes are formed de novo at the axon terminal in a stepwise assembly process, engulfing mitochondrial fragments, aggregated proteins, and bulk cytosol in what appears to be a nonselective uptake mechanism. Following formation, autophagosomes fuse with late endosomes/lysosomes and then are rapidly and efficiently transported along the axon toward the soma, driven by the microtubule motor cytoplasmic dynein...
March 13, 2018: Neuroscience Letters
Guillaume Dubeaux, Julie Neveu, Enric Zelazny, Grégory Vert
Plant roots forage the soil for iron, the concentration of which can be dramatically lower than those needed for growth. Soil iron uptake uses the broad metal spectrum IRT1 transporter that also transports zinc, manganese, cobalt, and cadmium. Sophisticated iron-dependent transcriptional regulatory mechanisms allow plants to tightly control the abundance of IRT1, ensuring optimal absorption of iron. Here, we uncover that IRT1 acts as a transporter and receptor (transceptor), directly sensing excess of its non-iron metal substrates in the cytoplasm, to regulate its own degradation...
March 15, 2018: Molecular Cell
Jeffrey Zielich, Elena Tzima, Eva Ayla Schröder, Faten Jemel, Barbara Conradt, Eric J Lambie
P5B ATPases are present in the genomes of diverse unicellular and multicellular eukaryotes, indicating that they have an ancient origin, and that they are important for cellular fitness. Inactivation of ATP13A2, one of the four human P5B ATPases, leads to early-onset Parkinson's disease (Kufor-Rakeb Syndrome). The presence of an invariant PPALP motif within the putative substrate interaction pocket of transmembrane segment M4 suggests that all P5B ATPases might have similar transport specificity; however, the identity of the transport substrate(s) remains unknown...
2018: PloS One
Nicola L D Overton, Axel A Brakhage, Andreas Thywißen, David W Denning, Paul Bowyer
Allergic bronchopulmonary aspergillosis (ABPA) in asthma is a severe, life-affecting disease that potentially affects over 4.8 million people globally. In the UK, ABPA is predominantly caused by the fungus Aspergillus fumigatus. Phagocytosis is important in clearance of this fungus, and Early Endosome Antigen 1 (EEA1) has been demonstrated to be involved in phagocytosis of fungi. We sought to investigate the role of EEA1 mutations and phagocytosis in ABPA. We used exome sequencing to identify variants in EEA1 associated with ABPA...
2018: PloS One
Da-Zhi Guo, Lin Xiao, Yi-Jun Liu, Chen Shen, Hui-Fang Lou, Yan Lv, Shu-Yi Pan
This study aimed to investigate the role of cathepsin D (CathD) in central nervous system (CNS) myelination and its possible mechanism. By using CathD knockout mice in conjunction with immunohistochemistry, immunocytochemistry and western blot assays, the myelination of the CNS and the development of oligodendrocyte lineage cells in vivo and in vitro were observed. Endocytosis assays, real-time-lapse experiments and total internal reflection fluorescence microscopy were used to demonstrate the location and movement of proteolipid protein in oligodendrocyte lineage cells...
March 16, 2018: Experimental & Molecular Medicine
Cristian De Gregorio, Paula Díaz, Rodrigo López-Leal, Patricio Manque, Felipe A Court
Exosomes are small (30-150 nm) vesicles of endosomal origin secreted by most cell types. Exosomes contain proteins, lipids, and RNA species including microRNA, mRNA, rRNA, and long noncoding RNAs. The mechanisms associated with exosome synthesis and cargo loading are still poorly understood. A role for exosomes in intercellular communication has been reported in physiological and pathological conditions both in vitro and in vivo. Previous studies have suggested that Schwann cell-derived exosomes regulate neuronal functions, but the mechanisms are still unclear...
2018: Methods in Molecular Biology
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