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Kotaro Furusawa, Akiko Asada, Pamela Urrutia, Christian Gonzalez-Billault, Mitsunori Fukuda, Shin-Ichi Hisanaga
: Neurons communicate with each other through their axons and dendrites. However, a full characterization of the molecular mechanisms involved in axon and dendrite formation is still incomplete. Neurite outgrowth requires the supply of membrane components for surface expansion. Two membrane sources for axon outgrowth are suggested, Golgi secretary vesicles and endocytic recycling endosomes. In non-neuronal cells, trafficking of secretary vesicles from Golgi is regulated by Rab8, a member of Rab small GTPases, and that of recycling endosomes is by Rab11, another member of Rabs...
December 9, 2016: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Janina Hendrick, Monilola A Olayioye
The spatial regulation of cellular Rho signaling by GEF and GAP proteins and the molecular mechanisms controlling the Rho regulators themselves are still incompletely understood. We previously reported that the poorly characterized RhoGAP protein DLC3 localizes to cell-cell adhesions and Rab8-positive membrane tubules. However, it was unclear how DLC3 is targeted to these subcellular sites to execute its functions. In our recent work, protein partners of DLC3 were identified by mass spectrometry, identifying the basolateral polarity protein Scribble as a scaffold for DLC3 at cell-cell contacts...
November 16, 2016: Small GTPases
Wenxiang Fu, Lei Wang, Sehyun Kim, Ji Li, Brian David Dynlacht
Intraflagellar transport sub-complex A (IFT-A) is known to regulate retrograde IFT in the cilium. To rigorously assess its other possible roles, we knocked out an IFT-A subunit, IFT121/WDR35, in mammalian cells and screened the localization of more than 50 proteins. We found that Wdr35 regulates cilium assembly by selectively regulating transport of distinct cargoes. Beyond its role in retrograde transport, we show that Wdr35 functions in fusion of Rab8 vesicles at the nascent cilium, protein exit from the cilium, and centriolar satellite organization...
November 1, 2016: Cell Reports
Ganiyu Olabanji Alli-Balogun, Christina A Gewinner, Ruth Jacobs, Janos Kriston-Vizi, Mark G Waugh, Shane Minogue
The type II phosphatidylinositol 4-kinase (PI4KII) enzymes synthesize the lipid phosphatidylinositol 4-phosphate (PI(4)P), which has been detected at the Golgi complex and endosomal compartments and recruits clathrin adaptors. Despite common mechanistic similarities between the isoforms, the extent of their redundancy is unclear. We found that depletion of PI4KIIα and PI4KIIβ using small interfering RNA led to actin remodeling. Depletion of PI4KIIβ also induced the formation of invadopodia containing membrane type I matrix metalloproteinase (MT1-MMP)...
December 15, 2016: Molecular Biology of the Cell
Fangyan Yu, Shruti Sharma, Agnieszka Skowronek, Kai Sven Erdmann
A primary cilium is present on most eukaryotic cells and represents a specialized organelle dedicated to signal transduction and mechanosensing. Defects in cilia function are the cause for several human diseases called ciliopathies. The serologically defined colon cancer antigen-3 (SDCCAG3) is a recently described novel endosomal protein mainly localized at early and recycling endosomes and interacting with several components of membrane trafficking pathways. Here we describe localization of SDCCAG3 to the basal body of primary cilia...
October 21, 2016: Scientific Reports
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
Viswanadh Madugula, Lei Lu
The sensory functions of cilia are dependent on the enrichment of cilium-resident proteins. Although it is known that ciliary targeting signals (CTSs) specifically target ciliary proteins to cilia, it is still unclear how CTSs facilitate the entry and retention of cilium-resident proteins at the molecular level. We found that non-ciliary membrane reporters can passively diffuse into cilia through the lateral transport pathway, and the translocation of membrane reporters through the ciliary diffusion barrier is facilitated by importin binding motifs and domains...
October 15, 2016: Journal of Cell Science
Amrita Rai, Anastasia Oprisko, Jeremy Campos, Yangxue Fu, Timon Friese, Aymelt Itzen, Roger S Goody, Emerich Mihai Gazdag, Matthias P Müller
In their active GTP-bound form, Rab proteins interact with proteins termed effector molecules. In this study, we have thoroughly characterized a Rab effector domain that is present in proteins of the Mical and EHBP families, both known to act in endosomal trafficking. Within our study, we show that these effectors display a preference for Rab8 family proteins (Rab8, 10, 13 and 15) and that some of the effector domains can bind two Rab proteins via separate binding sites. Structural analysis allowed us to explain the specificity towards Rab8 family members and the presence of two similar Rab binding sites that must have evolved via gene duplication...
2016: ELife
Satoshi Shibata, Tsubasa Kawanai, Takayuki Hara, Asuka Yamamoto, Taro Chaya, Yasunori Tokuhara, Chinami Tsuji, Manabu Sakai, Taro Tachibana, Shinobu Inagaki
The function of ARHGEF10, a known guanine nucleotide exchange factor (GEF) for RhoA with proposed roles in various diseases, is poorly understood. To understand the precise function of this protein, we raised a monoclonal antibody against ARHGEF10 and determined its localization in HeLa cells. ARHGEF10 was found to localize to vesicles containing Rab6 (of which there are three isoforms, Rab6a, Rab6b and Rab6c), Rab8 (of which there are two isoforms, Rab8a and Rab8b), and/or the secretion marker neuropeptide Y (NPY)-Venus in a Rab6-dependent manner...
October 1, 2016: Journal of Cell Science
Feng-Qian Li, Xingwang Chen, Cody Fisher, Saul S Siller, Klara Zelikman, Ryoko Kuriyama, Ken-Ichi Takemaru
Chibby1 (Cby1) is a small, conserved coiled-coil protein that localizes to centrioles/basal bodies and plays a crucial role in the formation and function of cilia. During early stages of ciliogenesis, Cby1 is required for the efficient recruitment of small vesicles at the distal end of centrioles to facilitate basal body docking to the plasma membrane. Here, we identified family with sequence similarity 92, member A (FAM92A) and FAM92B, which harbor predicted lipid-binding BAR domains, as novel Cby1-interacting partners using tandem affinity purification and mass spectrometry...
November 1, 2016: Molecular and Cellular Biology
Camille Corbier, Chantal Sellier
Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS-FTD) are devastating neurodegenerative disease affecting motoneurons from the spinal chord and neurons from the frontal and temporal cortex, respectively. The most common genetic cause for ALS-FTD is an expansion of GGGGCC repeats within the first intron of the C9ORF72 gene. However, little is known on the function of C9ORF72. Recently, other and we found that C9ORF72 forms a stable complex with the SMCR8 and WDR41 proteins. This complex acts as a GDP/GTP exchange factor for the small RAB GTPases Rab8a and Rab39b...
August 5, 2016: Small GTPases
Stacey Chung, Mikel Ghelfi, Jeffrey Atkinson, Robert Parker, Jinghui Qian, Cathleen Carlin, Danny Manor
α-Tocopherol (vitamin E) is an essential nutrient for all vertebrates. From the eight naturally occurring members of the vitamin E family, α-tocopherol is the most biologically active species and is selectively retained in tissues. The hepatic α-tocopherol transfer protein (TTP) preferentially selects dietary α-tocopherol and facilitates its transport through the hepatocyte and its secretion to the circulation. In doing so, TTP regulates body-wide levels of α-tocopherol. The mechanisms by which TTP facilitates α-tocopherol trafficking in hepatocytes are poorly understood...
August 12, 2016: Journal of Biological Chemistry
Sorana Ciura, Chantal Sellier, Maria-Letizia Campanari, Nicolas Charlet-Berguerand, Edor Kabashi
The most common genetic cause for amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD) is repeat expansion of a hexanucleotide sequence (GGGGCC) within the C9orf72 genomic sequence. To elucidate the functional role of C9orf72 in disease pathogenesis, we identified certain molecular interactors of this factor. We determined that C9orf72 exists in a complex with SMCR8 and WDR41 and that this complex acts as a GDP/GTP exchange factor for RAB8 and RAB39, 2 RAB GTPases involved in macroautophagy/autophagy...
August 2, 2016: Autophagy
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
Lei Wang, Kwanwoo Lee, Ryan Malonis, Irma Sanchez, Brian D Dynlacht
To elucidate the role of centriolar satellites in ciliogenesis, we deleted the gene encoding the PCM1 protein, an integral component of satellites. PCM1 null human cells show marked defects in ciliogenesis, precipitated by the loss of specific proteins from satellites and their relocation to centrioles. We find that an amino-terminal domain of PCM1 can restore ciliogenesis and satellite localization of certain proteins, but not others, pinpointing unique roles for PCM1 and a group of satellite proteins in cilium assembly...
2016: ELife
Philipp M Cromm, Sebastian Schaubach, Jochen Spiegel, Alois Fürstner, Tom N Grossmann, Herbert Waldmann
Bicyclic peptides are promising scaffolds for the development of inhibitors of biological targets that proved intractable by typical small molecules. So far, access to bioactive bicyclic peptide architectures is limited due to a lack of appropriate orthogonal ring-closing reactions. Here, we report chemically orthogonal ring-closing olefin (RCM) and alkyne metathesis (RCAM), which enable an efficient chemo- and regioselective synthesis of complex bicyclic peptide scaffolds with variable macrocycle geometries...
April 14, 2016: Nature Communications
Bret Wankel, Jiangyong Ouyang, Xuemei Guo, Krassimira Hadjiolova, Jeremy Miller, Yi Liao, Daniel Kai Long Tham, Rok Romih, Leonardo R Andrade, Iwona Gumper, Jean-Pierre Simon, Rakhee Sachdeva, Tanya Tolmachova, Miguel C Seabra, Mitsunori Fukuda, Nicole Schaeren-Wiemers, Wan Jin Hong, David D Sabatini, Xue-Ru Wu, Xiangpeng Kong, Gert Kreibich, Michael J Rindler, Tung-Tien Sun
Uroplakins (UPs) are major differentiation products of urothelial umbrella cells and play important roles in forming the permeability barrier and in the expansion/stabilization of the apical membrane. Further, UPIa serves as a uropathogenic Escherichia coli receptor. Although it is understood that UPs are delivered to the apical membrane via fusiform vesicles (FVs), the mechanisms that regulate this exocytic pathway remain poorly understood. Immunomicroscopy of normal and mutant mouse urothelia show that the UP-delivering FVs contained Rab8/11 and Rab27b/Slac2-a, which mediate apical transport along actin filaments...
May 15, 2016: Molecular Biology of the Cell
José J Bravo-Cordero, Marco Cordani, Silvia F Soriano, Begoña Díez, Carmen Muñoz-Agudo, María Casanova-Acebes, César Boullosa, Marta C Guadamillas, Iakes Ezkurdia, David González-Pisano, Miguel A Del Pozo, María C Montoya
Rab8 is a small Ras-related GTPase that regulates polarized membrane transport to the plasma membrane. Here, we developed a high-content analysis (HCA) tool to dissect Rab8-mediated actin and focal adhesion reorganization that revealed that Rab8 activation significantly induced Rac1 and Tiam1 to mediate cortical actin polymerization and RhoA-dependent stress fibre disassembly. Rab8 activation increased Rac1 activity, whereas its depletion activated RhoA, which led to reorganization of the actin cytoskeleton...
April 15, 2016: Journal of Cell Science
Lauren M Mavor, Hui Miao, Zhongyuan Zuo, Ryan M Holly, Yi Xie, Dinah Loerke, J Todd Blankenship
One of the most fundamental changes in cell morphology is the ingression of a plasma membrane furrow. The Drosophila embryo undergoes several cycles of rapid furrow ingression during early development that culminate in the formation of an epithelial sheet. Previous studies have demonstrated the requirement for intracellular trafficking pathways in furrow ingression; however, the pathways that link compartmental behaviors with cortical furrow ingression events are unclear. Here, we show that Rab8 has striking dynamic behaviors in vivo...
March 1, 2016: Development
Atsuhiro Nakajo, Shin-ichiro Yoshimura, Hiroko Togawa, Masataka Kunii, Tomohiko Iwano, Ayaka Izumi, Yuria Noguchi, Ayako Watanabe, Ayako Goto, Toshiro Sato, Akihiro Harada
The highly conserved Rab guanosine triphosphatase (GTPase) Rab8 plays a role in exocytosis toward the polarized plasma membrane in eukaryotic cells. In murine Rab8-deficient small intestine cells, apical proteins are missorted into lysosomes. In this study, we identified a novel Rab8-interacting protein complex containing an EH domain-binding protein 1-like 1 (EHBP1L1), Bin1/amphiphysin II, and dynamin. Biochemical analyses showed that EHBP1L1 directly bound to GTP-loaded Rab8 and Bin1. The spatial dependency of these complexes at the endocytic recycling compartment (ERC) was demonstrated through overexpression and knockdown experiments...
February 1, 2016: Journal of Cell Biology
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