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Grace Woodruff, Sol M Reyna, Mariah Dunlap, Rik Van Der Kant, Julia A Callender, Jessica E Young, Elizabeth A Roberts, Lawrence S B Goldstein
We investigated early phenotypes caused by familial Alzheimer's disease (fAD) mutations in isogenic human iPSC-derived neurons. Analysis of neurons carrying fAD PS1 or APP mutations introduced using genome editing technology at the endogenous loci revealed that fAD mutant neurons had previously unreported defects in the recycling state of endocytosis and soma-to-axon transcytosis of APP and lipoproteins. The endocytosis reduction could be rescued through treatment with a β-secretase inhibitor. Our data suggest that accumulation of β-CTFs of APP, but not Aβ, slow vesicle formation from an endocytic recycling compartment marked by the transcytotic GTPase Rab11...
October 11, 2016: Cell Reports
Jie Yin, Xiaocui Liu, Qing He, Lujun Zhou, Zengqiang Yuan, Siqi Zhao
Triggering receptor expressed on myeloid cells 2 (Trem2), an immune-modulatory receptor, is preferentially expressed in microglia of central nervous system. Trem2 might be involved in the development of Alzheimer's disease through regulating the inflammatory responses and phagocytosis of microglia. However, the intracellular trafficking of Trem2 remains unclear. In this study, we showed that Trem2 in the plasma membrane underwent endocytosis and recycling. Trem2 is internalized in a clathrin-dependent manner and then recycled back to the plasma membrane through Vps35, the key component of cargo recognition core of retromer complex, but not Rab11...
September 26, 2016: Traffic
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
Yuan-Chiang Chung, Wan-Chen Wei, Chia-Nung Hung, Jen-Fang Kuo, Chih-Ping Hsu, King-Jen Chang, Wei-Ting Chao
BACKGROUND: Collective cell migration, whereby the cell-cell contacts such as E-cadherin are maintained during migration, has only recently emerged and its detailed mechanisms are still unclear. In the present study, the role of Rab11, which functions in recycling endosomes, and its relationship to E-cadherin in colorectal carcinoma were identified, and the role of Rab11 in the collective cell migration of colon cancer cells was clarified. METHODS: A total of 107 patients with surgically resected colorectal carcinoma were enrolled in this immunohistochemical study...
October 3, 2016: European Journal of Clinical Investigation
Francisco J Calero-Cuenca, Sol Sotillos
A tight relationship between apico-basal polarity and trafficking is essential for epithelial physiology and tissue homeostasis. Recent studies have described how some Rab GTPases, key components of the intracellular traffic machinery, contribute to the establishment of cell polarity in vertebrates. We have demonstrated a novel connection between cell polarity and trafficking: in Drosophila epithelia, the apical determinant aPKC is recycled via Rab11-Nuf-recycling endosomes to maintain cell polarity. Furthermore, the phosphorylation of Nuf by aPKC allows aPKC to control the sub-cellular localization of Nuf and its own membrane accumulation...
September 29, 2016: Small GTPases
Praween Kumar Choubey, Jagat Kumar Roy
Rab11, a small monomeric GTPase associated with recycling endosomes, is a key molecule in the regulation of vesicular trafficking and is involved in the development and differentiation of many Drosophila tissues through interaction with diverse signaling pathways. In this study, we report for the first time that Rab11 affects endoreplication through a Ras-mediated pathway. Suppression of Rab11 activity in salivary glands, an endoreplicating tissue, leads to reduction in size of salivary glands with cells having a small nucleus...
September 27, 2016: Cell and Tissue Research
Christopher A Lamb, Andrea Longatti, Sharon A Tooze
Formation of autophagosomes requires vesicular trafficking from virtually every subcellular compartment to the formation site. This traffic must be tightly regulated but also adaptable as different membrane compartments will contribute varying amounts of membrane, lipids and proteins to the forming autophagosome depending on the stimulus. In mammalian cells, efforts to understand how autophagosomes form have been focused on the role of Rab proteins in autophagy. Rab proteins provide specificity through their interaction with coat proteins, vesicle tethers and SNAREs...
September 26, 2016: Small GTPases
Carlo Cosimo Campa, Emilio Hirsch
Rab11 and phosphoinositides are signal transducers able to direct the delivery of membrane components to the cell surface. Rab11 is a small GTPase that, by cycling from an active to an inactive state, controls key events of vesicular transport, while phosphoinositides are major determinants of membrane identity, modulating compartmentalized small GTPase function. By sharing common effectors, these two signal transducers synergistically direct vesicular traffic to specific intracellular membranes. This review focuses on the latest advances regarding the mechanisms that ensure the compartmentalized regulation of Rab11 function through its interaction with phosphoinositides...
September 14, 2016: Advances in Biological Regulation
Tone A Fykerud, Lars M Knudsen, Max Z Totland, Vigdis Sørensen, Shiva Dahal-Koirala, Ragnhild A Lothe, Andreas Brech, Edward Leithe
In order to achieve accurate chromosome segregation, eukaryotic cells undergo a dramatic change in morphology to obtain a spherical shape during mitosis. Interphase cells communicate directly with each other by exchanging ions and small molecules via gap junctions, which have important roles in controlling cell growth and differentiation. As cells round up during mitosis, the gap junctional communication between mitotic cells and adjacent interphase cells ceases. Whether mitotic cells use alternative mechanisms for mediating direct cell-cell communication during rounding is currently unknown...
September 13, 2016: Cell Cycle
Olena Pylypenko, Tobias Welz, Janine Tittel, Martin Kollmar, Florian Chardon, Gilles Malherbe, Sabine Weiss, Carina Ida Luise Michel, Annette Samol-Wolf, Andreas Till Grasskamp, Alistair Hume, Bruno Goud, Bruno Baron, Patrick England, Margaret A Titus, Petra Schwille, Thomas Weidemann, Anne Houdusse, Eugen Kerkhoff
There is growing evidence for a coupling of actin assembly and myosin motor activity in cells. However, mechanisms for recruitment of actin nucleators and motors on specific membrane compartments remain unclear. Here we report how Spir actin nucleators and myosin V motors coordinate their specific membrane recruitment. The myosin V globular tail domain (MyoV-GTD) interacts directly with an evolutionarily conserved Spir sequence motif. We determined crystal structures of MyoVa-GTD bound either to the Spir-2 motif or to Rab11 and show that a Spir-2:MyoVa:Rab11 complex can form...
2016: ELife
Yoshinobu Hara, Masahiro Fukaya, Kanehiro Hayashi, Takeshi Kawauchi, Kazunori Nakajima, Hiroyuki Sakagami
During neural development, endosomal trafficking controls cell shape and motility through the polarized transport of membrane proteins related to cell-cell and cell-extracellular matrix interactions. ADP ribosylation factor 6 (Arf6) is a critical small GTPase that regulates membrane trafficking between the plasma membrane and endosomes. We herein demonstrated that the knockdown of endogenous Arf6 in mouse cerebral cortices led to impaired neuronal migration in the intermediate zone and cytoplasmic retention of N-cadherin and syntaxin12 in migrating neurons...
July 2016: ENeuro
Benjamin M Schwenk, Hannelore Hartmann, Alperen Serdaroglu, Martin H Schludi, Daniel Hornburg, Felix Meissner, Denise Orozco, Alessio Colombo, Sabina Tahirovic, Meike Michaelsen, Franziska Schreiber, Simone Haupt, Michael Peitz, Oliver Brüstle, Clemens Küpper, Thomas Klopstock, Markus Otto, Albert C Ludolph, Thomas Arzberger, Peer-Hendrik Kuhn, Dieter Edbauer
Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces the number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43-knockdown neurons and decreased β2-transferrin levels in patient CSF Whole proteome quantification identified the upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons...
September 12, 2016: EMBO Journal
A L Dzierlenga, J D Clarke, N J Cherrington
Interindividual variability in drug response in nonalcoholic steatohepatitis (NASH) can be mediated by altered regulation of drug metabolizing enzymes and transporters. Among these is the mislocalization of multidrug resistance-associated protein (MRP2)/Mrp2 away from the canalicular membrane, which results in decreased transport of MRP2/Mrp2 substrates. The exact mechanism of this mislocalization is unknown, although increased activation of membrane retrieval processes may be one possibility. The current study measures the activation status of various mediators implicated in the active membrane retrieval or insertion of membrane proteins to identify which processes may be important in rodent methionine and choline deficient diet-induced NASH...
November 2016: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Govinda Sharma, Koji Tsutsumi, Taro Saito, Akiko Asada, Kanae Ando, Mineko Tomomura, Shin-Ichi Hisanaga
Neurite formation, a fundamental process in neuronal maturation, requires the coordinated regulation of cytoskeletal reorganization and membrane transport. Compared to the understanding of cytoskeletal functions, less is known about the supply of membranes to growing neurites. Lemur kinase 1A (LMTK1A) is an endosomal protein kinase that is highly expressed in neurons. We recently reported that LMTK1A regulates the trafficking of Rab11-positive recycling endosomes in growing axons and dendrites. Here, we used the kinase-negative (kn) mutant to investigate the role of the kinase activity of LMTK1A in its cellular localization and interactions with the cytoskeleton in Neuro2A and PC-12 cells...
October 2016: Genes to Cells: Devoted to Molecular & Cellular Mechanisms
Wei-Lun Hwang, Muh-Hwa Yang
The balance between the symmetric and asymmetric division of stem cells governs tissue homeostasis, and the deregulation of this balance initiates tumor formation. Although many functions of Numb have been demonstrated in normal stem cells, the role of Numb in cancer stem cells is relatively unclear. We recently demonstrated that in colorectal cancer stem cells, Numb was suppressed by miR-146a-5p, which resulted in the activation of the Wnt signaling pathway and symmetric template DNA division. Here, we demonstrate that the PKH26-labeled subcellular foci are enriched for endosomal markers such as EEA1 and RAB11...
October 17, 2016: Cell Cycle
Zhufeng Yang, Susan E Zimmerman, Jun Tsunezumi, Caitlin Braitsch, Cary Trent, David M Bryant, Ondine Cleaver, Consuelo González-Manchón, Denise K Marciano
Previous studies have shown CD34 family member Podocalyxin is required for epithelial lumen formation in vitro. We demonstrate that Endoglycan, a CD34 family member with homology to Podocalyxin, is produced prior to lumen formation in developing nephrons. Endoglycan localizes to Rab11-containing vesicles in nephron progenitors, and then relocalizes to the apical surface as progenitors epithelialize. Once an apical/luminal surface is formed, Endoglycan (and the actin-binding protein Ezrin) localize to large, intraluminal structures that may be vesicles/exosomes...
October 1, 2016: Developmental Biology
Mugdha Deshpande, Zachary Feiger, Amanda K Shilton, Christina C Luo, Ethan Silverman, Avital A Rodal
TAR DNA-binding protein 43 (TDP-43) is genetically and functionally linked to amyotrophic lateral sclerosis (ALS) and regulates transcription, splicing, and transport of thousands of RNA targets that function in diverse cellular pathways. In ALS, pathologically altered TDP-43 is believed to lead to disease by toxic gain-of-function effects on RNA metabolism, as well as by sequestering endogenous TDP-43 and causing its loss of function. However, it is unclear which of the numerous cellular processes disrupted downstream of TDP-43 dysfunction lead to neurodegeneration...
October 1, 2016: Molecular Biology of the Cell
Jérôme Bouchet, Mary W McCaffrey, Andrea Graziani, Andrés Alcover
Several families of small GTPases regulate a variety of fundamental cellular processes, encompassing growth factor signal transduction, vesicular trafficking and control of the cytoskeleton. Frequently, their action is hierarchical and complementary, but much of the detail of their functional interactions remains to be clarified. It is well established that Rab family members regulate a variety of intracellular vesicle trafficking pathways. Moreover, Rho family GTPases are pivotal for the control of the actin and microtubule cytoskeleton...
August 17, 2016: Small GTPases
Bao-Jun Shi, Chun-Chun Liu, Jing Zhou, Shi-Qi Wang, Zhi-Can Gao, Xiao-Min Zhang, Bin Zhou, Pu-Yan Chen
UNLABELLED: Classical swine fever virus (CSFV), a member of the genus Pestivirus within the family Flaviviridae, is a small, enveloped, positive-strand RNA virus. Due to its economic importance to the pig industry, the biology and pathogenesis of CSFV have been investigated extensively. However, the mechanisms of CSFV entry into cells are not well characterized. In this study, we used systematic approaches to dissect CSFV cell entry. We first observed that CSFV infection was inhibited by chloroquine and NH4Cl, suggesting that viral entry required a low-pH environment...
October 15, 2016: Journal of Virology
Anthony J Mangan, Daniel V Sietsema, Dongying Li, Jeffrey K Moore, Sandra Citi, Rytis Prekeris
Coordinated polarization of epithelial cells is a key step during morphogenesis that leads to the formation of an apical lumen. Rab11 and its interacting protein FIP5 are necessary for the targeting of apical endosomes to the midbody and apical membrane initiation site (AMIS) during lumenogenesis. However, the machinery that mediates AMIS establishment and FIP5-endosome targeting remains unknown. Here we identify a FIP5-interacting protein, Cingulin, which localizes to the AMIS and functions as a tether mediating FIP5-endosome targeting...
2016: Nature Communications
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