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Sharon A Tooze
The fusion of autophagosomes with lysosomes is an obligatory step in the self-eating process of autophagy. In this issue, Kumar et al. (2018. J. Cell Biol. identify a protein complex, the autophagosome recognition particle (ARP), that chaperones a key SNARE, syntaxin 17, to the autophagosome membrane. Intriguingly, this protein complex coordinates both delivery and membrane insertion as a prelude to fusion.
February 15, 2018: Journal of Cell Biology
Lang Tian, Yeyi Yang, Chunyun Li, Jia Chen, Zhuoying Li, Xin Li, Shentang Li, Fang Wu, Zhangxue Hu, Zuocheng Yang
Coxsackievirus B3 (CVB3) is an important human pathogen linked to cardiac arrhythmias and acute heart failure. CVB3 infection has been reported to induce the formation of autophagosomes that support the viral replication in host cells. Interestingly, our study shows that the accumulation of autophagosomes during CVB3 infection is caused by a blockage of autophagosome-lysosome fusion rather than the induction of autophagosome biogenesis. Moreover, CVB3 decreases the transcription and translation of syntaxin 17 (STX17), a SNARE (soluble N-ethylmaleimide-sensitive factor activating protein receptor) protein involved in autophagosome-lysosome fusion...
February 14, 2018: Cell Death & Disease
Petra Ebner, Isabella Poetsch, Luiza Deszcz, Thomas Hoffmann, Johannes Zuber, Fumiyo Ikeda
Autophagy has an important role in cellular homeostasis by degrading and recycling cytotoxic components. Ubiquitination is known to target cargoes for autophagy; however, key components of this pathway remain elusive. Here we performed an RNAi screen to uncover ubiquitin modifiers that are required for starvation-induced macroautophagy in mammalian cells. Our screen uncovered BRUCE/Apollon/Birc6, an IAP protein, as a new autophagy regulator. Depletion of BRUCE leads to defective fusion of autophagosomes and lysosomes...
February 9, 2018: Nature Communications
Suresh Kumar, Ashish Jain, Farzin Farzam, Jingyue Jia, Yuexi Gu, Seong Won Choi, Michal H Mudd, Aurore Claude-Taupin, Michael J Wester, Keith A Lidke, Tor-Erik Rusten, Vojo Deretic
Autophagy is a conserved eukaryotic process with metabolic, immune, and general homeostatic functions in mammalian cells. Mammalian autophagosomes fuse with lysosomes in a SNARE-driven process that includes syntaxin 17 (Stx17). How Stx17 translocates to autophagosomes is unknown. In this study, we show that the mechanism of Stx17 recruitment to autophagosomes in human cells entails the small guanosine triphosphatase IRGM. Stx17 directly interacts with IRGM, and efficient Stx17 recruitment to autophagosomes requires IRGM...
February 2, 2018: Journal of Cell Biology
Haocheng Nan, Lili Han, Jiequn Ma, Chengcheng Yang, Rujuan Su, Jianjun He
Syntaxin 3, also known as STX3, is a protein encoded by the STX3 gene in humans. This protein is one of the fundamental components of the exocytotic machinery required for the docking and fusion of secretory granules with the plasma membrane. The roles of STX3 in human breast cancer remains elusive. Here we report that STX3 acts as an oncogenic protein in human breast cancer. We analyzed the expression of STX3 in 148 patients with breast cancer. The mRNA and protein levels of STX3 are significantly up-regulated in human breast cancer compared with matched adjacent non-cancer tissues...
January 31, 2018: Biochimica et Biophysica Acta
T Bonfiglio, G Olivero, M Vergassola, L Di Cesare Mannelli, A Pacini, F Iannuzzi, M Summa, R Bertorelli, M Feligioni, C Ghelardini, A Pittaluga
The effect of "prophylactic" environmental stimulation on clinical symptoms and presynaptic defects in mice suffering from the experimental autoimmune encephalomyelitis (EAE) at the acute stage of disease (21 ± 1 days post immunization, d.p.i.) was investigated. In EAE mice raised in an enriched environment (EE), the clinical score was reduced when compared to EAE mice raised in standard environment (SE).Concomitantly, gain of weight and increased spontaneous motor activity and curiosity were observed, suggesting increased well-being in mice...
February 2, 2018: Neuropharmacology
Selma Angèlica Serra, Gemma G Gené, Xabier Elorza-Vidal, José M Fernández-Fernández
Modulation of CaV 2.1 channel activity plays a key role in interneuronal communication and synaptic plasticity. SNAREs interact with a specific synprint site at the second intracellular loop (LII-III) of the CaV 2.1 pore-forming α1A subunit to optimize neurotransmitter release from presynaptic terminals by allowing secretory vesicles docking near the Ca2+ entry pathway, and by modulating the voltage dependence of channel steady-state inactivation. Ca2+ influx through CaV 2.1 also promotes channel inactivation...
January 2018: Physiological Reports
Yun Kwon, Jinbo Shen, Myoung Hui Lee, Kyoung Rok Geem, Liwen Jiang, Inhwan Hwang
Protein trafficking is a fundamental mechanism of subcellular organization and contributes to organellar biogenesis. AtCAP2 is an Arabidopsis homolog of the Mesembryanthemum crystallinum calcium-dependent protein kinase 1 adaptor protein 2 (McCAP2), a member of the syntaxin superfamily. Here, we show that AtCAP2 plays an important role in the conversion to the lytic vacuole (LV) during early plant development. The AtCAP2 loss-of-function mutant atcap2-1 displayed delays in protein storage vacuole (PSV) protein degradation, PSV fusion, LV acidification, and biosynthesis of several vacuolar proteins during germination...
January 29, 2018: Proceedings of the National Academy of Sciences of the United States of America
Adekunle T Bademosi, Elsa Lauwers, Rumelo Amor, Patrik Verstreken, Bruno van Swinderen, Frédéric A Meunier
An increasing number of super-resolution microscopy techniques are helping to uncover the mechanisms that govern the nanoscale cellular world. Single-molecule imaging is gaining momentum as it provides exceptional access to the visualization of individual molecules in living cells. Here, we describe a technique that we developed to perform single-particle tracking photo-activated localization microscopy (sptPALM) in Drosophila larvae. Synaptic communication relies on key presynaptic proteins that act by docking, priming, and promoting the fusion of neurotransmitter-containing vesicles with the plasma membrane...
January 14, 2018: Journal of Visualized Experiments: JoVE
Erika N Sutanto, Amelia Scaffidi, Luke W Garratt, Kevin Looi, Clara J Foo, Michela A Tessari, Richard A Janssen, David F Fischer, Stephen M Stick, Anthony Kicic
BACKGROUND: Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene can reduce function of the CFTR ion channel activity and impair cellular chloride secretion. The gold standard method to assess CFTR function of ion transport using the Ussing chamber requires a high number of airway epithelial cells grown at air-liquid interface, limiting the application of this method for high throughput screening of potential therapeutic compounds in primary airway epithelial cells (pAECs) featuring less common CFTR mutations...
2018: PloS One
Subhankar Dolai, Tao Liang, Abrahim I Orabi, Douglas Holmyard, Li Xie, Dafna Greitzer-Antes, Youhou Kang, Huanli Xie, Tanveer A Javed, Patrick P Lam, Deborah C Rubin, Peter Thorn, Herbert Y Gaisano
BACKGROUND & AIMS: Pancreatic acinar cells are polarized epithelial cells that store enzymes required for digestion as inactive zymogens, tightly packed at the cell apex. Stimulation of acinar cells causes the zymogen granules to fuse with the apical membrane, and the cells undergo exocytosis to release proteases into the intestinal lumen. Autophagy maintains homeostasis of pancreatic acini. Syntaxin 2 (STX2), an abundant SNARE protein in pancreatic acini, has been reported to mediate apical exocytosis...
January 19, 2018: Gastroenterology
Nan Zhang, Zhongyi Li, Fuding Bai, Na Ji, Yichun Zheng, Yi Li, Jimin Chen, Xiawa Mao
Although alterations in microRNA (miRNA) expression have been previously investigated prostate cancer, the expression of miRNAs specifically in benign prostate hyperplasia (BPH) of the prostatic stroma remains to be fully elucidated. In the present study, miRNAs and gene expression profiles were investigated using microarray analysis and reverse transcription quantitative‑polymerase chain reaction (RT‑qPCR) in BPH tissue to clarify the associations between miRNA expression and target genes. Prostate tissue samples from five patients with BPH and five healthy men were analyzed using human Affymetrix miRNA and mRNA microarrays and differentially expressed miRNAs were validated using RT‑qPCR with 30 BPH and 5 healthy control samples...
December 19, 2017: Molecular Medicine Reports
Chong Ding, Xin Cong, Yan Zhang, Sheng-Lin Li, Li-Ling Wu, Guang-Yan Yu
Autologous submandibular gland transplantation is an effective treatment for severe dry eye syndrome. However, the protein secretion in transplanted gland is altered by a mechanism that remains to be elucidated. In the present study, we found that β1-adrenoceptor (b1-AR) and β2-AR expression and the phosphorylation of the downstream molecule protein kinase A (PKA) were elevated in transplanted submandibular glands obtained from epiphora patients. Synaptobrevin/vesicle-associated membrane protein 2 (VAMP-2) interacted with syntaxin-4 and actin in human submandibular gland...
January 22, 2018: Bioscience Reports
Guillaume Alain Castillon, Patricia Burriat-Couleru, Daniel Abegg, Nina Criado Santos, Reika Watanabe
Recently studies in animal models demonstrate potential roles for clathrin and AP1 in apical protein sorting in epithelial tissue. However, the precise functions of these proteins in apical protein transport remain unclear. Here, we reveal mis-targeting of endogenous GPI-APs and soluble secretory proteins in MDCK cells upon clathrin heavy chain or AP1 subunit knockdown (KD). Using a novel directional endocytosis and recycling assay, we found that these KD cells are not only affected for apical sorting of GPI-APs in biosynthetic pathway but also for their apical recycling and basal to apical transcytosis routes...
January 20, 2018: Traffic
Jinchao Zhang, Yunjie Huang, Jing Chen, Haining Zhu, Sidney W Whiteheart
Platelets regulate vascular integrity by secreting a host of molecules that promote hemostasis and its sequelae. Given the importance of platelet exocytosis, it is critical to understand how it is controlled. The t-SNAREs, SNAP-23 and syntaxin-11, lack classical transmembrane domains (TMDs), yet both are associated with platelet membranes and redistributed into cholesterol-dependent, lipid rafts when platelets were activated. Using metabolic labeling and hydroxylamine/HCl (HA) treatment, we showed that both contain thioester-linked acyl groups...
January 19, 2018: Journal of Biological Chemistry
Inga Baasch Christensen, Esben Nees Mogensen, Helle Hasager Damkier, Jeppe Praetorius
The choroid plexus epithelial cells (CPECs) belong to a small group of polarized cells, where the Na+,K+-ATPase is expressed in the luminal membrane. The basic polarity of the cells is, therefore, still debated. We investigated the subcellular distribution of an array of proteins known to play fundamental roles in either in establishing and maintaining basic cell polarity or the polarized delivery and recycling of plasma membrane proteins. Immunofluorescence histochemical analysis was applied to determine the subcellular localization of apical and basolateral membrane determinants...
January 10, 2018: American Journal of Physiology. Cell Physiology
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
Maria Borisovska
SNAREs and SNARE-binding accessory proteins are believed to be central molecular components of neurotransmitter release, although the precise sequence of molecular events corresponding to distinct physiological states is unclear. The mechanism of docking of vesicles to the plasma membrane remains elusive, as the anchoring protein residing on vesicles is unknown. Here I show that targeting small amounts of syntaxin to granules by transmembrane domain alteration leads to a substantial enhancement of syntaxin clustering beneath granules, as well as of morphological granule docking...
January 9, 2018: Scientific Reports
Subhankar Dolai, Tao Liang, Abrahim I Orabi, Li Xie, Douglas Holmyard, Tanveer A Javed, Nestor A Fernandez, Huanli Xie, Mark S Cattral, Debbie C Thurmond, Peter Thorn, Herbert Y Gaisano
Epithelial pancreatic acinar cells perform crucial functions in food digestion, and acinar cell homoeostasis required for secretion of digestive enzymes relies on SNARE-mediated exocytosis. The ubiquitously expressed Sec1/Munc18 protein mammalian uncoordinated-18c (Munc18c) regulates membrane fusion by activating syntaxin-4 (STX-4) to bind cognate SNARE proteins to form a SNARE complex that mediates exocytosis in many cell types. However, in the acinar cell, Munc18c's functions in exocytosis and homeostasis remain inconclusive...
December 28, 2017: Journal of Biological Chemistry
Badr M Rasheed Alsaleem, Amna Basheer M Ahmed, Musa Ahmad Fageeh
Microvillus inclusion disease (MVID) is a rare autosomal recessive congenital enteropathy characterized by intractable secretory diarrhea. We report a case of MVID variant with a homozygous gene mutation in syntaxin 3 (STX3). The patient is a male Saudi infant who presented shortly after birth with severe vomiting, metabolic acidosis, and mild diarrhea. Electron microscopy study for small intestinal biopsy was consistent with MVID. MYO5B gene mutation was excluded; subsequently, whole exome sequencing (WES) was performed, which revealed homozygous gene mutation in STX3...
September 2017: Case Reports in Gastroenterology
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