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Fumiyo Ikeda
The Inhibitor of Apoptosis (IAP) family member, BIRC6/BRUCE is a ubiquitin conjugating E2 enzyme and a well-established anti-apoptosis regulator. However, its role in mammalian autophagy has not been shown. We identified BIRC6 as an important positive regulator of macroautophagy/autophagy by performing an siRNA screen targeting enzymes in the ubiquitin pathway. Compared to wild-type cells, BIRC6-deficient cells show accumulation of lipidated LC3B both at basal and starved conditions. Furthermore, BIRC6 deficiency blocks starvation-induced autophagic flux monitored by a tandem fluorescent autophagy sensor, mCherry-GFP-LC3B...
June 21, 2018: Autophagy
Kohei Arasaki, Haruki Nagashima, Yuri Kurosawa, Hana Kimura, Naoki Nishida, Naoshi Dohmae, Akitsugu Yamamoto, Shigeru Yanagi, Yuichi Wakana, Hiroki Inoue, Mitsuo Tagaya
In fed cells, syntaxin 17 (Stx17) is associated with microtubules at the endoplasmic reticulum-mitochondria interface and promotes mitochondrial fission by determining the localization and function of the mitochondrial fission factor Drp1. Upon starvation, Stx17 dissociates from microtubules and Drp1, and binds to Atg14L, a subunit of the phosphatidylinositol 3-kinase complex, to facilitate phosphatidylinositol 3-phosphate production and thereby autophagosome formation, but the mechanism underlying this phenomenon remains unknown...
June 19, 2018: EMBO Reports
Oriol Ros, Pablo José Barrecheguren, Tiziana Cotrufo, Martina Schaettin, Cristina Roselló-Busquets, Alba Vílchez-Acosta, Marc Hernaiz-Llorens, Ramón Martínez-Marmol, Fausto Ulloa, Esther T Stoeckli, Sofia J Araújo, Eduardo Soriano
Axonal growth and guidance rely on correct growth cone responses to guidance cues. Unlike the signaling cascades that link axonal growth to cytoskeletal dynamics, little is known about the crosstalk mechanisms between guidance and membrane dynamics and turnover. Recent studies indicate that whereas axonal attraction requires exocytosis, chemorepulsion relies on endocytosis. Indeed, our own studies have shown that Netrin-1/Deleted in Colorectal Cancer (DCC) signaling triggers exocytosis through the SNARE Syntaxin-1 (STX1)...
June 18, 2018: PLoS Genetics
Tingsong Li, Min Cheng, Juan Wang, Siqi Hong, Mei Li, Shuang Liao, Lingling Xie, Yajun Qin, Li Jiang
OBJECTIVE: To detect syntaxin-binding protein 1 (STXBP1) mutations in Chinese patients with early onset epileptic encephalopathy (EOEE) of unknown etiology. METHODS: Targeted next-generation sequencing was used to identify STXBP1 mutations in 143 Chinese patients with EOEE of unknown etiology. A filtering process was applied to prioritize rare variants of potential functional significance. Then Sanger sequencing was employed to validate the parental origin of the variants...
June 13, 2018: Genes, Brain, and Behavior
Cristiana Perrotta, Davide Cervia, Ilaria Di Renzo, Claudia Moscheni, Maria Teresa Bassi, Lara Campana, Cristina Martelli, Elisabetta Catalani, Matteo Giovarelli, Silvia Zecchini, Marco Coazzoli, Annalisa Capobianco, Luisa Ottobrini, Giovanni Lucignani, Patrizia Rosa, Patrizia Rovere-Querini, Clara De Palma, Emilio Clementi
Tumor microenvironment is fundamental for cancer progression and chemoresistance. Among stromal cells tumor-associated macrophages (TAMs) represent the largest population of infiltrating inflammatory cells in malignant tumors, promoting their growth, invasion, and immune evasion. M2-polarized TAMs are endowed with the nitric oxide (NO)-generating enzyme inducible nitric oxide synthase (iNOS). NO has divergent effects on tumors, since it can either stimulate tumor cells growth or promote their death depending on the source of it; likewise the role of iNOS in cancer differs depending on the cell type...
2018: Frontiers in Immunology
Josep Rizo
Research for three decades and major recent advances have provided crucial insights into how neurotransmitters are released by Ca2+ -triggered synaptic vesicle exocytosis, leading to reconstitution of basic steps that underlie Ca2+ -dependent membrane fusion and yielding a model that assigns defined functions for central components of the release machinery. The SNAREs syntaxin-1, SNAP-25 and synaptobrevin-2 form a tight SNARE complex that brings the vesicle and plasma membranes together and is key for membrane fusion...
June 12, 2018: Protein Science: a Publication of the Protein Society
Maaike Schillemans, Ellie Karampini, Bart van den Eshof, Anastasia Gangaev, Menno Hofman, Dorothee van Breevoort, Henriët Meems, Hans Janssen, Aat A Mulder, Carolina R Jost, Johanna C Escher, Rüdiger Adam, Tom Carter, Abraham J Koster, Maartje van den Biggelaar, Jan Voorberg, Ruben Bierings
OBJECTIVE: Endothelial cells store VWF (von Willebrand factor) in rod-shaped secretory organelles, called Weibel-Palade bodies (WPBs). WPB exocytosis is coordinated by a complex network of Rab GTPases, Rab effectors, and SNARE (soluble NSF attachment protein receptor) proteins. We have previously identified STXBP1 as the link between the Rab27A-Slp4-a complex on WPBs and the SNARE proteins syntaxin-2 and -3. In this study, we investigate the function of syntaxin-3 in VWF secretion. APPROACH AND RESULTS: In human umbilical vein endothelial cells and in blood outgrowth endothelial cells (BOECs) from healthy controls, endogenous syntaxin-3 immunolocalized to WPBs...
June 7, 2018: Arteriosclerosis, Thrombosis, and Vascular Biology
Na-Ryum Bin, Ke Ma, Hidekiyo Harada, Chi-Wei Tien, Fiona Bergin, Kyoko Sugita, Thomas T Luyben, Masahiro Narimatsu, Zhengping Jia, Jeffrey L Wrana, Philippe P Monnier, Liang Zhang, Kenichi Okamoto, Shuzo Sugita
Trafficking of neurotransmitter receptors on postsynaptic membranes is critical for basal neurotransmission and synaptic plasticity, yet the underlying mechanisms remain elusive. Here, we investigated the role of syntaxin 4 in postsynaptic hippocampal CA1 neurons by analyzing conditional knockout (syntaxin 4 cKO) mice. We show that syntaxin 4 cKO resulted in reduction of basal neurotransmission without changes in paired-pulse ratios. Both α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartic acid (NMDA) receptor-mediated charge transfers were diminished...
June 5, 2018: Cell Reports
Ambra Lanzo, Bryan D Safratowich, Sirisha R Kudumala, Ivan Gallotta, Giuseppina Zampi, Elia Di Schiavi, Lucia Carvelli
The dopamine transporter (DAT) is a cell membrane protein whose main function is to reuptake the dopamine (DA) released in the synaptic cleft back into the dopaminergic neurons. Previous studies suggested that the activity of DAT is regulated by allosteric proteins such as Syntaxin-1A and is altered by drugs of abuse such as amphetamine (Amph). Because Caenorhabditis elegans expresses both DAT (DAT-1) and Syntaxin-1A (UNC-64), we used this model system to investigate the functional and behavioral effects caused by lack of expression of unc-64 in cultured dopaminergic neurons and in living animals...
2018: Frontiers in Physiology
António C Silva, Cristina Lemos, Francisco Q Gonçalves, Anna V Pliássova, Nuno J Machado, Henrique B Silva, Paula M Canas, Rodrigo A Cunha, João Pedro Lopes, Paula Agostinho
Alzheimer's disease (AD) begins with a deficit of synaptic function and adenosine A2A receptors (A2A R) are mostly located in synapses controlling synaptic plasticity. The over-activation of adenosine A2A receptors (A2A R) causes memory deficits and the blockade of A2A R prevents memory damage in AD models. We now enquired if this prophylactic role of A2A R might be extended to a therapeutic potential. We used the triple transgenic model of AD (3xTg-AD) and defined that the onset of memory dysfunction occurred at 4 months of age in the absence of locomotor or emotional alterations...
May 31, 2018: Neurobiology of Disease
Kunihiko Kanatsu, Yukiko Hori, Ihori Ebinuma, Yung Wen Chiu, Taisuke Tomita
The aberrant metabolism of amyloid-β protein (Aβ) in the human brain has been implicated in the etiology of Alzheimer disease (AD). γ-Secretase is the enzyme that generates various forms of Aβ, such as Aβ40 and Aβ42, the latter being an aggregation-prone toxic peptide that is involved in the pathogenesis of AD. Recently, we found that clathrin-mediated endocytosis of γ-secretase affects the production and deposition of Aβ42 in vivo, suggesting that the membrane trafficking of γ-secretase affects its enzymatic activity...
May 31, 2018: Journal of Neurochemistry
Takahide Matsui, Peidu Jiang, Saori Nakano, Yuriko Sakamaki, Hayashi Yamamoto, Noboru Mizushima
Macroautophagy is an evolutionarily conserved catabolic mechanism that delivers intracellular constituents to lysosomes using autophagosomes. To achieve degradation, lysosomes must fuse with closed autophagosomes. We previously reported that the soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) protein syntaxin (STX) 17 translocates to autophagosomes to mediate fusion with lysosomes. In this study, we report an additional mechanism. We found that autophagosome-lysosome fusion is retained to some extent even in STX17 knockout (KO) HeLa cells...
May 22, 2018: Journal of Cell Biology
Vijayakumar Govindaraj, Radhika Nagamangalam Shridharan, Addicam Jagannadha Rao
Although neonatal exposure to estrogen or estrogenic compounds results in irreversible changes in the brain function and reproductive abnormalities during adulthood but the underlying mechanisms are still largely unknown. The present study has attempted to compare the protein profiles of sexually dimorphic brain regions of adult female rats which were exposed to estradiol- 17β during neonatal period. The total proteins extracted from pre-optic area (POA), hypothalamus, hippocampus and pituitary of control and neonatally E2 treated female rats was subjected to 2D-SDS-PAGE and differentially expressed proteins were identification by MALDI TOF/TOF-MS...
May 16, 2018: General and Comparative Endocrinology
Claudia A Bertuccio, Tony T Wang, Kirk L Hamilton, Diego J Rodriguez-Gil, Steven B Condliffe, Daniel C Devor
We previously demonstrated endocytosis of KCa2.3 is caveolin-1-, dynamin II- and Rab5-dependent. KCa2.3 then enters Rab35/EPI64C- and RME-1-containing recycling endosomes and is returned to the plasma membrane (PM). Herein, we report on the mechanism by which KCa2.3 is inserted into the PM during recycling and following exit from the Golgi. We demonstrate KCa2.3 colocalizes with SNAP-23 and Syntaxin-4 in the PM of HEK and endothelial cells by confocal immunofluorescence microscopy. We further show KCa2.3 can be co-immunoprecipitated with SNAP-23 and Syntaxin-4...
2018: PloS One
Yuina Hirose, Kota Shirai, Yohei Hirai
Spatial and temporal epithelial-mesenchymal transition (EMT) is a critical event for the generation of asymmetric epithelial architectures. We found that only restricted cell populations in the morphogenic mammary epithelia extrude syntaxin-4, a plasmalemmal t-SNARE protein, and that epithelial cell clusters with artificial heterogenic presentation of extracellular syntaxin-4 undergo asymmetric morphogenesis. A previous study revealed that inducible expression of cell surface syntaxin-4 causes EMT-like cell behaviors in the clonal mammary epithelial cells, where laminin-mediated signals were abolished so that cells readily succumb to initiate EMT...
May 16, 2018: Journal of Cellular Biochemistry
Zsuzsanna Sasvari, Nikolay Kovalev, Paulina Alatriste Gonzalez, Kai Xu, Peter D Nagy
Positive-strand RNA viruses assemble numerous membrane-bound viral replicase complexes within large replication compartments to support their replication in infected cells. Yet the detailed mechanism of how given subcellular compartments are subverted by viruses is incompletely understood. Although, Tomato bushy stunt virus (TBSV) uses peroxisomal membranes for replication, in this paper, we show evidence that the ER-resident SNARE (soluble NSF attachment protein receptor) proteins play critical roles in the formation of active replicase complexes in yeast model host and in plants...
May 10, 2018: PLoS Pathogens
Xiaowen He, Yanhong Huo, Xiuxia Liu, Qianqian Zhou, Shouqian Feng, Xiang Shen, Baohua Li, Shujing Wu, Xuesen Chen
In plants, the vesicle fusion process plays a vital role in pathogen defence. However, the importance of the vesicle fusion process in apple ring rot has not been studied. Here, we isolated and characterised the apple syntaxin gene MdSYP121 . Silencing the MdSYP121 gene in transgenic apple calli increased tolerance to Botryosphaeria dothidea infection; this increased tolerance was correlated with salicylic acid (SA) synthesis-related and signalling-related gene transcription. In contrast, overexpressing MdSYP121 in apple calli resulted in the opposite phenotypes...
2018: Horticulture Research
Susumu Rokudai, Yingchun Li, Yukihiro Otaka, Michiru Fujieda, David M Owens, Angela M Christiano, Masahiko Nishiyama, Carol Prives
Levels of the N-terminally truncated isoform of p63 (ΔN p63), well documented to play a pivotal role in basal epidermal gene expression and epithelial maintenance, need to be strictly regulated. We demonstrate here that the anaphase-promoting complex/cyclosome (APC/C) complex plays an essential role in the ubiquitin-mediated turnover of ΔNp63α through the M-G1 phase. In addition, syntaxin-binding protein 4 (Stxbp4), which we previously discovered to bind to ΔNp63, can suppress the APC/C-mediated proteolysis of ΔNp63...
May 7, 2018: Proceedings of the National Academy of Sciences of the United States of America
Shunli Liu, Liyuan Wang, Xiao Tang Cai, Hui Zhou, Dan Yu, Zhiling Wang
RATIONALE: The case report aims to discuss the clinical symptoms and treatment of encephalopathy caused by a novel syntaxin- binding protein 1 (STXBP1) genetic mutation. PATIENT CONCERNS: The patient, a girl, was born at 38+4 weeks of gestation. She had frequent spasm attacks accompanied by obvious psychomotor development retardation since the neonatal period. Genetic screening identified a novel STXBP1 genetic mutation. DIAGNOSES: Early-onset epileptic encephalopathy with STXBP1 mutation...
May 2018: Medicine (Baltimore)
Takuya Kiyohara, Kei Miyano, Sachiko Kamakura, Junya Hayase, Kanako Chishiki, Akira Kohda, Hideki Sumimoto
Transmembrane glycoproteins, synthesized at the endoplasmic reticulum (ER), generally reach the Golgi apparatus in COPII-coated vesicles en route to the cell surface. Here, we show that the bona fide nonglycoprotein Nox5, a transmembrane superoxide-producing NADPH oxidase, is transported to the cell surface in a manner resistant to co-expression of Sar1 (H79G), a GTP-fixed mutant of the small GTPase Sar1, which blocks COPII vesicle fission from the ER. In contrast, Sar1 (H79G) effectively inhibits ER-to-Golgi transport of glycoproteins including the Nox5-related oxidase Nox2...
June 2018: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
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