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Molecular Biology of the Cell

Xi Wen, Xuehua Xu, Wenxiang Sun, Keqiang Chen, Miao Pan, Ji Ming Wang, Silvia M Bolland, Tian Jin
A dogma of innate immunity is that neutrophils use G-Protein-coupled receptors (GPCRs) for chemoattractant to chase bacteria through chemotaxis and then use phagocytic receptors coupled with tyrosine kinases to destroy opsonized bacteria via phagocytosis. Our current work showed that G-protein-coupled formyl peptide receptors (FPRs) directly mediate neutrophil phagocytosis. Mouse neutrophils lacking formyl peptide receptors (Fpr1/2-/- ) are defective in the phagocytosis of E. coli and the chemoattractant fMLP-coated beads...
December 12, 2018: Molecular Biology of the Cell
Eric T Hall, Elizabeth Hoesing, Endre Sinkovics, Esther M Verheyen
Actomyosin contractility can influence the canonical Wnt signaling pathway in processes like mesoderm differentiation and tissue stiffness during tumorigenesis. We identified that increased non-muscle myosin II activation and cellular contraction inhibited Wnt target gene transcription in developing Drosophila imaginal discs. Genetic interactions studies were used to show that this effect was due to myosin-induced accumulation of cortical F-actin resulting in clustering and accumulation of E-cadherin to the adherens junctions...
December 12, 2018: Molecular Biology of the Cell
Youjun Wu, Bingjie Han, Timothy J Gauvin, Jarrett Smith, Abhyudai Singh, Erik E Griffin
During the asymmetric division of the C. elegans zygote, germ (P) granules are disassembled in the anterior cytoplasm and stabilized/assembled in the posterior cytoplasm, leading to their inheritance by the germline daughter cell. P granule segregation depends on MEG-3 and MEG-4, which are enriched in P granules and in the posterior cytoplasm surrounding P granules. Here, we use single molecule imaging and tracking to characterize the reaction/diffusion mechanisms that underpin MEG-3::Halo segregation. We find that the anteriorly-enriched RNA-binding proteins MEX-5 and MEX-6 suppress the retention of MEG-3 in the anterior cytoplasm, leading to MEG-3 enrichment in the posterior...
December 12, 2018: Molecular Biology of the Cell
Christian Makhoul, Prajakta Gosavi, Regina Duffield, Bronwen Delbridge, Nicholas A Williamson, Paul A Gleeson
The maintenance of the Golgi ribbon relies on a dynamic balance between the actin and microtubule networks, however the pathways controlling actin networks remain poorly defined. Previously, we showed that the TGN membrane tether/golgin, GCC88, modulates the Golgi ribbon architecture (Gosavi et al., 2018). Here we show that dispersal of the Golgi ribbon by GCC88 is dependent on actin and the involvement of non-muscle myosin IIA. We have identified the long isoform of intersectin-1 (ITSN-1), a guanine nucleotide exchange factor for Cdc42, as a novel Golgi component and an interaction partner of GCC88 responsible for mediating the actin-dependent dispersal of the Golgi ribbon...
December 12, 2018: Molecular Biology of the Cell
Akiko Shitara, Lenka Malec, Seham Ebrahim, Desu Chen, Christopher Bleck, Matthew P Hoffman, Roberto Weigert
Lumen establishment and maintenance are fundamental for tubular organs physiological functions. Most of the studies investigating the mechanisms regulating this process have been carried out in cell cultures or in smaller organisms, whereas little has been done in mammalian model systems in vivo. Here we used the salivary glands of live mice to examine the role of the small GTPase Cdc42 in the regulation of the homeostasis of the intercellular canaliculi, a specialized apical domain of the acinar cells, where protein and fluid secretion occur...
December 12, 2018: Molecular Biology of the Cell
Josephine A Bonventre, Chelsea Holman, Aayushi Manchanda, Sara J Codding, Trisha Chau, Jacob Huegel, Carrie Barton, Robert Tanguay, Colin P Johnson
The precise spatial and temporal expression of genes is essential for proper organismal development. Despite their importance however, many developmental genes have yet to be identified. We have determined that Fer1L6, a member of the ferlin family of genes, is a novel factor in zebrafish development. We find that Fer1L6 is expressed broadly in the trunk and head of zebrafish larvae and is more restricted to gills and female gonads in adult zebrafish. Using both genetic mutant and morpholino knockdown models, we found that loss of Fer1L6 led to deformation of striated muscle tissues, delayed development of the heart, and high morbidity...
December 5, 2018: Molecular Biology of the Cell
Vidyaramanan Ganesan, Stephen D Willis, Kai-Ti Chang, Samuel Beluch, Katrina F Cooper, Randy Strich
Mitochondria exist in an equilibrium between fragmented and fused that shifts heavily toward fission in response to cellular damage. Nuclear to cytoplasmic cyclin C relocalization is essential for dynamin-related protein 1 (Drp1)-dependent mitochondrial fission in response to oxidative stress. This study finds that cyclin C directly interacts with the Drp1 GTPase domain, increases its affinity to GTP and stimulates GTPase activity in vitro. In addition, the cyclin C domain that binds Drp1 is contained within the non-Cdk binding second cyclin box domain common to all cyclin family members...
December 5, 2018: Molecular Biology of the Cell
Mansi Gujrati, Rohit Mittal, Lakhan Ekal, Ram Kumar Mishra
The architecture of the cytoskeleton and its remodeling are tightly regulated by dynamic reorganization of keratin-rich intermediate filaments. Plakin family proteins associate with the network of intermediate filaments (IFs) and affect its reorganization during migration, differentiation, and response to stress. The smallest plakin, periplakin (PPL), interacts specifically with intermediate filament proteins K8, K18, and vimentin via its C-terminal linker domain. Here, we show that periplakin is SUMOylated at a conserved lysine in its linker domain (K1646) preferentially by SUMO1...
December 5, 2018: Molecular Biology of the Cell
Jovana Deretic, Alastair Kerr, Julie P I Welburn
Aurora kinases play a major role in mitosis by regulating diverse substrates. Defining their critical downstream targets is important to understand Aurora kinase function. Here we have developed an unbiased computational approach to identify new Aurora kinase substrates based on phosphorylation site clustering, protein localization, protein structure, and species conservation. We validate the microtubule-associated proteins Clasp2, Elys, TTLL4 and SPICE1 as Aurora A and B kinases substrates in vitro. We also demonstrate that SPICE1 localization is regulated by Aurora kinases during mitosis...
November 28, 2018: Molecular Biology of the Cell
Arron Sullivan, Ryan L Wallace, Rachel Wellington, Xiangxia Luo, Andrew P Capaldi
The Target of Rapamycin Kinase Complex 1 (TORC1) regulates cell growth and metabolism in eukaryotes. In Saccharomyces cerevisiae, TORC1 activity is known to be controlled by the conserved GTPases, Gtr1/2, and movement into and out of an inactive agglomerate/body. However, it is unclear if/how these regulatory steps are coupled. Here we show that active Gtr1/2 is a potent inhibitor of TORC1-body formation, but cells missing Gtr1/2 still form TORC1-bodies in a glucose/nitrogen starvation dependent manner. We also identify 13 new activators of TORC1-body formation and show that seven of these proteins regulate the Gtr1/2 dependent repression of TORC1-body formation, while the remaining proteins drive the subsequent steps in TORC1 agglomeration...
November 28, 2018: Molecular Biology of the Cell
David Melville, Amita Gorur, Randy Schekman
COPII coated vesicles are the primary mediators of ER-to-Golgi trafficking. Sar1, one of the five core COPII components, is a highly conserved small GTPase, which, upon GTP binding, recruits the other COPII proteins to the ER membrane. It has been hypothesized that the changes in the kinetics of SAR1 GTPase may allow for the secretion of large cargos. Here we developed a cell-free assay to recapitulate COPII-dependent budding of large lipoprotein cargos from the ER. We identified Fatty-acid Binding Protein 5 (FABP5) as an enhancer of this budding process...
November 28, 2018: Molecular Biology of the Cell
Miriam V Gutschow, John C Mason, Keara M Lane, Inbal Maayan, Jacob J Hughey, Bryce T Bajar, Debha N Amatya, Sean D Valle, Markus W Covert
During the course of a bacterial infection, cells are exposed simultaneously to a range of bacterial and host factors, which converge on the central transcription factor nuclear factor (NF)-κB. How do single cells integrate and process these converging stimuli? Here, we tackle the question of how cells process combinatorial signals by making quantitative single-cell measurements of the NF-κB response to combinations of bacterial lipopolysaccharide (LPS) and the stress cytokine Tumor Necrosis Factor (TNF)...
November 21, 2018: Molecular Biology of the Cell
Ilkka Paatero, Ville Veikkolainen, Matias Mäenpää, Etienne Schmelzer, Heinz-Georg Belting, Lauri J Pelliniemi, Klaus Elenius
Tyrosine kinase inhibitors are widely used in the clinic, but limited information is available about their toxicity in developing organisms. Here, we tested the effect of tyrosine kinase inhibitors targeting the ErbB receptors for their effects on developing zebrafish ( Danio rerio) embryos. Embryos treated with wide-spectrum pan-ErbB inhibitors or erbb4a-targeting antisense oligonucleotides demonstrated reduced locomotion, reduced diameter of skeletal muscle fibers, reduced expression of muscle-specific genes, as well as reduced motoneuron length...
November 21, 2018: Molecular Biology of the Cell
Benjamin M Stormo, Donald T Fox
To ensure faithful genome propagation, mitotic cells alternate one round of chromosome duplication with one round of chromosome separation. Chromosome separation failure thus causes genome reduplication, which alters mitotic chromosome structure. Such structural alterations are well-documented to impair mitotic fidelity following aberrant genome re-duplication, including in diseased states. In contrast, we recently showed that naturally occurring genome re-duplication does not alter mitotic chromosome structure in Drosophila papillar cells...
November 21, 2018: Molecular Biology of the Cell
Annie S Tam, Tianna S Sihota, Karissa L Milbury, Anni Zhang, Veena Mathew, Peter C Stirling
RNA processing mutants have been broadly implicated in genome stability but mechanistic links are often unclear. Two predominant models have emerged: one involving changes in gene expression that perturb other genome maintenance factors, and another in which genotoxic DNA:RNA hybrids, called R-loops, impair DNA replication. Here we characterize genome instability phenotypes in yeast splicing factor mutants and find that mitotic defects, and in some cases R-loop accumulation, are causes of genome instability...
November 21, 2018: Molecular Biology of the Cell
Richard De Mets, Irene Wang, Martial Balland, Christiane Oddou, Philippe Moreau, Bertrand Fourcade, Corinne Albiges-Rizo, Antoine Delon, Olivier Destaing
Integrins are transmembrane receptors that have a pivotal role in mechanotransduction processes by connecting the extracellular matrix to the cytoskeleton. Although it is well established that integrin activation/inhibition cycles are due to highly dynamic interactions, whether integrin mobility depends on local tension and cytoskeletal organization remains surprisingly unclear. Using an original approach combining micropatterning on glass substrates to induce standardized local mechanical constraints within a single cell with temporal image correlation spectroscopy (tICS), we measured the mechanosensitive response of integrin mobility at the whole cell level and in adhesion sites under different mechanical constraints...
November 21, 2018: Molecular Biology of the Cell
Ramesh Rijal, Kristen M Consalvo, Christopher K Lindsey, Richard H Gomer
Eukaryotic chemoattraction signal transduction pathways, such as those used by Dictyostelium discoideum to move towards cAMP, use a G protein-coupled receptor to activate multiple conserved pathways such as PI3 kinase/Akt/PKB to induce actin polymerization and pseudopod formation at the front of a cell, and PTEN to localize myosin II to the rear of a cell. Relatively little is known about chemorepulsion. We previously found that AprA is a chemorepellent protein secreted by Dictyostelium cells. Here we used 29 cell lines with disruptions of cAMP and/or AprA signal transduction pathway components, and delineated the AprA chemorepulsion pathway...
November 21, 2018: Molecular Biology of the Cell
Thu Ly, Christopher T Pappas, Dylan Johnson, William Schlecht, Mert Colpan, Vitold E Galkin, Carol C Gregorio, Wen-Ji Dong, Alla S Kostyukova
Missense mutations K15N and R21H in striated muscle tropomyosin are linked to dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), respectively. Tropomyosin, together with the troponin complex, regulates muscle contraction and, along with tropomodulin and leiomodin, controls the uniform thin filament lengths crucial for normal sarcomere structure and function. We used Förster resonance energy transfer to study effects of the tropomyosin mutations on the structure and kinetics of the cardiac troponin core domain associated with the Ca2+ -dependent regulation of cardiac thin filaments...
November 21, 2018: Molecular Biology of the Cell
Gregory E Miner, Katherine D Sullivan, Annie Guo, Brandon C Jones, Logan R Hurst, Ez C Ellis, Matthew L Starr, Rutilio A Fratti
Phosphoinositides (PIs) regulate myriad cellular functions including membrane fusion, as exemplified by the yeast vacuole, which uses various PIs at different stages of fusion. In light of this, the effect of phosphatidylinositol 3,5-bisphosphate [PI(3,5)P2 ] on vacuole fusion remains unknown. PI(3,5)P2 is made by the PI3P 5-kinase Fab1 and has been characterized as a regulator of vacuole fission during hyperosmotic shock where it interacts with the TRP Ca2+ channel Yvc1. Here we demonstrate that exogenously added dioctanoyl (C8) PI(3,5)P2 abolishes homotypic vacuole fusion...
November 14, 2018: Molecular Biology of the Cell
Tsai-Shin Chiang, Ming-Chieh Lin, Meng-Chen Tsai, Chieh-Hsin Chen, Li-Ting Jang, Fang-Jen S Lee
Cell migration is a highly regulated event that is initiated by cell membrane protrusion and actin reorganization. Robo1, a single-pass transmembrane receptor, is crucial for neuronal guidance and cell migration. ADP-ribosylation factor (Arf)-like 4A (Arl4A), an Arf small GTPase, functions in cell morphology, cell migration, and actin cytoskeleton remodeling; however, the molecular mechanisms of Arl4A in cell migration are unclear. Here, we report that the binding of Arl4A to Robo1 modulates cell migration by promoting Cdc42 activation...
November 14, 2018: Molecular Biology of the Cell
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