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Molecular Biology of the Cell

Florian Geisler, Harald Gerhardus, Katrin Carberry, Wayne Davis, Erik Jorgensen, Christine Richardson, Olaf Bossinger, Rudolf E Leube
Intermediate filaments are major cytoskeletal components whose assembly into complex networks and isotype-specific functions are still largely unknown. Caenorhabditis elegans provides an excellent model system to study intermediate filament organization and function in vivo Its intestinal intermediate filaments localize exclusively to the endotube, a circumferential sheet just below the actin-based terminal web. A genetic screen for defects in the organization of intermediate filaments identified a mutation in the catalytic domain of the MAP kinase 7 ortholog sma-5(kc1) In sma-5(kc1) mutants pockets of lumen penetrate the cytoplasm of the intestinal cells...
October 12, 2016: Molecular Biology of the Cell
Hafida Sellou, Théo Lebeaupin, Catherine Chapuis, Rebecca Smith, Anna Hegele, Hari R Singh, Marek Kozlowski, Sebastian Bultmann, Andreas G Ladurner, Gyula Timinszky, Sébastien Huet
Chromatin relaxation is one of the earliest cellular responses to DNA damage. However, what determines these structural changes, including their ATP requirement, is not well understood. Using live-cell imaging and laser microirradiation to induce DNA lesions, we show that the local chromatin relaxation at DNA damage sites is regulated by PARP1 enzymatic activity. We also report that H1 is mobilized at DNA damage sites but, since this mobilization is largely independent of poly(ADP-ribosyl)ation, it cannot solely explain the chromatin relaxation...
October 12, 2016: Molecular Biology of the Cell
Colin James Stockdale Klaus, Krishnan Raghunathan, Emmanuele DiBenedetto, Anne K Kenworthy
Diffusion of particles in curved surfaces is inherently complex compared with diffusion in a flat membrane owing to the non-planarity of the surface. The consequence of such non-planar geometry on diffusion is poorly understood but is highly relevant in the case of cell membranes, which often adopt complex geometries. To address this question, we developed a new finite element approach to model diffusion on curved membrane surfaces based on solutions to Fick's law of diffusion and used this to study the effects of geometry on the entry of surface-bound particles into tubules by diffusion...
October 12, 2016: Molecular Biology of the Cell
Valerie C Coffman, Matthew B A McDermott, Blerta Shtylla, Adriana T Dawes
Positioning of microtubule organizing centers (MTOCs) incorporates biochemical and mechanical cues for proper alignment of the mitotic spindle and cell division site. Current experimental and theoretical studies in the early C. elegans embryo assume remarkable changes in the origin and polarity of forces acting on the MTOCs. These changes must occur over a few minutes, between initial centration and rotation of the pronuclear complex and entry into mitosis, and the models do not replicate in vivo timing of centration and rotation...
October 12, 2016: Molecular Biology of the Cell
Daniel A Hernandez, Christina M Bennett, Lyubov Dunina-Barkovskaya, Tatjana Wedig, Yassemi Capetanaki, Harald Herrmann, Gloria M Conover
In the hearts of patients bearing nebulette mutations, a severe general disorganization in cardiomyocytes of the extrasarcomeric desmin intermediate filament system is frequently observed. However, the molecular and functional relationship between the desmin cytoskeleton and nebulette-containing sarcomeres is still unclear. Here we report a high-affinity in vitro interaction between nebulette and desmin filaments. A major interaction site has been mapped to the desmin α-helical rod domain indicating that the filament core is directly involved in the binding of nebulette...
October 12, 2016: Molecular Biology of the Cell
Efrat Gottlieb-Abraham, Orit Gutman, Govind M Pai, Ignacio Rubio, Yoav I Henis
The interactions of Src family kinases (SFKs) with the plasma membrane are crucial for their activity. They depend on their fatty-acylated N-termini, containing N-myristate and either a polybasic cluster (in Src) or palmitoylation sites (e.g., Fyn). To investigate the roles of these moieties in SFK membrane association, we employed FRAP beam-size analysis to study the membrane interactions of c-Src-GFP or Fyn-GFP fatty-acylation mutants. Our studies showed for the first time that the membrane association of Fyn is more stable than that of Src, an effect lost in a Fyn mutant lacking the palmitoylation sites...
October 12, 2016: Molecular Biology of the Cell
Dipen Rajgor, Jonathan G Hanley, Catherine M Shanahan
Nesprins are highly conserved spectrin-repeat containing scaffold proteins pre-dominantly known to function at the nuclear envelope (NE). However, nesprin isoforms are emerging with localizations and scaffolding functions at sites away from the NE, suggesting their functions are more diverse than originally thought. In this study, we combined nesprin-1 coimmunoprecipitations with mass spectrometry to identify novel nesprin-1 binding partners for isoforms that localize to subcellular compartments beyond the NE...
October 12, 2016: Molecular Biology of the Cell
Yoshiki Tanaka, Natsuki Ono, Takahiro Shima, Gaku Tanaka, Yohei Katoh, Kazuhisa Nakayama, Hiroyuki Takatsu, Hye-Won Shin
Type IV P-type ATPases (P4-ATPases) are phospholipid flippases that translocate phospholipids from the exoplasmic (or luminal) to the cytoplasmic leaflet of lipid bilayers. In Saccharomyces cerevisiae, P4-ATPases are localized to specific subcellular compartments and play roles in compartment-mediated membrane trafficking; however, roles of mammalian P4-ATPases in membrane traffic are poorly understood. We previously reported that ATP9A, one of 14 human P4-ATPases, is localized to endosomal compartments and the Golgi complex...
October 12, 2016: Molecular Biology of the Cell
Jason Yi, Asit Manna, Valarie A Barr, Jennifer Hong, Keir C Neuman, Lawrence E Samelson
Investigation of heterogeneous cellular structures using single molecule localization microscopy has been limited by poorly defined localization accuracy and inadequate multiplexing capacity. Utilizing fluorescent nano-diamonds as fiducial markers, we define and achieve localization precision required for single molecule accuracy in dSTORM images. Coupled with this advance, our new multiplexing strategy, madSTORM allows accurate targeting of multiple molecules using sequential binding and elution of fluorescent antibodies...
October 5, 2016: Molecular Biology of the Cell
Felicitas Rataj, Séverine Planel, Agnès Desroches-Castan, Juliette Le Douce, Khadija Lamribet, Josiane Denis, Jean-Jacques Feige, Nadia Cherradi
TIS11b/BRF1 belongs to the Tristetraprolin (TTP) family of zinc-finger proteins which bind to mRNAs containing AU-rich elements (ARE) in their 3'-untranslated region and target them for degradation. Regulation of TTP family function through phosphorylation by p38 MAPK and PKB/Akt signalling pathways has been extensively studied. In contrast, the role of cAMP-dependent protein kinase (PKA) in the control of TTP family activity in mRNA decay remains largely unknown. Here, we show that PKA activation induces TIS11b gene expression and protein phosphorylation...
October 5, 2016: Molecular Biology of the Cell
Samuel Génier, Jade Degrandmaison, Pierrick Moreau, Pascale Labrecque, Terence E Hébert, Jean-Luc Parent
Mechanisms that prevent aggregation and promote folding of nascent G protein-coupled receptors (GPCRs) remain poorly understood. We identified CCT7 as an interacting partner of the β-isoform of thromboxane A2 receptor (TPβ) by yeast two-hybrid screening. CCT7 coimmunoprecipitated with overexpressed TPβ and β2-adrenergic receptor (β2AR) in HEK 293 cells, but also with endogenous β2AR. CCT7 depletion by siRNA reduced total and cell surface expression of both receptors, and caused redistribution of the receptors to juxta-nuclear aggresomes, significantly moreso for TPβ than β2AR...
October 5, 2016: Molecular Biology of the Cell
Mengke Xing, Marshall C Peterman, Robert L Davis, Karen Oegema, Andrew K Shiau, Seth J Field
The mechanism of directional cell migration remains an important problem with relevance to cancer invasion and metastasis. GOLPH3 is a common oncogenic driver of human cancers, and is the first oncogene that functions at the Golgi in trafficking to the plasma membrane. Overexpression of GOLPH3 is reported to drive enhanced cell migration. Here we show that the PtdIns(4)P/GOLPH3/MYO18A/F-actin pathway that is critical for Golgi-to-plasma membrane trafficking is necessary and limiting for directional cell migration...
October 5, 2016: Molecular Biology of the Cell
Ying Li, Yeou-Cherng Bor, Mark P Fitzgerald, Kevin S Lee, David Rekosh, Marie-Louise Hammarskjold
The Nxf1 protein is a major nuclear export receptor for the transport of mRNA and it also is essential for export of retroviral mRNAs with retained introns. In the latter case, it binds to RNA elements known as Constitutive Transport Elements (CTEs) and functions in conjunction with a cofactor known as Nxt1. The NXF1 gene also regulates expression of its own intron-containing RNA through the use of a functional CTE within intron 10. mRNA containing this intron is exported to the cytoplasm where it can be translated into the 356 amino acid short Nxf1(sNxf1) protein, despite the fact that it is a prime candidate for nonsense mediated decay (NMD)...
October 5, 2016: Molecular Biology of the Cell
Avinash Chandel, Krishna K Das, Anand K Bachhawat
Glutathione depletion and calcium influx into the cytoplasm are two hallmarks of apoptosis. We have been investigating how glutathione depletion leads to apoptosis in yeast. We show here that glutathione depletion in yeast leads to the activation of two cytoplasmically inward facing channels, the plasma membrane, Cch1p and the vacuolar calcium channel, Yvc1p. Deletion of these channels partially rescues cells from glutathione depletion induced cell death. Subsequent investigations on the Yvc1p channel, a homolog of the mammalian TRP channels, revealed that the channel is activated by glutathionylation...
October 5, 2016: Molecular Biology of the Cell
Raphael Jorand, Sunetra Biswas, Devin L Wakefield, Steven J Tobin, Ottavia Golfetto, Kelsey Hilton, Michelle Ko, Joe W Ramos, Alexander R Small, Peiguo Chu, Gagandeep Singh, Tijana Jovanovic-Talisman
Pancreatic ductal adenocarcinoma (PDAC), a particularly aggressive malignancy, has been linked to atypical levels, certain mutations, and aberrant signaling of G-protein coupled receptors (GPCRs). GPCRs have been challenging to target in cancer because they organize into complex networks in tumor cells. To dissect such networks with nanometer-scale precision, traditional biochemical approaches were combined herein with super-resolution microscopy methods. A novel interaction specific to PDAC was identified between mu opioid receptor (MOR) and somatostatin receptor 2 (SSTR2)...
September 28, 2016: Molecular Biology of the Cell
Zhengang Zhang, Wei Li, Yong Zhang, Ling Zhang, Maria E Teves, Hong Liu, Jerome F Strauss, Gregory J Pazour, James A Foster, Rex A Hess, Zhibing Zhang
Intraflagellar transport (IFT) is a conserved mechanism thought to be essential for the assembly and maintenance of cilia and flagella. However, little is known about its role in mammalian sperm flagella formation. To fill this gap, we disrupted the Ift20 gene in male germ cells. Homozygous mutant mice were infertile with significantly reduced sperm counts and motility. In addition, abnormally shaped elongating spermatid heads and bulbous round spermatids were found in the lumen of the seminiferous tubules...
September 28, 2016: Molecular Biology of the Cell
Devin Dersh, Yuichiro Iwamoto, Yair Argon
Loss of function of the enzyme β-hexosaminidase A (HexA) causes the lysosomal storage disorder Tay Sachs disease (TSD). It has been proposed that mutations in the α chain of HexA can impair folding, enzyme assembly, and/or trafficking, yet there is surprisingly little known about the mechanisms of these potential routes of pathogenesis. We therefore investigated the biosynthesis and trafficking of TSD-associated HexA α mutants, seeking to identify relevant cellular quality control mechanisms. α mutants E482K and G269S are defective in enzymatic activity, unprocessed by lysosomal proteases, and exhibit altered folding pathways compared to WT α...
September 28, 2016: Molecular Biology of the Cell
Cristina Manatschal, Ana-Maria Farcas, Miriam Steiner Degen, Mathias Bayer, Anil Kumar, Christiane Landgraf, Rudolf Volkmer, Yves Barral, Michel O Steinmetz
The Kar9 pathway promotes nuclear fusion during mating and spindle alignment during metaphase in budding yeast. How Kar9 supports the different outcome of these two divergent processes is an open question. Here, we show that three sites in the C-terminal disordered domain of Kar9 mediate tight Kar9 interaction with the C-terminal dimerization domain of Bim1 (EB1 orthologue). Site1 and Site2 contain SxIP motifs; however, Site3 defines a novel type of EB1-binding site. Whereas Site2 and Site3 mediate Kar9 recruitment to microtubule tips, nuclear movement and karyogamy, solely Site2 functions in spindle positioning during metaphase...
September 28, 2016: Molecular Biology of the Cell
Jonathan X Chia, Nadia Efimova, Tatyana M Svitkina
Actin polymerization is a universal mechanism to drive plasma membrane protrusion in motile cells. One apparent exception to this rule is continuing, or even accelerated outgrowth of neuronal processes in the presence of actin polymerization inhibitors. This fact together with a key role of microtubule dynamics in neurite outgrowth led to the concept that microtubules directly drive plasma membrane protrusion, either in the course of polymerization or motor-driven sliding. Surprisingly, a possibility that unextinguished actin polymerization drives neurite outgrowth in the presence of actin drugs was not explored...
September 28, 2016: Molecular Biology of the Cell
Stefan F Ehrentraut, Valerie F Curtis, Ruth X Wang, Bejan J Saeedi, Heidi Ehrentraut, Joseph C Onyiah, Caleb J Kelly, Eric L Campbell, Louise E Glover, Douglas J Kominsky, Sean P Colgan
Recent work has revealed a central role for neddylation (the conjugation of a Nedd8-moiety to Cullin proteins) in the fine tuning of the NF-κB response (via Cullin-1). In the present study, we investigated the contribution of Cullin-1 neddylation and NF-κB signaling to mucosal inflammatory responses in vitro and in vivo. Initial in vitro studies using cultured intestinal epithelial cells revealed that the neddylation inhibitor MLN4924 prominently induces the deneddylation of Cullin-1. Parallel western blot, luciferase reporter and gene target assays identified MLN4924 as a potent inhibitor of intestinal epithelial NF-κB...
September 28, 2016: Molecular Biology of the Cell
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