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Aleksandra Gil-Krzewska, Yousuke Murakami, Giovanna Peruzzi, Kevin J O'Brien, Melissa A Merideth, Andrew R Cullinane, William A Gahl, John E Coligan, Bernadette R Gochuico, Konrad Krzewski
Hermansky-Pudlak syndrome (HPS) encompasses disorders with abnormal function of lysosomes and lysosome-related organelles, and some patients who develop immunodeficiency. The basic mechanisms contributing to immune dysfunction in HPS are ill-defined. We analysed natural killer (NK) cells from patients diagnosed with HPS-1, HPS-2, HPS-4, and an unreported HPS subtype. NK cells from an HPS-2 and an unreported HPS subtype share a similar cellular phenotype with defective granule release and cytotoxicity, but differ in cytokine exocytosis...
October 21, 2016: British Journal of Haematology
Melanie Ott, Débora Marques, Christina Funk, Susanne M Bailer
BACKGROUND: Herpes simplex virus type 1 (HSV1), a member of the alphaherpesvirinae, can cause recurrent facial lesions and encephalitis. Two membrane envelopment processes, one at the inner nuclear membrane and a second at cytoplasmic membranes are crucial for a productive viral infection. Depending on the subfamily, herpesviruses encode more than 11 different transmembrane proteins including members of the tail-anchored protein family. HSV1 encodes three tail-anchored proteins pUL34, pUL56 and pUS9 characterized by a single hydrophobic region positioned at their C-terminal end that needs to be released from the ribosome prior to posttranslational membrane insertion...
October 20, 2016: Virology Journal
Emily R Troemel
Microsporidia comprise a phylum of obligate intracellular pathogens related to fungi that infect virtually all animals. Recently, the nematode Caenorhabditis elegans has been developed as a convenient model for studying microsporidia infection in a whole-animal host through the identification and characterization of a natural microsporidian pathogen of this commonly studied laboratory organism. The C. elegans natural microsporidian pathogen is named Nematocida parisii, and it causes a lethal intestinal infection in C...
October 2016: Microbiology Spectrum
Sayak Bhattacharya, Kevin E McElhanon, Liubov Gushchina, Noah Weisleder
Phosphatidylinositol-4,5-bisphosphate 3-kinases (PI3Ks) are regulatory enzymes involved in the generation of lipid species that modulate cellular signaling pathways through downstream effectors to influence a variety of cellular functions. Years of intensive study of PI3Ks have produced a significant body of literature in many areas, including that PI3K can mediate intracellular vesicular trafficking and through these actions contribute to a number of important physiological functions. This review focuses on the crucial roles that PI3K and AKT, a major downstream partner of PI3K, play in the regulation of vesicle trafficking during various forms of vesicular endocytosis and exocytosis...
October 16, 2016: Life Sciences
Emeline Puissant, Marielle Boonen
Osteoclasts are giant bone-resorbing cells originating from monocytes/macrophages. During their differentiation, they overexpress two lysosomal enzymes, cathepsin K and TRAP, which are secreted into the resorption lacuna, an acidified sealed area in contact with bone matrix where bone degradation takes place. Here we report that the acid hydrolase HYAL1, a hyaluronidase able to degrade the glycosaminoglycans hyaluronic acid (HA) and chondroitin sulfate, is also upregulated upon osteoclastogenesis. The mRNA expression and protein level of HYAL1 are markedly increased in osteoclasts differentiated from RAW264...
2016: PloS One
Wolfgang Löscher, Michel Gillard, Zara A Sands, Rafal M Kaminski, Henrik Klitgaard
The synaptic vesicle glycoprotein SV2A belongs to the major facilitator superfamily (MFS) of transporters and is an integral constituent of synaptic vesicle membranes. SV2A has been demonstrated to be involved in vesicle trafficking and exocytosis, processes crucial for neurotransmission. The anti-seizure drug levetiracetam was the first ligand to target SV2A and displays a broad spectrum of anti-seizure activity in various preclinical models. Several lines of preclinical and clinical evidence, including genetics and protein expression changes, support an important role of SV2A in epilepsy pathophysiology...
October 17, 2016: CNS Drugs
Xuejing Cui, Bin Wan, Liang-Hong Guo, Yu Yang, Xiao-Min Ren
Co-existence of nanomaterials and environmental pollutants requires in-depth understanding of combined toxicity and underlying mechanism. In this work, we found that co-exposure to the mixture of non-cytotoxic level of single-walled carbon nanotubes (SWCNTs) (10 µg/mL) and Ni2+ (20 µM) induced significant cytotoxicity in macrophages. However, almost equal amount of intracellular Ni2+ was detected after Ni2+/SWCNT co-exposure or Ni2+ single exposure, indicating no enhanced cellular uptake of Ni2+ occurred...
October 17, 2016: Environmental Science & Technology
Delyan R Mutavchiev, Marcin Leda, Kenneth E Sawin
The Rho family GTPase Cdc42 is a key regulator of eukaryotic cellular organization and cell polarity [1]. In the fission yeast Schizosaccharomyces pombe, active Cdc42 and associated effectors and regulators (the "Cdc42 polarity module") coordinate polarized growth at cell tips by controlling the actin cytoskeleton and exocytosis [2-4]. Localization of the Cdc42 polarity module to cell tips is thus critical for its function. Here we show that the fission yeast stress-activated protein kinase Sty1, a homolog of mammalian p38 MAP kinase, regulates localization of the Cdc42 polarity module...
October 1, 2016: Current Biology: CB
Z Schultzhaus, T B Johnson, B D Shaw
Cell growth necessitates extensive membrane remodeling events including vesicle fusion or fission, processes that are regulated by coat proteins. The hyphal cells of filamentous fungi concentrate both exocytosis and endocytosis at the apex. This investigation focuses on clathrin in Aspergillus nidulans, with the aim of understanding its role in membrane remodeling in growing hyphae. We examined clathrin heavy chain (ClaH-GFP) which localized to three distinct subcellular structures: late Golgi (trans-Golgi equivalents of filamentous fungi), which are concentrated just behind the hyphal tip but are intermittently present throughout all hyphal cells; the region of concentrated endocytosis just behind the hyphal apex (the "endocytic collar"); and small, rapidly moving puncta that were seen trafficking long distances in nearly all hyphal compartments...
October 14, 2016: Molecular Microbiology
Aneeqa Noor, Saadia Zahid
Synaptosomal-associated protein 25 kDa (SNAP-25) is one of the key proteins involved in formation of neural soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes, which are responsible for the calcium-dependent exocytosis of neurotransmitters - a major step in neurotransmission and the key to normal functioning of brain. Several studies have reported abnormalities in its expression and structure and highlighted it as an important player in pathology of various neurological disorders like Alzheimer's disease, schizophrenia, attention deficient hyperactivity disorder, epilepsy and few others...
October 13, 2016: International Journal of Neuroscience
Mahalakshmi Ramadass, Jennifer Linda Johnson, Sergio D Catz
Neutrophil secretory proteins are mediators of systemic inflammation in infection, trauma, and cancer. In response to specific inflammatory mediators, neutrophil granules are mobilized and cargo proteins released to modulate the microenvironment of inflammatory sites and tumors. In particular, GM-CSF, a cytokine secreted by several immune, nonimmune, and tumor cells, regulates neutrophil priming and exocytosis. Whereas a comprehensive understanding of this process is necessary to design appropriate anti-inflammatory therapies, the molecular effectors regulating GM-CSF-dependent priming of neutrophil exocytosis are currently unknown...
October 12, 2016: Journal of Leukocyte Biology
Seiji Takeuchi, Shintaro Iwama, Hiroshi Takagi, Atsushi Kiyota, Kohtaro Nakashima, Hisakazu Izumida, Haruki Fujisawa, Naoko Iwata, Hidetaka Suga, Takashi Watanabe, Kozo Kaibuchi, Yutaka Oiso, Hiroshi Arima, Yoshihisa Sugimura
Arginine vasopressin (AVP) is secreted via exocytosis; however, the precise molecular mechanism underlying the exocytosis of AVP remains to be elucidated. To better understand the mechanisms of AVP secretion, in our study we have identified proteins that bind with a 25 kDa synaptosomal-associated protein (SNAP25). SNAP25 plays a crucial role in exocytosis, in the posterior pituitary. Embryonic stem (ES) cell-derived AVP neurons were established to investigate the functions of the identified proteins. Using glutathione S-transferase (GST)-pulldown assays and proteomic analyses, we identified tomosyn-1 (syntaxin-binding protein 5) as a SNAP25-binding protein in the posterior pituitary...
2016: PloS One
Paulo S Pinheiro, Sébastien Houy, Jakob B Sørensen
The molecular mechanisms for calcium-triggered membrane fusion have long been sought for, and detailed models now exist that account for at least some of the functions of the many proteins involved in the process. Key players in the fusion reaction are a group of proteins that, upon binding to calcium, trigger the merger of cargo-filled vesicles with the plasma membrane. Low-affinity, fast-kinetics calcium sensors of the synaptotagmin family - especially synaptotagmin-1 and synaptotagmin-2 - are the main calcium sensors for fast exocytosis triggering in many cell types...
October 12, 2016: Journal of Neurochemistry
Nicola Strenzke, Rituparna Chakrabarti, Hanan Al-Moyed, Alexandra Müller, Gerhard Hoch, Tina Pangrsic, Gulnara Yamanbaeva, Christof Lenz, Kuan-Ting Pan, Elisabeth Auge, Ruth Geiss-Friedlander, Henning Urlaub, Nils Brose, Carolin Wichmann, Ellen Reisinger
The multi-C2 domain protein otoferlin is required for hearing and mutated in human deafness. Some OTOF mutations cause a mild elevation of auditory thresholds but strong impairment of speech perception. At elevated body temperature, hearing is lost. Mice homozygous for one of these mutations, Otof(I515T/I515T), exhibit a moderate hearing impairment involving enhanced adaptation to continuous or repetitive sound stimulation. In Otof(I515T/I515T) inner hair cells (IHCs), otoferlin levels are diminished by 65%, and synaptic vesicles are enlarged...
October 11, 2016: EMBO Journal
Olusoji A T Afuwape, Catherine R Wasser, Thomas Schikorski, Ege T Kavalali
Earlier studies suggest that spontaneous and evoked neurotransmitter release processes are maintained by synaptic vesicles which are segregated into functionally distinct pools. However, direct interrogation of the link between this putative synaptic vesicle pool heterogeneity and neurotransmission has been difficult. To examine this link, we tagged vesicles with horseradish peroxidase (HRP) - a heme containing plant enzyme - or antibodies against synaptotagmin-1 (syt1). Filling recycling vesicles in hippocampal neurons with HRP and subsequent treatment with hydrogen peroxide (H2 O2 ) modified the properties of neurotransmitter release depending on the route of HRP uptake...
October 10, 2016: Journal of Physiology
Henry Hui, Kathy A Fuller, Wendy N Erber, Matthew D Linden
Platelets are subcellular blood elements with a well-established role in haemostasis. Upon activation platelets undergo granule exocytosis, resulting in α-granule P-Selectin being expressed on the cell membrane. This allows binding of activated platelets to P-Selectin glycoprotein ligand 1 (PSGL-1) expressing leukocytes, forming leukocyte-platelet aggregates (LPAs). Whole blood flow cytometry (FCM) has demonstrated that elevated circulating LPAs (especially monocyte LPAs) are linked to atherothrombosis in high risk patients, and that activated platelet binding influences monocytes towards a pro-adhesive and pro-atherogenic phenotype...
October 5, 2016: Methods: a Companion to Methods in Enzymology
Melissa Frick, Pierre Mouchacca, Grégory Verdeil, Yannick Hamon, Cyrille Billaudeau, Michel Buferne, Mathieu Fallet, Nathalie Auphan-Anezin, Anne-Marie Schmitt-Verhulst, Claude Boyer
Cancer-germline genes in both human and mice have been shown to encode antigens susceptible to targeting by cytotoxic CD8 T effector cells (CTL). We analyzed the ability of CTL to kill different tumor cell lines expressing the same cancer-germline gene P1A (Trap1a). We previously demonstrated that CTL expressing a TCR specific for the P1A35-43 peptide associated with H-2L(d) , although able to induce regression of P1A-expressing P815 mastocytoma cells, were much less effective against P1A-expressing melanoma cells...
October 7, 2016: Immunology
C Kinnear, L Rodriguez-Lorenzo, M J D Clift, B Goris, S Bals, B Rothen-Rutishauser, A Petri-Fink
The impact of nanoparticles (NPs) upon biological systems can be fundamentally associated with their physicochemical parameters. A further often-stated tenet is the importance of NP shape on rates of endocytosis. However, given the convoluted parameters concerning the NP-cell interaction, it is experimentally challenging to attribute any findings to shape alone. Herein we demonstrate that shape, below a certain limit, which is specific to nanomedicine, is not important for the endocytosis of spherocylinders by either epithelial or macrophage cells in vitro...
September 15, 2016: Nanoscale
Tomohiro Mori, Nozomu Abe, Kazutomo Saito, Hiroaki Toyama, Yasuhiro Endo, Yutaka Ejima, Masanori Yamauchi, Mariko Goto, Hajime Mushiake, Itsuro Kazama
BACKGROUND: Besides their anti-inflammatory properties, corticosteroid drugs exert anti-allergic effects. Exocytosis of mast cells is electrophysiologically detected as the increase in the whole-cell membrane capacitance (Cm). Therefore, the lack of such increase after exposure to the drugs suggests their mast cell-stabilizing effects. METHODS: We examined the effects of 1, 10, 100 and 200μM hydrocortisone or dexamethasone on the degranulation from rat peritoneal mast cells...
September 5, 2016: Pharmacological Reports: PR
Ludmila A Kasatkina
4-aminopyridine is commonly used to stimulate neurotransmitter release resulting from sustained plasma membrane depolarization and Ca(2+)-influx from the extracellular space. This paper elucidated unconventional mechanism of 4-aminopyridine-stimulated glutamate release from neurons and non-neuronal cells which proceeds in the absence of external Ca(2+). In brain nerve terminals, primary neurons and platelets 4-aminopyridine induced the exocytotic release of glutamate that was independent of external Ca(2+) and was triggered by the sequestration of Ca(2+) from intracellular stores...
October 5, 2016: Scientific Reports
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