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Christy R Gaines, Emre Tkacik, Amalia Rivera-Oven, Phoebe Somani, Alecia Achimovich, Tawakalitou Alabi, Angela Zhu, Noel Getachew, Ae Lim Yang, Matthew McDonough, Tarik Hawkins, Zoe Spadaro, Michael F Summers
The N-terminally myristoylated matrix domain (MA) of the HIV-1 Gag polyprotein promotes virus assembly by targeting Gag to the inner leaflet of the plasma membrane (PM). Recent studies indicate that, prior to membrane binding, MA associates with cytoplasmic tRNAs (including tRNALys3 ), and in vitro studies of tRNA-dependent MA interactions with model membranes have led to proposals that competitive tRNA interactions contribute to membrane discrimination. We have characterized interactions between native, mutant, and unmyristylated (myr-) MA proteins and recombinant tRNALys3 by NMR spectroscopy and isothermal titration calorimetry (ITC)...
May 9, 2018: Journal of Molecular Biology
Mark R Lundquist, Marcus D Goncalves, Ryan M Loughran, Elite Possik, Tarika Vijayaraghavan, Annan Yang, Chantal Pauli, Archna Ravi, Akanksha Verma, Zhiwei Yang, Jared L Johnson, Jenny C Y Wong, Yilun Ma, Katie Seo-Kyoung Hwang, David Weinkove, Nullin Divecha, John M Asara, Olivier Elemento, Mark A Rubin, Alec C Kimmelman, Arnim Pause, Lewis C Cantley, Brooke M Emerling
While the majority of phosphatidylinositol-4, 5-bisphosphate (PI-4, 5-P2 ) in mammalian cells is generated by the conversion of phosphatidylinositol-4-phosphate (PI-4-P) to PI-4, 5-P2 , a small fraction can be made by phosphorylating phosphatidylinositol-5-phosphate (PI-5-P). The physiological relevance of this second pathway is not clear. Here, we show that deletion of the genes encoding the two most active enzymes in this pathway, Pip4k2a and Pip4k2b, in the liver of mice causes a large enrichment in lipid droplets and in autophagic vesicles during fasting...
May 3, 2018: Molecular Cell
Vamseedhar Rayaprolu, Perrine Royal, Karen Stengel, Guillaume Sandoz, Susy C Kohout
Multimerization is a key characteristic of most voltage-sensing proteins. The main exception was thought to be the Ciona intestinalis voltage-sensing phosphatase (Ci-VSP). In this study, we show that multimerization is also critical for Ci-VSP function. Using coimmunoprecipitation and single-molecule pull-down, we find that Ci-VSP stoichiometry is flexible. It exists as both monomers and dimers, with dimers favored at higher concentrations. We show strong dimerization via the voltage-sensing domain (VSD) and weak dimerization via the phosphatase domain...
April 25, 2018: Journal of General Physiology
Zhengpeng Wan, Chenguang Xu, Xiangjun Chen, Hengyi Xie, Zongyu Li, Jing Wang, Xingyu Ji, Haodong Chen, Qinghua Ji, Samina Shaheen, Yang Xu, Fei Wang, Zhuo Tang, Ji-Shen Zheng, Wei Chen, Jizhong Lou, Wanli Liu
B lymphocytes use B cell receptors (BCRs) to sense the chemical and physical features of antigens. The activation of isotype-switched IgG-BCR by mechanical force exhibits a distinct sensitivity and threshold in comparison with IgM-BCR. However, molecular mechanisms governing these differences remain to be identified. In this study, we report that the low threshold of IgG-BCR activation by mechanical force is highly dependent on tethering of the cytoplasmic tail of the IgG-BCR heavy chain (IgG-tail) to the plasma membrane...
April 23, 2018: Journal of Cell Biology
Malvina Schatz, Phuoc Bao Viet Tong, Bruno Beaumelle
Although largely less numerous and characterized than bacterial secreted effectors, several viral virulence factors are secreted by virus infected cells. However, their mode of secretion only starts to be studied at the molecular level. Several of these viral effectors are secreted using an unconventional secretion pathway, i.e. despite the lack of signal sequence. We here review recent results illustrating the diversity of these pathways. In the case of HIV-1 proteins Tat and matrix (p17) proteins, secretion directly takes place at the plasma membrane level following binding to PI(4,5)P2 ...
March 20, 2018: Seminars in Cell & Developmental Biology
Nassima Chouaki-Benmansour, Kilian Ruminski, Anne-Marie Sartre, Marie-Claire Phelipot, Audrey Salles, Elise Bergot, Ambroise Wu, Gaëtan Chicanne, Mathieu Fallet, Sophie Brustlein, Cyrille Billaudeau, Anthony Formisano, Sébastien Mailfert, Bernard Payrastre, Didier Marguet, Sophie Brasselet, Yannick Hamon, Hai-Tao He
Phosphoinositides (PIs) play important roles in numerous membrane-based cellular activities. However, their involvement in the mechanism of T cell receptor (TCR) signal transduction across the plasma membrane (PM) is poorly defined. Here, we investigate their role, and in particular that of phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2] in TCR PM dynamics and activity in a mouse T-cell hybridoma upon ectopic expression of a PM-localized inositol polyphosphate-5-phosphatase (Inp54p). We observed that dephosphorylation of PI(4,5)P2 by the phosphatase increased the TCR/CD3 complex PM lateral mobility prior stimulation...
March 21, 2018: Scientific Reports
Dan Chen, Chao Yang, Sha Liu, Weijian Hang, Xianghong Wang, Juan Chen, Anbing Shi
Arf6/ARF-6 is a crucial regulator of the endosomal phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) pool in endocytic recycling. To further characterize ARF-6 regulation, we performed an ARF-6 interactor screen in Caenorhabditis elegans and identified SAC-1, the homologue of the phosphoinositide phosphatase Sac1p in yeast, as a novel ARF-6 partner. In the absence of ARF-6, basolateral endosomes show a loss of SAC-1 staining in epithelial cells. Steady-state cargo distribution assays revealed that loss of SAC-1 specifically affected apical secretory delivery and basolateral recycling...
March 21, 2018: Journal of Cell Biology
Eric Barklis, August O Staubus, Andrew Mack, Logan Harper, Robin Lid Barklis, Ayna Alfadhli
The matrix (MA) domain of the HIV-1 precursor Gag protein (PrGag) has been shown interact with the HIV-1 envelope (Env) protein, and to direct PrGag proteins to plasma membrane (PM) assembly sites by virtue of its affinity to phosphatidylinositol-4,5-bisphosphate (PI[4,5]P2). Unexpectedly, HIV-1 viruses with large MA deletions (ΔMA) have been shown to be conditionally infectious as long as they are matched with Env truncation mutant proteins or alternative viral glycoproteins. To characterize the interactions of wild type (WT) and ΔMA Gag proteins with PI(4,5)P2 and other acidic phospholipids, we have employed a set of lipid biosensors as probes...
May 2018: Virology
Daniel V Olivença, Inna Uliyakina, Luis L Fonseca, Margarida D Amaral, Eberhard O Voit, Francisco R Pinto
Phosphoinositides are signalling lipids that constitute a complex network regulating many cellular processes. We propose a computational model that accounts for all species of phosphoinositides in the plasma membrane of mammalian cells. The model replicates the steady-state of the pathway and most known dynamic phenomena. Sensitivity analysis demonstrates model robustness to alterations in the parameters. Model analysis suggest that the greatest contributor to phosphatidylinositol 4,5-biphosphate (PI(4,5)P2 ) production is a flux representing the direct transformation of PI into PI(4,5)P2 , also responsible for the maintenance of this pool when phosphatidylinositol 4-phosphate (PI(4)P) is decreased...
March 2, 2018: Scientific Reports
Mira Sohn, Marek Korzeniowski, James P Zewe, Rachel C Wills, Gerald R V Hammond, Jana Humpolickova, Lukas Vrzal, Dominika Chalupska, Vaclav Veverka, Gregory D Fairn, Evzen Boura, Tamas Balla
Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 ) is a critically important regulatory lipid of the plasma membrane (PM); however, little is known about how cells regulate PM PI(4,5)P2 levels. Here, we show that the phosphatidylinositol 4-phosphate (PI4P)/phosphatidylserine (PS) transfer activity of the endoplasmic reticulum (ER)-resident ORP5 and ORP8 is regulated by both PM PI4P and PI(4,5)P2 Dynamic control of ORP5/8 recruitment to the PM occurs through interactions with the N-terminal Pleckstrin homology domains and adjacent basic residues of ORP5/8 with both PI4P and PI(4,5)P2 Although ORP5 activity requires normal levels of these inositides, ORP8 is called on only when PI(4,5)P2 levels are increased...
May 7, 2018: Journal of Cell Biology
Hai H Bui, Phillip E Sanders, Diane Bodenmiller, Ming Shang Kuo, Gregory P Donoho, Anthony S Fischl
Phosphatidylinositol (3,4,5) trisphosphate (PIP3 ) is a biologically active membrane phospholipid that is essential for the growth and survival of all eukaryotic cells. We describe a new method that directly measures PIP3 and describe the HPLC separation and measurement of the positional isomers of phosphatidylinositol bisphosphate, PI(3,5)P2 , PI(3,4)P2 and PI(4,5)P2 . Mass spectrometric analyses were performed online using ultra-high performance liquid chromatography (UHPLC)-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) in the negative multiple-reaction monitoring (MRM) modes...
April 15, 2018: Analytical Biochemistry
Marina Besprozvannaya, Eamonn Dickson, Hao Li, Kenneth S Ginburg, Donald M Bers, Johan Auwerx, Jodi Nunnari
Endoplasmic reticulum (ER) membrane contact sites (MCSs) are crucial regulatory hubs in cells, playing roles in signaling, organelle dynamics, and ion and lipid homeostasis. Previous work demonstrated that the highly conserved yeast Ltc/Lam sterol transporters localize and function at ER MCSs. Our analysis of the human family members, GRAMD1a and GRAMD2a, demonstrates that they are ER-PM MCS proteins, which mark separate regions of the plasma membrane (PM) and perform distinct functions in vivo. GRAMD2a, but not GRAMD1a, co-localizes with the E-Syt2/3 tethers at ER-PM contacts in a PIP lipid-dependent manner and pre-marks the subset of PI(4,5)P2-enriched ER-PM MCSs utilized for STIM1 recruitment...
February 22, 2018: ELife
Julia P Steringer, Walter Nickel
As illustrated by a diverse set of examples in this special issue, multiple mechanisms of protein secretion have been identified in eukaryotes that do not involve the endoplasmic reticulum (ER) and the Golgi apparatus. Here we focus on the type I pathway with Fibroblast Growth Factor 2 (FGF2) being the most prominent example. Unconventional secretion of FGF2 from cells is mediated by direct protein translocation across the plasma membrane. A unique feature of this process is the ability of FGF2 to form its own membrane translocation intermediate through oligomerization and membrane insertion...
March 5, 2018: Seminars in Cell & Developmental Biology
Chun Liu, Sanghamitra Deb, Vinicius S Ferreira, Eric Xu, Tobias Baumgart
Phosphatidylinositides play important roles in cellular signaling and migration. Phosphatidylinositol-3,4,5-trisphosphate (PI(3,4,5)P3) is an important phosphatidylinositide because it acts as a secondary messenger to trigger cell movement and proliferation. A high level of PI(3,4,5)P3 at the plasma membrane is known to contribute to tumorigenesis. One key enzyme that regulates PI(3,4,5)P3 levels at the plasma membrane is phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which dephosphorylates PI(3,4,5)P3 through hydrolysis to form phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2)...
2018: PloS One
Xiaofan Chen, Jun Wan, Bo Yu, Yarui Diao, Wei Zhang
BACKGROUND: Skeletal muscle satellite cell-derived myoblasts are mainly responsible for postnatal muscle growth and injury-induced regeneration. Many intracellular signaling pathways are essential for myogenic differentiation, while a number of kinases are involved in this modulation process. Type I phosphatidylinositol 4-phosphate 5-kinase (PIP5KI) was identified as one of the key kinases involved in myogenic differentiation, but the underlying molecular mechanism is still unclear. METHODS: PIP5K1α was quantified by quantitative reverse transcriptase PCR and western blot assay...
February 9, 2018: Stem Cell Research & Therapy
Markku Hakala, Maria Kalimeri, Giray Enkavi, Ilpo Vattulainen, Pekka Lappalainen
Membrane phosphoinositides control organization and dynamics of the actin cytoskeleton by regulating the activities of several key actin-binding proteins. Twinfilin is an evolutionarily conserved protein that contributes to cytoskeletal dynamics by interacting with actin monomers, filaments, and the heterodimeric capping protein. Twinfilin also binds phosphoinositides, which inhibit its interactions with actin, but the underlying mechanism has remained unknown. Here, we show that the high-affinity binding site of twinfilin for phosphoinositides is located at the C-terminal tail region, whereas the two actin-depolymerizing factor (ADF)/cofilin-like ADF homology domains of twinfilin bind phosphoinositides only with low affinity...
March 30, 2018: Journal of Biological Chemistry
Thomas Stanislas, Matthieu Pierre Platre, Mengying Liu, Léa E S Rambaud-Lavigne, Yvon Jaillais, Olivier Hamant
BACKGROUND: In plants, the shoot apical meristem (SAM) has two main functions, involving the production of all aerial organs on the one hand and self-maintenance on the other, allowing the production of organs during the entire post-embryonic life of the plant. Transcription factors, microRNA, hormones, peptides and forces have been involved in meristem function. Whereas phosphatidylinositol phosphates (PIPs) have been involved in almost all biological functions, including stem cell maintenance and organogenesis in animals, the processes in meristem biology to which PIPs contribute still need to be delineated...
February 7, 2018: BMC Biology
Samsuzzoha Mondal, Amitava Chandra, Ravindra Venkatramani, Ankona Datta
We present a systematic experimental and computational study of phospholipid induced peptide coil-helix transitions which are relevant in the context of proteins mediating cytoskeletal rearrangement via membrane binding. We developed a sensitive Förster resonance energy transfer (FRET) based assay to address whether coil-helix transitions in phospholipid binding motifs of actin-binding proteins can be induced by physiologically-relevant concentrations (1-20 μM) of phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) phospholipids...
April 17, 2018: Faraday Discussions
Justyna M Meissner, Jay M Bhatt, Eunjoo Lee, Melanie L Styers, Anna A Ivanova, Richard A Kahn, Elizabeth Sztul
ADP-ribosylation factors (ARF) GTPases are activated by guanine nucleotide exchange factors (GEFs) to support cellular homeostasis. Key to understanding spatio-temporal regulation of ARF signaling is the mechanism of GEF recruitment to membranes. Small GEFs are recruited through phosphoinositide (PIP) binding by a pleckstrin homology (PH) domain downstream from the catalytic Sec7 domain (Sec7d). The large GEFs lack PH domains, and their recruitment mechanisms are poorly understood. We probed Golgi recruitment of GBF1, a GEF catalyzing ARF activation required for Golgi homeostasis...
February 5, 2018: Journal of Cell Science
Thanh Kha Phan, Fung T Lay, Mark D Hulett
Host defense peptides (HDPs) are well-characterized for their antimicrobial activities but also variously display potent immunomodulatory effects. Human β-defensin 3 (HBD-3) belongs to a well-known HDP family known as defensins and is able to induce leukocyte chemotactic recruitment, leukocyte activation/maturation, proinflammatory cytokine release, and co-stimulatory marker expression. HBD-3-stimulated cytokine induction is NF-κB-dependent and was initially suggested to act via G protein-coupled C-C chemokine receptor phospholipase C (PLC) and/or Toll-like receptor signaling...
January 2018: Immunology and Cell Biology
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