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Filling in the GAPs in GLUT4 trafficking

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Filling in the GAPs in GLUT4 trafficking

ITPK1 is an InsP_(6)/ADP phosphotransferase that controls phosphate signaling in Arabidopsis.

细胞—生命的基础——中国细胞生物学学会2013年全国学术大会·武汉

作者： Hong Yu Wang Bingxian Xie Chao Quan Qiaoli Chen Liang Chen Kei Sakamoto Carol MacKintosh Shuai Chen MOE Key Laboratory of Model Animal for Disease Study Model Animal Research CenterNanjing University Nestle Institute of Health Sciences SA Campus EPFLQuartier de l'Innovation mrc Protein Phosphorylation unit College of Life SciencesUniversity of Dundee Division of cell and Developmental Biology College of Life SciencesUniversity of Dundee

Blood sugar lowering effect is one of the major functions of insulin,and insulin sensitivity is most often referred to its ability to regulate glucose *** binding to its receptor,insulin shifts phospho-proteome to stimulate translocation of glucose transporter GLUT4 onto cell surface in skeletal muscle and fat for assimilation of glucose from the *** of this process can directly cause type II diabetes(T2D).Type II diabetic patients often receive treatments such as exercise

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Molecular Plant 2021年第11期14卷 1864-1880页

作者： Esther Riemer Danye Qiu Debabrata Laha Robert K.Harmel Philipp Gaugler Verena Gaugler Michael Frei Mohammad-Reza Hajirezaei Nargis Parvin Laha Lukas Krusenbaum Robin Schneider Adolfo Saiardi Dorothea Fiedler Henning J.Jessen Gabriel Schaaf Ricardo F.H.Giehl Department of Plant Nutrition Institute of Crop Science and Resource ConservationRheinische Friedrich-Wilhelms-Universitat Bonn53115 BonnGermany Department of Chemistry and Pharmacy and CIBSS-Centre for Integrative Biological Signalling Studies Albert-Ludwigs University Freiburg79104 FreiburgGermany Medical Research Council Laboratory for Molecular cell Biology(mrc-LMCB) University College LondonLondon WC1E 6BTUK Department of Biochemistry Indian Institute of ScienceBengaluruKarnataka 560012India Leibniz-Forschungsinstitut fur Molekulare Pharmakologie 13125 BerlinGermany Department of Chemistry Humboldt Universitat zu Berlin12489 BerlinGermany Institute of Agronomy and Crop Physiology Justus-Liebig University Giessen35392 GiessenGermany Department of Physiology&cell Biology Leibniz-lnstitute of Plant Genetics and Crop Plant Research06466 GaterslebenGermany

In plants, phosphate (Pi) homeostasis is regulated by the interaction of PHR transcription factors with stand-alone SPX proteins, which act as sensors for inositol pyrophosphates. Here, we combined different methods to obtain a comprehensive picture of how inositol (pyro)phosphate metabolism is regulated by Pi and dependent on the inositol phosphate kinase ITPK1. We found that inositol pyrophosphates are more responsive to Pi than lower inositol phosphates, a response conserved across kingdoms. With CE-ESI-MS we could separate different InsP7 isomers in Arabidopsis and rice, and identify 4/6-InsP7 and a PP-InsP4 isomer hitherto not reported in plants. We found that the inositol pyrophosphates 1/3-InsP7, 5-InsP7 and InsP8 increase severalfold in shoots after Pi resupply and that tissue-specific accumulation of inositol pyrophosphates relies on ITPK1 activities and MRP5-dependent InsP6 compartmentalization. Notably, ITPK1 is critical for Pi-dependent 5-InsP7 and InsP8 synthesis in planta and its activity regulates Pi starvation responses in a PHR-dependent manner. Furthermore, we demonstrate that ITPK1-mediated conversion of InsP6 to 5-InsP7 requires high ATP concentrations and that Arabidopsis ITPK1 has an ADP phosphotransferase activity to dephosphorylate specifically 5-InsP7 under low ATP. Collectively, our study provides deeper insights into Pi-dependent changes in nutritional and energetic states with the synthesis of regulatory inositol pyrophosphates.

关键词： diphosphoinositol pentakisphosphate kinase inositol 1,3,4-trisphosphate 5/6-kinase 1 inositol phosphates inositol pyrophosphates phosphate homeostasis phosphate signaling

A variant in IL6ST with a selective IL-11 signaling defect in human and mouse

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Bone Research 2020年第2期8卷 157-168页

作者： Tobias Schwerd Freia Krause Stephen R.F.Twigg Dominik Aschenbrenner Yin-Huai Chen Uwe Borgmeyer Miryam Müller Santiago Manrique Neele Schumacher Steven A.Wall Jonathan Jung Timo Damm Claus-Christian Glüer Jürgen Scheller Stefan Rose-John E.Yvonne Jones Arian Laurence Andrew O.M.Wilkie Dirk Schmidt-Arras Holm H.Uhlig Translational Gastroenterology unit John Radcliffe HospitalUniversity of OxfordOxfordUK Department of Pediatrics Dr von Hauner Children’s HospitalLMU MunichMunichGermany Christian-Albrechts-University Kiel Institute of BiochemistryKielGermany Clinical Genetics Group MRC Weatherall Institute of Molecular MedicineUniversity of OxfordJohn Radcliffe HospitalOxfordUK Center for Molecular Neurobiology Hamburg(ZMNH) University Medical Center Hamburg-EppendorfHamburgGermany Division of Structural Biology Wellcome Trust Centre for Human GeneticsUniversity of OxfordOxfordUK Craniofacial unit Department of Plastic and Reconstructive SurgeryOxford University Hospitals NHS Foundation TrustJohn Radcliffe HospitalOxfordUK Section Biomedical Imaging Department of Radiology and NeuroradiologyUniversity Medical Center Schleswig-HolsteinKielGermany Institute of Biochemistry and Molecular Biology Ⅱ Medical FacultyHeinrich-Heine-UniversityDüsseldorfGermany Department of Paediatrics University of OxfordOxfordUK NIHR Oxford Biomedical Research Centre OxfordUK The Beatson Institute for cancer Research GlasgowUK School of Medicine University of GlasgowGlasgowUK

The GP130 cytokine receptor subunit encoded by IL6ST is the shared receptor for ten cytokines of the IL-6 family. We describe a homozygous non-synonymous variant in IL6 ST(p.R281 Q) in a patient with craniosynostosis and retained deciduous teeth. We characterize the impact of the variant on cytokine signaling in vitro using transfected cell lines as well as primary patient-derived cells and support these findings using a mouse model with the corresponding genome-edited variant Il6 st p.R279 Q. We show that human GP130 p.R281 Q is associated with selective loss of IL-11 signaling without affecting IL-6, IL-27, OSM, LIF, CT1, CLC, and CNTF signaling. In mice Il6 st p.R279 Q lowers litter size and causes facial synostosis and teeth abnormalities. The effect on IL-11 signaling caused by the GP130 variant shows incomplete penetrance but phenocopies aspects of IL11 RA deficiency in humans and mice. Our data show that a genetic variant in a pleiotropic cytokine receptor can have remarkably selective defects.

关键词： IL11 cytokine facial

ER stress-induced aggresome trafficking of HtrA1 protects against proteotoxicity

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Journal of Molecular cell Biology 2017年第6期9卷 516-532页

作者： Maximilian J. Gerhardt Joseph A. Marsh Margaux Morrison Andrius Kazlauskas Arogya Khadka Stephan Rosenkranz Margaret M. DeAngelis Magali Saint-Geniez Sarah Melissa P. Jacobo Department of Ophthalmology Harvard Medical School The Schepens Eye Research Institute and Massachusetts Eye and Ear Infirmary Boston MA 02114 USA Department III of Internal Medicine Cologne University Heart Center Center for Molecular Medicine University of Cologne 50931 Cologne Germany mrc Human Genetics unit Institute of Genetics and Molecular Medicine University of Edinburgh Edinburgh EH4 2XU UK Department of Ophthalmology and Visual Sciences University of Utah and John A. Moran Eye Center Salt Lake City UT 84132 USA

High temperature requirement A1 （HtrA1） belongs to an ancient protein family that is linked to various human disorders. The pre- cise role of exon 1-encoded N-terminal domains and how these influence the biological functions of human HtrAZ remain elusive. In this study, we traced the evolutionary origins of these N-terminal domains to a single gene fusion event in the most recent common ancestor of vertebrates. We hypothesized that human HtrA1 is impticated in unfotded protein response. ｜n highly secre- tory cells of the retinal pigmented epithelia, endoplasmic reticulum （ER） stress upregulated HtrA1. HtrA1 co-localized with vimen- tin intermediate filaments in highly arborized fashion. Upon ER stress, HtrA1 tracked along intermediate filaments, which collapsed and bundled in an aggresome at the microtubule organizing center. Gene silencing of HtrA1 altered the schedule and amplitude of adaptive signaling and concomitantly resulted in apoptosis. Restoration of wild-type HtrA1, but not its protease inactive mutant, was necessary and sufficient to protect from apoptosis. A variant of HtrA1 that harbored exon 1 substitutions dis- played reduced efficacy in rescuing cells from proteotoxicity. Our results illuminate the integration of HtrA1 in the toolkit of mam- malian cells against protein misfolding and the implications of defects in HtrA1 in proteostasis.

关键词： ER stress unfolded protein response RPE HtrA1 multi-domain protein evolution proteostasis

Differential Expressions of Selected Activating and Inhibitory Receptors on K562-Stimulated Natural Killer (NK) cells in HIV-1 and HIV-2 Infections

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World Journal of AIDS 2015年第1期5卷 21-29页

作者： Samuel V. Nuvor Sarah Rowland-Jones Hilton Whittle Assan Jaye mrc Laboratories Fajara Banjul The Gambia School of Medical Sciences University of Cape Coast Cape Coast Ghana mrc Human Immunology unit Weatherall Institute of Molecular Medicine John Radcliffe Hospital Oxford UK London School of Hygiene & Tropical Medicine London UK Hopital A. Le Dantec Laboratoire de Bacteriologie Virologie (LBV) Universite Cheikh Anta Diop (UCAD) Dakar Senegal

Context: The functional activity of NK cells depends on the balance between the engagement of activating and inhibitory receptors on the cell surface with their ligands, which enables them to kill infected cells. Objectives: The aim of this study was to evaluate and compare expressions of selected activating and inhibitory receptors on stimulated NK cells in HIV-1 and HIV-2 infections. Methods: PBMCs were analysed for activating (NKp30, NKp44, NKp46) and inhibitory (CD158a, CD158b, p70) receptor expressions in 30 HIV-1, 30 HIV-2 and 30 HIV uninfected healthy control (HC) subjects by flow cytometry after stimulating with K562 cells. Results: There was an expression of other receptors following an already in vitro engagement of NK cells with K562 cells. Higher expression of the activating receptors, NKp44 (p = 0.029) and NKp46 (p = 0.032) on NK cells from HIV-2 compared to HIV-1 infected individuals but similar NKp30 expression (p = 0.980). The levels of expression of inhibitory receptor CD158a were similar between HIV-1 and HIV-2 infected subjects (p = 0.309) but there was significant up-regulation of inhibitory receptors p70 (p = 0.010) and CD158b (p = 0.05) in HIV-1 compared to HIV-2 subjects. Conclusion: Despite the in vitro engagement of NK cells with stimulating K562 cells, our data showed differential expressions of other selected activating and inhibitory receptors in HIV-1 and HIV-2 infected subjects.

关键词： NK cells HIV-1 HIV-2 IFN-γ CD4 T cells

Higher Type 1 Interferon Levels in Plasma of Asymptomatic HIV-2 than in HIV-1 Individuals

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Advances in Infectious Diseases 2016年第1期6卷 15-23页

作者： Samuel V. Nuvor Hilton Whittle Sarah Rowland-Jones Assan Jaye mrc Laboratories Fajara Banjul The Gambia School of Medical Sciences University of Cape Coast Cape Coast Ghana London School of Hygiene & Tropical Medicine London UK mrc Human Immunology unit Weatherall Institute of Molecular Medicine John Radcliffe Hospital Oxford UK Hospital A. le Dantec Laboratoire de Bacteriologie Virologie (LBV) Universite Cheikh Anta Diop (UCAD) Dakar Senegal

A number of cytokines are secreted during HIV infection that enhances both innate and adaptive immune responses. Interferon-α/β/γ, IL-12, IL-15 and IL-18 have been found to contribute to the development, maturation, differentiation and function of NK and other immune cells. The levels of IFN-α/β/γ, IL-12, IL-15 and IL-18 were compared in the plasma of 90 HIV-1 infected and 90 HIV-2 infected subjects by ELISA or Cytometric Beads Array assays. The HIV-infected subjects were stratified according to CD4+ T cell counts into three groups: >500, 200 - 500 and cells/ul, with 30 subjects in each group. Cytokine levels were also determined in the plasma of 50 HIV uninfected blood bank donors. Among the cytokines tested, IFN-α was found to be significantly increased in HIV-2 infected compared to HIV-1 infected subjects at high CD4+ T cell counts (p = 0.001). The levels of IFN-β were seen to differ between the two infections in patients from the category of medium CD4+ T cell counts: this was significantly increased in HIV-2 infected patients (p + T cell categories except for an increase in HIV-2 infected patients at low CD4+ T cell counts (p = 0.02). The levels of these cytokines were similar in all HIV-1 subjects. Also, the level of IL-12p70 was similar between the two infections but significantly higher in HIV-2 at low compared to medium CD4+ T cells categories (p = 0.047). Similar to IFN-γ and IL-12p70, the levels of both IL-18 and IL-15 were found to be significantly higher in HIV-2 infected patients compared to HIV-1 at low CD4+ T cell counts (p < 0.05). These data show that there is variability in the levels of innate cytokines at different stages of HIV infection but the finding of increased IFN-α in HIV-2 infected asymptomatic subjects is consistent with the high innate NK respo

关键词： Type I Interferon HIV-I HIV-2 Cytokines Interleukins

The role of the osteocyte in bone turnover

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The role of the osteocyte in bone turnover

Extracellular vesicles as mediators of alloimmunity and their therapeutic potential in liver transplantation

International Conference on Osteoporosis and Bone Research 2008

作者： Brendon Noble mrc Centre for Regenerative Medicine Edinburgh UniversityUK

＜正＞Osteocytes are the most abundant cell type in bone;however,they remain the least characterized of *** theories have been proposed regarding their function,including;osteolysis,sensing the strains produced in response to mechanical loading of bones and producing signals that affect the function of osteoblasts and osteo-

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World Journal of Transplantation 2020年第11期10卷 330-344页

作者： Sotiris Mastoridis Marc Martinez-Llordella Alberto Sanchez-Fueyo Department ofSurgery Oxford University HospitalsOxford OX37LEUnited Kingdom Institute of Liver Studies King's College HospitalMedical Research Council(MRC)Centre for TransplantationLondon SE59NUUnited Kingdom Department of Liver Sciences King's College HospitalMedical Research Council(MRC)Centre for TransplantationLondon SE59NUUnited Kingdom

Extracellular vesicles(EVs)are a heterogenous group of nanosized,membranebound particles which are released by most cell *** are known to play an essential role in cellular communication by way of their varied cargo which includes selectively enriched proteins,lipids,and nucleic *** the last two decades,wide-ranging evidence has established the involvement of EVs in the regulation of immunity,with EVs released by immune and non-immune cells shown to be capable of mediating immune stimulation or suppression and to drive inflammatory,autoimmune,and infectious disease *** recently,studies have demonstrated the involvement of allograft-derived EVs in alloimmune responses following transplantation,with EVs shown to be capable of eliciting allograft rejection as well as promoting *** insights are necessitating the reassessment of standard paradigms of T cell *** this article,we explore the latest understanding of the impact of EVs on alloresponses following transplantation and we highlight the recent technological advances which have enabled the study of EVs in clinical ***,we discuss the rapid progress afoot in the development of EVs as novel therapeutic vehicles in clinical transplantation with particular focus on liver transplantation.

关键词： Extracellular vesicle Transplantation Liver Alloimmunity Tolerance Therapy

Generation and characterization of novel stromal specific antibodies

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cell Research 2005年第9期 64-69页

作者： Sapna HALDER,Debbie L. HARDIE,Dagmar SCHEEL-TOELLNER,Mike SALMON,Christopher D. BUCKLEY Prostate cancer Research Centre Institute of Urology (3rd floor) University College London 67 Riding House Street London W1W 7EJ UK Rheumatology Research Group mrc Centre for Immune Regulation Institute of Biomedical Research (3rd or 4th floor) University of Birmingham Birmingham B15 2TT U K Rheumatology Research Group mrc Centre for Immune Regulation Institute of Biomedical Research (3rd or 4th floor) University of Birmingham Birmingham B15 2TT U K Rheumatology Research Group mrc Centre for Immune Regulation Institute of Biomedical Research (3rd or 4th floor) University of Birmingham Birmingham B15 2TT U K Rheumatology Research Group mrc Centre for Immune Regulation Institute of Biomedical Research (3rd or 4th floor) University of Birmingham Birmingham B15 2TT U K

Rheumatoid synovial fibroblasts were used as an immunogen to produce monoclonal antibodies selected for their reactivity with stromal cell antigens. Mice were immunised with low passage whole cell preparations and the subsequent hybridomas were screened by immunohistochemistry on rheumatoid synovium and tonsil sections. The aim was to identify those antibodies that recognised antigens that were restricted to stromal cells and were not expressed on CD45 positive leucocytes. A significant number of antibodies detected antigen that identified endothelial cells. These antibodies were further characterised to determine whether the vessels identified by these antibodies were vascular or lymphatic. From five fusions clones were identified with predominant reactivity with: 1) fibroblasts and endothelial cells; or 2) broad stromal elements (fibroblast, endothelium, epithelium, follicular dendritic cells). A fibroblast-specific antibody that did not also identify vessels was not generated. Examples of each reactivity pattern are discussed.

关键词： stromal mesenchymal non-haematopoietic rheumatoid fibroblasts CD45.