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https://www.readbyqxmd.com/read/29602783/quantitative-imaging-flow-cytometry-of-legionella-infected-dictyostelium-reveals-the-impact-of-retrograde-trafficking-on-pathogen-vacuole-composition
#1
Amanda Welin, Stephen Weber, Hubert Hilbi
The ubiquitous environmental bacterium Legionella pneumophila survives and replicates within amoebae and human macrophages by forming a Legionella -containing vacuole (LCV). In an intricate process governed by the bacterial Icm/Dot type IV secretion system and a plethora of "effector proteins" the nascent LCV interferes with a number of intracellular trafficking pathways, including retrograde transport from endosomes to the Golgi apparatus. Conserved retrograde trafficking components such as the retromer coat complex or the phosphoinositide (PI) 5-phosphatase Dd5P4/OCRL restrict intracellular replication of L...
March 30, 2018: Applied and Environmental Microbiology
https://www.readbyqxmd.com/read/29482628/lrrk2-mediated-rab8a-phosphorylation-promotes-lipid-storage
#2
Miao Yu, Muhammad Arshad, Wenmin Wang, Dongyu Zhao, Li Xu, Linkang Zhou
BACKGROUND: Several mutations in leucine rich repeat kinase 2 (LRRK2) gene have been associated with pathogenesis of Parkinson's disease (PD), a neurodegenerative disorder marked by resting tremors, and rigidity, leading to Postural instability. It has been revealed that mutations that lead to an increase of kinase activity of LRRK2 protein are significantly associated with PD pathogenesis. Recent studies have shown that some Rab GTPases, especially Rab8, serve as substrates of LRRK2 and undergo phosphorylation in its switch II domain upon interaction...
February 27, 2018: Lipids in Health and Disease
https://www.readbyqxmd.com/read/29396404/the-ciliopathy-protein-talpid3-kiaa0586-acts-upstream-of-rab8-activation-in-zebrafish-photoreceptor-outer-segment-formation-and-maintenance
#3
Irene Ojeda Naharros, Flavia B Cristian, Jingjing Zang, Matthias Gesemann, Philip W Ingham, Stephan C F Neuhauss, Ruxandra Bachmann-Gagescu
Ciliopathies are human disorders caused by dysfunction of primary cilia, ubiquitous microtubule-based organelles involved in signal transduction. Cilia are anchored inside the cell through basal bodies (BBs), modified centrioles also acting as microtubule-organization centers. Photoreceptors (PRs) are sensory neurons, whose primary cilium forms a highly specialized compartment called the outer segment (OS) responsible for sensing incoming light. Thus, ciliopathies often present with retinal degeneration. Mutations in KIAA0586/TALPID3 (TA3) cause Joubert syndrome, in which 30% of affected individuals develop retinal involvement...
February 2, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29318657/crystal-structure-of-tetrameric-human-rabin8-gef-domain
#4
Melanie Vetter, Niels Boegholm, Anni Christensen, Sagar Bhogaraju, Marie B Andersen, Anna Lorentzen, Esben Lorentzen
Rab GTPases and their effectors, activators and guanine nucleotide exchange factors (GEFs) are essential for vesicular transport. Rab8 and its GEF Rabin8 function in formation of the cilium organelle important for developmental signaling and sensory reception. Here, we show by size exclusion chromatography and analytical ultracentrifugation that Rabin8 exists in equilibrium between dimers and tetramers. The crystal structure of tetrameric Rabin8 GEF domain reveals an occluded Rab8 binding site suggesting that this oligomer is enzymatically inactive, a notion we verify experimentally using Rabin8/Rab8 GEF assays...
April 2018: Proteins
https://www.readbyqxmd.com/read/29281629/loss-of-function-of-the-ciliopathy-protein-cc2d2a-disorganizes-the-vesicle-fusion-machinery-at-the-periciliary-membrane-and-indirectly-affects-rab8-trafficking-in-zebrafish-photoreceptors
#5
Irene Ojeda Naharros, Matthias Gesemann, José M Mateos, Gery Barmettler, Austin Forbes, Urs Ziegler, Stephan C F Neuhauss, Ruxandra Bachmann-Gagescu
Ciliopathies are human disorders caused by dysfunction of primary cilia, ubiquitous organelles involved in transduction of environmental signals such as light sensation in photoreceptors. Concentration of signal detection proteins such as opsins in the ciliary membrane is achieved by RabGTPase-regulated polarized vesicle trafficking and by a selective barrier at the ciliary base, the transition zone (TZ). Dysfunction of the TZ protein CC2D2A causes Joubert/Meckel syndromes in humans and loss of ciliary protein localization in animal models, including opsins in retinal photoreceptors...
December 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29277005/landmarks-of-endosomal-remodeling-in-the-early-phase-of-cytomegalovirus-infection
#6
Ljerka Karleuša, Hana Mahmutefendić, Maja Ilić Tomaš, Gordana Blagojević Zagorac, Pero Lučin
Cytomegaloviruses (CMVs) extensively rearrange the cellular membrane system to develop assembly compartment (AC), but the earliest events in this process are poorly characterized. Here, we demonstrate that murine CMV (MCMV) infection restrains endosomal trafficking of cargo molecules that travel along the recycling (TfR and MHC-I) and the late endosomal (EGFR, M6PR, Lamp1) circuit. Internalized cargo accumulates in Arf6-, Rab5-, Rab22A-, and Rab11-positive and Rab35-, Rab8-, and Rab10-negative juxtanuclear endosomes, suggesting the disruption of Arf/Rab regulatory cascade at the stage of sorting endosomes and the endosomal recycling compartment...
February 2018: Virology
https://www.readbyqxmd.com/read/29244804/conditional-knockout-mice-for-the-distal-appendage-protein-cep164-reveal-its-essential-roles-in-airway-multiciliated-cell-differentiation
#7
Saul S Siller, Himanshu Sharma, Shuai Li, June Yang, Yong Zhang, Michael J Holtzman, Wipawee Winuthayanon, Holly Colognato, Bernadette C Holdener, Feng-Qian Li, Ken-Ichi Takemaru
Multiciliated cells of the airways, brain ventricles, and female reproductive tract provide the motive force for mucociliary clearance, cerebrospinal fluid circulation, and ovum transport. Despite their clear importance to human biology and health, the molecular mechanisms underlying multiciliated cell differentiation are poorly understood. Prior studies implicate the distal appendage/transition fiber protein CEP164 as a central regulator of primary ciliogenesis; however, its role in multiciliogenesis remains unknown...
December 2017: PLoS Genetics
https://www.readbyqxmd.com/read/29203866/rpgrip1-is-required-for-rod-outer-segment-development-and-ciliary-protein-trafficking-in-zebrafish
#8
Rakesh K Raghupathy, Xun Zhang, Fei Liu, Reem H Alhasani, Lincoln Biswas, Saeed Akhtar, Luyuan Pan, Cecilia B Moens, Wenchang Li, Mugen Liu, Breandan N Kennedy, Xinhua Shu
Mutations in the RPGR-interacting protein 1 (RPGRIP1) gene cause recessive Leber congenital amaurosis (LCA), juvenile retinitis pigmentosa (RP) and cone-rod dystrophy. RPGRIP1 interacts with other retinal disease-causing proteins and has been proposed to have a role in ciliary protein transport; however, its function remains elusive. Here, we describe a new zebrafish model carrying a nonsense mutation in the rpgrip1 gene. Rpgrip1homozygous mutants do not form rod outer segments and display mislocalization of rhodopsin, suggesting a role for RPGRIP1 in rhodopsin-bearing vesicle trafficking...
December 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/29177506/lrrk2-phosphorylates-membrane-bound-rabs-and-is-activated-by-gtp-bound-rab7l1-to-promote-recruitment-to-the-trans-golgi-network
#9
Zhiyong Liu, Nicole Bryant, Ravindran Kumaran, Alexandra Beilina, Asa Abeliovich, Mark R Cookson, Andrew B West
Human genetic studies implicate LRRK2 and RAB7L1 in susceptibility to Parkinson disease (PD). These two genes function in the same pathway, as knockout of Rab7L1 results in phenotypes similar to LRRK2 knockout, and studies in cells and model organisms demonstrate LRRK2 and Rab7L1 interact in the endolysosomal system. Recently, a subset of Rab proteins have been identified as LRRK2 kinase substrates. Herein, we find that Rab8, Rab10, and Rab7L1 must be membrane and GTP-bound for LRRK2 phosphorylation. LRRK2 mutations that cause PD including R1441C, Y1699C, and G2019S all increase LRRK2 phosphorylation of Rab7L1 four-fold over wild-type LRRK2 in cells, resulting in the phosphorylation of nearly one-third the available Rab7L1 protein in cells...
January 15, 2018: Human Molecular Genetics
https://www.readbyqxmd.com/read/29117553/drosophila-embryonic-hemocytes-produce-laminins-to-strengthen-migratory-response
#10
Besaiz J Sánchez-Sánchez, José M Urbano, Kate Comber, Anca Dragu, Will Wood, Brian Stramer, María D Martín-Bermudo
The most prominent developmental function attributed to the extracellular matrix (ECM) is cell migration. While cells in culture can produce ECM to migrate, the role of ECM in regulating developmental cell migration is classically viewed as an exogenous matrix presented to the moving cells. In contrast to this view, we show here that Drosophila embryonic hemocytes deposit their own laminins in streak-like structures to migrate efficiently throughout the embryo. With the help of transplantation experiments, live microscopy, and image quantification, we demonstrate that autocrine-produced laminin regulates hemocyte migration by controlling lamellipodia dynamics, stability, and persistence...
November 7, 2017: Cell Reports
https://www.readbyqxmd.com/read/29073233/transcriptional-and-post-translational-changes-in-the-brain-of-mice-deficient-in-cholesterol-removal-mediated-by-cytochrome-p450-46a1-cyp46a1
#11
Natalia Mast, Joseph B Lin, Kyle W Anderson, Ingemar Bjorkhem, Irina A Pikuleva
Cytochrome P450 46A1 (CYP46A1) converts cholesterol to 24-hydroxycholesterol and thereby controls the major pathways of cholesterol removal from the brain. Cyp46a1-/- mice have a reduction in the rate of cholesterol biosynthesis in the brain and significant impairments to memory and learning. To gain insights into the mechanisms underlying Cyp46a1-/- phenotype, we used Cyp46a1-/- mice and quantified their brain sterol levels and the expression of the genes pertinent to cholesterol homeostasis. We also compared the Cyp46a1-/- and wild type brains for protein phosphorylation and ubiquitination...
2017: PloS One
https://www.readbyqxmd.com/read/29058908/intracellular-fate-of-nanoparticles-with-polydopamine-surface-engineering-and-a-novel-strategy-for-exocytosis-inhibiting-lysosome-impairment-based-cancer-therapy
#12
Li Ding, Xianbing Zhu, Yiling Wang, Bingyang Shi, Xiang Ling, Houjie Chen, Wenhao Nan, Austin Barrett, Zilei Guo, Wei Tao, Jun Wu, Xiaojun Shi
Polydopamine (PDA) coating as a bioinspired strategy for nanoparticles (NPs) has been extensively applied in cancer theranostics. However, a cellular-level understanding of nano-biointeraction of these PDA-coated NPs (PDNPs), which drives the fate of them and acts as a critical step to determine their efficacy, still remains unknown. Herein, we utilized the representative mesoporous silica NPs (MSNs) to be coated with PDA and study their nano-bioactivities in cancer cells. HeLa cell line was utilized as a model in this study...
November 8, 2017: Nano Letters
https://www.readbyqxmd.com/read/29054881/ablation-of-tfr1-in-purkinje-cells-inhibits-mglu1-trafficking-and-impairs-motor-coordination-but-not-autistic-like-behaviors
#13
Jia-Huan Zhou, Xin-Tai Wang, Liang Zhou, Lin Zhou, Fang-Xiao Xu, Li-Da Su, Hao Wang, Fan Jia, Fu-Qiang Xu, Gui-Quan Chen, Chris I De Zeeuw, Ying Shen
Group 1 metabotropic glutamate receptors (mGlu1/5s) are critical to synapse formation and participate in synaptic LTP and LTD in the brain. mGlu1/5 signaling alterations have been documented in cognitive impairment, neurodegenerative disorders, and psychiatric diseases, but underlying mechanisms for its modulation are not clear. Here, we report that transferrin receptor 1 (TFR1), a transmembrane protein of the clathrin complex, modulates the trafficking of mGlu1 in cerebellar Purkinje cells (PCs) from male mice...
November 22, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/29051265/regulation-of-notch-signaling-by-rab7-and-rab8-requires-carboxyl-methylation-by-icmt
#14
Helen Court, Ian M Ahearn, Marc Amoyel, Erika A Bach, Mark R Philips
Isoprenylcysteine carboxyl methyltransferase (ICMT) methylesterifies C-terminal prenylcysteine residues of CaaX proteins and some RAB GTPases. Deficiency of either ICMT or NOTCH1 accelerates pancreatic neoplasia in Pdx1-Cre ; LSL-KrasG12D mice, suggesting that ICMT is required for NOTCH signaling. We used Drosophila melanogaster wing vein and scutellar bristle development to screen Rab proteins predicted to be substrates for ICMT (ste14 in flies). We identified Rab7 and Rab8 as ICMT substrates that when silenced phenocopy ste14 deficiency...
December 4, 2017: Journal of Cell Biology
https://www.readbyqxmd.com/read/29020629/differential-regulation-of-lipoprotein-and-hepatitis-c-virus-secretion-by-rab1b
#15
Constantin N Takacs, Ursula Andreo, Viet Loan Dao Thi, Xianfang Wu, Caroline E Gleason, Michelle S Itano, Gabriella S Spitz-Becker, Rachel L Belote, Brenna R Hedin, Margaret A Scull, Charles M Rice, Sanford M Simon
Secretory cells produce diverse cargoes, yet how they regulate concomitant secretory traffic remains insufficiently explored. Rab GTPases control intracellular vesicular transport. To map secretion pathways, we generated a library of lentivirus-expressed dominant-negative Rab mutants and used it in a large-scale screen to identify regulators of hepatic lipoprotein secretion. We identified several candidate pathways, including those mediated by Rab11 and Rab8. Surprisingly, inhibition of Rab1b, the major regulator of transport from the endoplasmic reticulum to the Golgi, differently affected the secretion of the very-low-density lipoprotein components ApoE and ApoB100, despite their final association on mature secreted lipoprotein particles...
October 10, 2017: Cell Reports
https://www.readbyqxmd.com/read/28970336/scd1-and-scd2-form-a-complex-that-functions-with-the-exocyst-and-rabe1-in-exocytosis-and-cytokinesis
#16
Jonathan Russell Mayers, Tianwei Hu, Chao Wang, Jessica J Cárdenas, Yuqi Tan, Jianwei Pan, Sebastian Y Bednarek
Although exocytosis is critical for the proper trafficking of materials to the plasma membrane, relatively little is known about the mechanistic details of post-Golgi trafficking in plants. Here, we demonstrate that the DENN (Differentially Expressed in Normal and Neoplastic cells) domain protein STOMATAL CYTOKINESIS DEFECTIVE1 (SCD1) and SCD2 form a previously unknown protein complex, the SCD complex, that functionally interacts with subunits of the exocyst complex and the RabE1 family of GTPases in Arabidopsis thaliana Consistent with a role in post-Golgi trafficking, scd1 and scd2 mutants display defects in exocytosis and recycling of PIN2-GFP...
October 2017: Plant Cell
https://www.readbyqxmd.com/read/28960163/overexpression-of-ypt6-restores-invasive-filamentous-growth-and-secretory-vesicle-clustering-in-a-candida-albicans-arl1-mutant
#17
Rohan Wakade, Hayet Labbaoui, Danièle Stalder, Robert A Arkowitz, Martine Bassilana
Virulence of the human fungal pathogen Candida albicans depends on the switch from budding to filamentous growth. Deletion of the Arf GTPase Arl1 results in hyphae that are shorter as well as reduced virulence. How Arl1 is regulated during hyphal growth, a process characteristic of filamentous fungi, yet absent in S. cerevisiae, is unknown. Here, we investigated the importance of the Rab6 homolog, Ypt6, in Arl1-dependent hyphal growth and determined that YPT6 overexpression specifically rescued the hyphal growth defect of an arl1 mutant, but not the converse...
September 29, 2017: Small GTPases
https://www.readbyqxmd.com/read/28894007/rabif-mss4-is-a-rab-stabilizing-holdase-chaperone-required-for-glut4-exocytosis
#18
Daniel R Gulbranson, Eric M Davis, Brittany A Demmitt, Yan Ouyang, Yihong Ye, Haijia Yu, Jingshi Shen
Rab GTPases are switched from their GDP-bound inactive conformation to a GTP-bound active state by guanine nucleotide exchange factors (GEFs). The first putative GEFs isolated for Rabs are RABIF (Rab-interacting factor)/MSS4 (mammalian suppressor of Sec4) and its yeast homolog DSS4 (dominant suppressor of Sec4). However, the biological function and molecular mechanism of these molecules remained unclear. In a genome-wide CRISPR genetic screen, we isolated RABIF as a positive regulator of exocytosis. Knockout of RABIF severely impaired insulin-stimulated GLUT4 exocytosis in adipocytes...
September 26, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28876998/meiosis-specific-localization-of-the-exocytic-rab-ypt2-in-fission-yeast
#19
Kazuki Imada, Taro Nakamura
Fission yeast Ypt2, an orthologue of the mammalian small GTPase Rab8, is responsible for post-Golgi membrane trafficking. During meiosis, Ypt2 localizes at the spindle pole body (SPB), where it regulates de novo biogenesis of the spore plasma membrane. Recruitment of Ypt2 to the SPB is dependent on its meiosis-specific GDP/GTP exchange factor (GEF), the SPB-resident protein Spo13. Here we have examined the SPB recruitment of Ypt2 by Spo13. The GEF activity of Spo13 was required, but not essential for recruitment...
September 6, 2017: Small GTPases
https://www.readbyqxmd.com/read/28822075/recycling-endosomes-in-human-cytotoxic-t-lymphocytes-constitute-an-auxiliary-intracellular-trafficking-pathway-for-newly-synthesized-perforin
#20
Kelsey Lesteberg, Jordan Orange, George Makedonas
Although cytotoxic T lymphocytes (CTLs) store perforin within cytoplasmic secretory granules for immediate use, perforin is synthesized anew within hours of TCR stimulation. Previously, we observed new perforin protein at an immunologic synapse independent of secretory lysosomes; herein, we aimed to determine how new perforin transits to the synapse if not via lytic granules. We analyzed antigen-specific human CTLs via imaging flow cytometry and high-resolution confocal microscopy, with attention to intracellular trafficking components and new perforin...
October 2017: Immunologic Research
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