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Jinxie Zhang, Xudong Zhang, Gan Liu, Danfeng Chang, Xin Liang, Xianbing Zhu, Wei Tao, Lin Mei
The inner membrane vesicle system is a complex transport system that includes endocytosis, exocytosis and autophagy. However, the details of the intracellular trafficking pathway of nanoparticles in cells have been poorly investigated. Here, we investigate in detail the intracellular trafficking pathway of protein nanocapsules using more than 30 Rab proteins as markers of multiple trafficking vesicles in endocytosis, exocytosis and autophagy. We observed that FITC-labeled protein nanoparticles were internalized by the cells mainly through Arf6-dependent endocytosis and Rab34-mediated micropinocytosis...
2016: Theranostics
Otilia V Vieira
Disruption of the cell plasma membrane can occur due to mechanical damage, pore forming toxins, etc. Resealing or plasma membrane repair (PMR) is the emergency response required for cell survival. It is triggered by Ca(2+) entering through the disruption, causing organelles such as lysosomes located underneath the plasma membrane to fuse rapidly with the adjacent plasma membrane. We have recently identified some of the molecular traffic machinery that is involved in this vital process. Specifically, we showed that 2 members of the Rab family of small GTPases, Rab3a and Rab10, are essential for lysosome exocytosis and PMR in cells challenged with a bacterial toxin, streptolysin-O (SLO)...
September 29, 2016: Small GTPases
Patrick A Eyers
Protein kinases catalyse the addition of phosphate groups to Ser/Thr and Tyr residues in cognate substrates and are mutated or hyperactive in a variety of diseases, making them important targets for rationally designed drugs. A good example is the Parkinson's disease-associated kinase, leucine-rich repeat kinase 2 (LRRK2), which is mutated (and probably hyperactive) in a small, but significant, subset of patients. An exciting new approach for personalised therapy is the development of central nervous system (CNS)-active small-molecule kinase inhibitors, which could be employed to 'normalise' LRRK2 signalling in affected cell types...
September 15, 2016: Biochemical Journal
Genta Ito, Kristina Katsemonova, Francesca Tonelli, Pawel Lis, Marco A S Baptista, Natalia Shpiro, Graham Duddy, Steve Wilson, Philip Wing-Lok Ho, Shu-Leong Ho, Alastair D Reith, Dario R Alessi
Autosomal dominant mutations that activate the leucine-rich repeat kinase 2 (LRRK2) cause inherited Parkinson's disease. Recent work has revealed that LRRK2 directly phosphorylates a conserved threonine/serine residue in the effector-binding switch-II motif of a number of Rab GTPase proteins, including Rab10. Here we describe a facile and robust method to assess phosphorylation of endogenous Rab10 in mouse embryonic fibroblasts (MEFs), lung and spleen-derived B-cells, based on the ability of the Phos-tag reagent to retard the electrophoretic mobility of LRRK2-phosphorylated Rab10...
September 1, 2016: Biochemical Journal
Adam J Isabella, Sally Horne-Badovinac
Basement membranes (BMs) are planar protein networks that support epithelial function. Regulated changes to BM architecture can also contribute to tissue morphogenesis, but how epithelia dynamically remodel their BMs is unknown. In Drosophila, elongation of the initially spherical egg chamber correlates with the generation of a polarized network of fibrils in its surrounding BM. Here, we use live imaging and genetic manipulations to determine how these fibrils form. BM fibrils are assembled from newly synthesized proteins in the pericellular spaces between the egg chamber's epithelial cells and undergo oriented insertion into the BM by directed epithelial migration...
July 11, 2016: Developmental Cell
Ranjay Jayadev, David R Sherwood
In this issue of Developmental Cell, Isabella and Horne-Badovinac (2016) show that Rab10 directs site-specific secretion of basement membrane components, which assemble into fibrils that spool out to elongate the Drosophila egg chamber. These findings establish the basement membrane's active role in tissue sculpting.
July 11, 2016: Developmental Cell
Joanne Bruno, Alexandria Brumfield, Natasha Chaudhary, David Iaea, Timothy E McGraw
RAB10 is a regulator of insulin-stimulated translocation of the GLUT4 glucose transporter to the plasma membrane (PM) of adipocytes, which is essential for whole-body glucose homeostasis. We establish SEC16A as a novel RAB10 effector in this process. Colocalization of SEC16A with RAB10 is augmented by insulin stimulation, and SEC16A knockdown attenuates insulin-induced GLUT4 translocation, phenocopying RAB10 knockdown. We show that SEC16A and RAB10 promote insulin-stimulated mobilization of GLUT4 from a perinuclear recycling endosome/TGN compartment...
July 4, 2016: Journal of Cell Biology
Peixiang Wang, Hang Liu, Yu Wang, Ou Liu, Jing Zhang, Adenrele Gleason, Zhenrong Yang, Hui Wang, Anbing Shi, Barth D Grant
EHBP-1 (Ehbp1) is a conserved regulator of endocytic recycling, acting as an effector of small GTPases including RAB-10 (Rab10). Here we present evidence that EHBP-1 associates with tubular endosomal phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] enriched membranes through an N-terminal C2-like (NT-C2) domain, and define residues within the NT-C2 domain that mediate membrane interaction. Furthermore, our results indicate that the EHBP-1 central calponin homology (CH) domain binds to actin microfilaments in a reaction that is stimulated by RAB-10(GTP)...
June 2016: PLoS Genetics
Reema P Vazirani, Akanksha Verma, L Amanda Sadacca, Melanie S Buckman, Belen Picatoste, Muheeb Beg, Christopher Torsitano, Joanne H Bruno, Rajesh T Patel, Kotryna Simonyte, Joao P Camporez, Gabriela Moreira, Domenick J Falcone, Domenico Accili, Olivier Elemento, Gerald I Shulman, Barbara B Kahn, Timothy E McGraw
Insulin controls glucose uptake into adipose and muscle cells by regulating the amount of GLUT4 in the plasma membrane. The effect of insulin is to promote the translocation of intracellular GLUT4 to the plasma membrane. The small Rab GTPase, Rab10, is required for insulin-stimulated GLUT4 translocation in cultured 3T3-L1 adipocytes. Here we demonstrate that both insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane are reduced by about half in adipocytes from adipose-specific Rab10 knockout (KO) mice...
June 2016: Diabetes
Yuta Homma, Mitsunori Fukuda
Many aspects of membrane-trafficking events are regulated by Rab-family small GTPases. Neurite outgrowth requires massive addition of proteins and lipids to the tips of growing neurites by membrane trafficking, and although several Rabs, including Rab8, Rab10, and Rab11, have been implicated in this process, their regulatory mechanisms during neurite outgrowth are poorly understood. Here, we show that Rabin8, a Rab8-guanine nucleotide exchange factor (GEF), regulates nerve growth factor (NGF)-induced neurite outgrowth of PC12 cells...
July 1, 2016: Molecular Biology of the Cell
Hilary K Truchan, Chelsea L Cockburn, Kathryn S Hebert, Forgivemore Magunda, Susan M Noh, Jason A Carlyon
The genus Anaplasma consists of tick-transmitted obligate intracellular bacteria that invade white or red blood cells to cause debilitating and potentially fatal infections. A. phagocytophilum, a human and veterinary pathogen, infects neutrophils to cause granulocytic anaplasmosis. A. marginale invades bovine erythrocytes. Evidence suggests that both species may also infect endothelial cells in vivo. In mammalian and arthropod host cells, A. phagocytophilum and A. marginale reside in host cell derived pathogen-occupied vacuoles (POVs)...
2016: Frontiers in Cellular and Infection Microbiology
Paul Duffield Brewer, Estifanos N Habtemichael, Irina Romenskaia, Adelle C F Coster, Cynthia Corley Mastick
Insulin increases glucose uptake by increasing the rate of exocytosis of the facilitative glucose transporter isoform 4 (Glut4) relative to its endocytosis. Insulin also releases Glut4 from highly insulin-regulated secretory compartments (GSVs or Glut4 storage vesicles) into constitutively cycling endosomes. Previously it was shown that both overexpression and knockdown of the small GTP-binding protein Rab14 decreased Glut4 translocation to the plasma membrane (PM). To determine the mechanism of this perturbation, we measured the effects of Rab14 knockdown on the trafficking kinetics of Glut4 relative to two proteins that partially co-localize with Glut4, the transferrin (Tf) receptor and low-density-lipoprotein-receptor-related protein 1 (LRP1)...
May 15, 2016: Biochemical Journal
Wilhelm W Just, Johan Peränen
In this review article, we summarize current knowledge on peroxisome biogenesis/functions and the role that small GTPases may play in these processes. Precise intracellular distribution of cell organelles requires their regulated association to microtubules and the actin cytoskeleton. In this respect, RhoGDP/RhoGTP favor binding of peroxisomes to microtubules and actin filaments. In its GTP-bound form, RhoA activates a regulatory cascade involving Rho kinaseII and non-muscle myosinIIA. Such interactions frequently depend on phosphoinositides (PIs) of which PI4P, PI(4,5)P2, and PI(3,5)P2 were found to be present in the peroxisomal membrane...
May 2016: Biochimica et Biophysica Acta
Paul Duffield Brewer, Estifanos N Habtemichael, Irina Romenskaia, Cynthia Corley Mastick, Adelle C F Coster
The RabGAP AS160/TBC1D4 controls exocytosis of the insulin-sensitive glucose transporter Glut4 in adipocytes. Glut4 is internalized and recycled through a highly regulated secretory pathway in these cells. Glut4 also cycles through a slow constitutive endosomal pathway distinct from the fast transferrin (Tf) receptor recycling pathway. This slow constitutive pathway is the only Glut4 cycling pathway in undifferentiated fibroblasts. The α2-macroglobulin receptor LRP1 cycles with Glut4 and the Tf receptor through all three exocytic pathways...
January 8, 2016: Journal of Biological Chemistry
Wei Zou, Smita Yadav, Laura DeVault, Yuh Nung Jan, David R Sherwood
Formation of elaborately branched dendrites is necessary for the proper input and connectivity of many sensory neurons. Previous studies have revealed that dendritic growth relies heavily on ER-to-Golgi transport, Golgi outposts and endocytic recycling. How new membrane and associated cargo is delivered from the secretory and endosomal compartments to sites of active dendritic growth, however, remains unknown. Using a candidate-based genetic screen in C. elegans, we have identified the small GTPase RAB-10 as a key regulator of membrane trafficking during dendrite morphogenesis...
2015: PLoS Genetics
Ou Liu, Barth D Grant
The small GTPase RAB-5/Rab5 is a master regulator of the early endosome, required for a myriad of coordinated activities, including the degradation and recycling of internalized cargo. Here we focused on the recycling function of the early endosome and the regulation of RAB-5 by GAP protein TBC-2 in the basolateral C. elegans intestine. We demonstrate that downstream basolateral recycling regulators, GTPase RAB-10/Rab10 and BAR domain protein AMPH-1/Amphiphysin, bind to TBC-2 and help to recruit it to endosomes...
2015: PLoS Genetics
Hiroyuki Sano, Grantley R Peck, Stephanie Blachon, Gustav E Lienhard
Insulin increases glucose transport in fat and muscle cells by stimulating the exocytosis of specialized vesicles containing the glucose transporter GLUT4. This process, which is referred to as GLUT4 translocation, increases the amount of GLUT4 at the cell surface. Previous studies have provided evidence that insulin signaling increases the amount of Rab10-GTP in the GLUT4 vesicles and that GLUT4 translocation requires the exocyst, a complex that functions in the tethering of vesicles to the plasma membrane, leading to exocytosis...
September 25, 2015: Biochemical and Biophysical Research Communications
Scott M Vanderwerf, David C Buck, Phillip A Wilmarth, Leila M Sears, Larry L David, David B Morton, Kim A Neve
Lipid rafts are specialized, cholesterol-rich membrane compartments that help to organize transmembrane signaling by restricting or promoting interactions with subsets of the cellular proteome. The hypothesis driving this study was that identifying proteins whose relative abundance in rafts is altered by the abused psychostimulant methamphetamine would contribute to fully describing the pathways involved in acute and chronic effects of the drug. Using a detergent-free method for preparing rafts from rat brain striatal membranes, we identified density gradient fractions enriched in the raft protein flotillin but deficient in calnexin and the transferrin receptor, markers of non-raft membranes...
2015: PloS One
Hilary K Truchan, Lauren VieBrock, Chelsea L Cockburn, Nore Ojogun, Brian P Griffin, Dayanjan S Wijesinghe, Charles E Chalfant, Jason A Carlyon
Anaplasma phagocytophilum is an emerging human pathogen and obligate intracellular bacterium. It inhabits a host cell-derived vacuole and cycles between replicative reticulate cell (RC) and infectious dense-cored (DC) morphotypes. Host-pathogen interactions that are critical for RC-to-DC conversion are undefined. We previously reported that A. phagocytophilum recruits green fluorescent protein (GFP)-tagged Rab10, a GTPase that directs exocytic traffic from the sphingolipid-rich trans-Golgi network (TGN) to its vacuole in a guanine nucleotide-independent manner...
February 2016: Cellular Microbiology
Yanxin Zhao, Wei Tan, Wenhua Sheng, Xiaohong Li
BACKGROUND: This study aimed to explore the biomarkers of Alzheimer's disease (AD). METHODS: The microarray data of GSE16759 were from the expression profile samples of 4 parietal lobe tissues from patients with AD and 4 ones from age-matched control participants. The differentially expressed micro RNAs (miRNAs) and genes (DEGs) underwent hierarchical clustering and function analysis followed by target genes prediction. Finally, DEGs were mapped to the target genes to construct miRNA-regulated networks...
March 2016: American Journal of Alzheimer's Disease and Other Dementias
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