A01 Project Movie
A01
In the 1st funding period we identified novel components of NAADP signaling (DUOX2, HN1L/JPT2, RYR1). By combining our expertise regarding Ca2+ signaling and central nervous system (CNS) autoimmunity, we will (i) unravel regulation of the NAADPH/NAADP redox cycle by DUOX enzymes and glucose 6-phosphate dehydrogenase (GLC6P-DH), (ii) probe CNS autoimmunity by knock-out of DUOX enzymes and availability of substrate O2, (iii) analyze HN1L/JPT2’s binding sites for NAADP and for RYR1, (iv) construct and validate a sensor for intracellular NAADP imaging, and (v) probe the role of NAADP signaling in T cell mediated autoimmunity in vivo.
Prof. Dr. Dr. Andreas H. Guse
E-Mail: guse©uke.uni-hamburg.de
www: Dept. of Biochemistry and Molecular Cell Biology, University Medical Centre Hamburg-Eppendorf (UKE)
Prof. Dr. Alexander Flügel
E-Mail: fluegel©med.uni-goettingen.de
www: Institute for Neuroimmunology and Multiple Sclerosis Research, University Medical Center Göttingen (UMG)
Prof. Dr. Dr. Andreas H. Guse
Selected publications (*equal contribution)
- Brock VJ, Wolf IMA, Er-Lukowiak M, Lory N, Stähler T, Woelk LM, Mittrücker HW, Müller CE, Koch-Nolte F, Rissiek B, Werner R, Guse AH, Diercks BP. P2X4 and P2X7 are essential players in basal T cell activity and Ca2+ signaling milliseconds after T cell activation. Science Adv. 2022; 8(5):eabl9770.
- Gu F, Krüger A, Roggenkamp HG, Alpers R, Lodygin D, Jaquet V, Möckl F, Hernandez C LC, Winterberg K, Bauche A, Rosche A, Grasberger H, Kao JY, Schetelig D, Werner R, Schröder K, Carty M, Bowie AG, Huber S, Meier C, Mittrücker HW, Heeren J, Krause KH, Flügel A, Diercks B-P*, Guse AH*. Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are necessary for Ca2+ signaling during T cell activation. Science Signal. 2021; 14 eabe3800.
- Roggenkamp HG, Khansahib I, Hernandez C LC, Zhang Y, Lodygin D, Krüger A, Gu F, Möckl F, Löhndorf A, Wolters V, Woike D, Rosche A, Bauche A, Schetelig D, Werner R, Schlüter H, Failla AV, Meier C, Fliegert R, Walseth TF, Flügel A, Diercks B-P*, Guse AH*. HN1L/JPT2: A signaling protein that connects NAADP generation to Ca2+ microdomain formation. Science Signal. 2021; 14:eabd5647.
- Zhu D, Feng L, Feliu N, Guse AH, Parak WJ. Stimulation of Local Cytosolic Calcium Release by Photothermal Heating for Studying Intra- and Intercellular Calcium Waves. Adv Mater 2021; 5:e2008261.
- Diercks BP, Werner R, Weidemüller P, Czarniak F, Hernandez L, Lehmann C, Rosche A, Krüger A, Kaufmann U, Vaeth M, Failla AV, Zobiak B, Kandil FI, Schetelig D, Ruthenbeck A, Meier C, Lodygin D, Flügel A, Ren D, Wolf IMA, Feske S, Guse AH (2018) ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+ microdomains upon T cell activation. Science Signal 2018 Dec 18;11(561):eaat0358
- Wolf IM, Diercks BP, Gattkowski E, Czarniak F, Kempski J, Werner R, Schetelig D, Mittrücker HW, Schumacher V, von Osten M, Lodygin D, Flügel A, Fliegert R, Guse AH (2015) Frontrunners of T cell activation: Initial, localized Ca2+ signals mediated by NAADP and the type 1 ryanodine receptor. Science Signal 8:ra102.
- Cordiglieri C, Odoardi F, Zhang B, Nebel M, Kawakami N, Klinkert WE, Lodygin D, Lühder F, Breunig E, Schild D, Ulaganathan VK, Dornmair K, Dammermann W, Potter BV*, Guse AH*, Flügel A* (2010) Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system. Brain 133:1930-1943. *equal contribution as last authors
- Dammermann W, Zhang B, Nebel M, Cordiglieri C, Odoardi F, Kirchberger T, Kawakami N, Dowden J, Schmid F, Dornmair K, Hohenegger M, Flügel* A, Guse AH*, Potter BV* (2009) NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist. Proc Natl Acad Sci USA 106:10678-10683.
- Berg I, Potter BV, Mayr GW, Guse AH. Nicotinic acid adenine dinucleotide phosphate (NAADP+) is an essential regulator of T-lymphocyte Ca2+-signaling. J Cell Biol 2000; 150:581-588.
- Guse AH, da Silva CP, Berg I, Skapenko AL, Weber K, Heyer P, Hohenegger M, Ashamu GA, Schulze-Koops H, Potter BV, Mayr GW. Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose. Nature 1999; 398:70-73.
Prof. Dr. Alexander Flügel
Selected publications (*equal contribution)
- Lodygin D*, Hermann M*, Schweingruber N, Flügel-Koch C, Watanabe T, Schlosser C, Merlini A, Körner H, Chang H-F, Fischer HJ, Reichardt HM, Zagrebelsky M, Mollenhauer B, Frahm J, Stadelmann C, Kügler S, Fitzner D, Haberl M, Odoardi F* & Flügel A* (2019) β Synuclein reactive T cells induce autoimmune CNS grey matter degeneration. Nature 566:503-508.
- Flach A*, Litke T*, Strauss J*, Haberl M, Cordero Gómez C, Reindl M, Saiz A, Fehling HJ, Wienands J, Odoardi F, Lühder F, Flügel A (2016) Autoantibody-boosted T-cell reactivation in the target organ triggers manifestation of autoimmune CNS disease. Proc Natl Acad Sci USA 113: 3323-3328.
- Schläger C*, Körner H*, Krueger M, Vidoli S, Haberl M, Mielke D, Brylla E, Issekutz T, Cabañas C, Nelson PJ, Ziemssen T, Rohde V, Bechmann I, Lodygin D, Odoardi F*, Flügel A*. (2016) Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature 530:349-353. *equal contribution
- Lodygin D, Odoardi F, Schläger C, Körner H, Kitz A, Nosov M, van den Brandt J, Reichardt HM, Haberl M, Flügel A (2013) A combination of fluorescent NFAT and H2B sensors uncovers dynamics of T cell activation in real time during CNS autoimmunity. Nat Med 19:784-790.
- Odoardi F, Sie C, Streyl K, Ulaganathan VK, Schläger C, Lodygin D, Heckelsmiller K, Nietfeld W, Ellwart J, Klinkert WE, Lottaz C, Nosov M, Brinkmann V, Spang R, Lehrach H, Vingron M, Wekerle H, Flügel-Koch C, Flügel A (2012) T cells become licensed in the lung to enter the central nervous system. Nature 488:675-679.
- Cordiglieri C, Odoardi F, Zhang B, Nebel M, Kawakami N, Klinkert WE, Lodygin D, Lühder F, Breunig E, Schild D, Ulaganathan VK, Dornmair K, Dammermann W, Potter BV*, Guse AH*, Flügel A* (2010) Nicotinic acid adenine dinucleotide phosphate-mediated calcium signalling in effector T cells regulates autoimmunity of the central nervous system. Brain 133:1930-1943. *equal contribution as last authors
- Bartholomäus I*, Kawakami N*, Odoardi F, Schläger C, Miljkovic D, Ellwart JW, Klinkert WE, Flügel-Koch C, Issekutz TB, Wekerle H, Flügel A (2009) Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature 462:94-98. *equal contribution
- Dammermann W, Zhang B, Nebel M, Cordiglieri C, Odoardi F, Kirchberger T, Kawakami N, Dowden J, Schmid F, Dornmair K, Hohenegger M, Flügel A*, Guse AH*, Potter BV* (2009) NAADP-mediated Ca2+ signaling via type 1 ryanodine receptor in T cells revealed by a synthetic NAADP antagonist. Proc Natl Acad Sci USA 106:10678-10683.
- Odoardi F, Kawakami N, Klinkert WEF, Wekerle H, Flügel A (2007) Blood-born soluble protein antigen intensifies T cell activation in autoimmune CNS lesions and exacerbates clinical disease. Proc Natl Acad Sci USA 104:18625-18630.
Our Team

Prof. Dr. Dr. Andreas H. Guse
Department of Biochemistry and Molecular Cell Biology
University Medical Center Hamburg-Eppendorf (UKE)

Dr. Anke Löhndorf
Department of Biochemistry and Molecular Cell Biology
University Medical Center Hamburg-Eppendorf (UKE)

M.Sc. Feng Gu
Department of Biochemistry and Molecular Cell Biology
University Medical Center Hamburg-Eppendorf (UKE)

Dr. Mariella Weiß
Department of Biochemistry and Molecular Cell Biology
University Medical Center Hamburg-Eppendorf (UKE)

Dr. Sukanya Arcot Kannabiran
Department of Biochemistry and Molecular Cell Biology
University Medical Center Hamburg-Eppendorf (UKE)

Prof. Dr. Alexander Flügel
Institute of Neuroimmunology and Multiple Sclerosis Research
University Medical Center Göttingen (UMG)

Prof. Dr. Francesca Odoardi
Project Manager
Institute of Neuroimmunology and Multiple Sclerosis Research
University Medical Center Göttingen (UMG)

Dr. Henrike Körner
Institute of Neuroimmunology and Multiple Sclerosis Research
University Medical Center Göttingen (UMG)

Dr. Dmitri Lodygin
Project Manager
Institute of Neuroimmunology and Multiple Sclerosis Research
University Medical Center Göttingen (UMG)

Roger Cugato Canals, PhD
Institute of Neuroimmunology and Multiple Sclerosis Research
University Medical Center Göttingen (UMG)

Dr. Marc-André Lécuyer
Institute of Neuroimmunology and Multiple Sclerosis Research
University Medical Center Göttingen (UMG)
Alumni

Dr. Yunpeng Zhang
Department of Biochemistry and Molecular Cell Biology
University Medical Center Hamburg-Eppendorf (UKE)

M.Sc. Imrankhan Khansahib
Department of Biochemistry and Molecular Cell Biology
University Medical Center Hamburg-Eppendorf (UKE)