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)
- Krukenberg S, Möckl F, Weiß M, Dekiert P, Hofmann M, Gerlach F, Winterberg KJ, Kovacevic D, Khansahib I, Troost B, Hinrichs M, Granato V, Nawrocki M, Hub T, Tsvilovskyy V, Medert R, Woelk LM, Förster F, Li H, Werner R, Altfeld M, Huber S, Clarke OB, Freichel M, Diercks BP, Meier C*, Guse AH*. MASTER-NAADP: a membrane permeable precursor of the Ca2+mobilizing second messenger NAADP. Nat Commun. 2024 Sep 13;15(1):8008.
- Weiß M, Hernandez LC, Gil Montoya DC, Löhndorf A, Krüger A, Kopdag M, Uebler L, Landwehr M, Nawrocki M, Huber S, Woelk LM, Werner R, Failla AV, Flügel A, Dupont G, Guse AH, Diercks BP. Adhesion to laminin-1 and collagen IV induces the formation of Ca2+ microdomains that sensitize mouse T cells for activation. Science Signal. 2023 Jun 20;16(790):eabn9405.
- Hosang L, Löhndorf A, Dohle W, Rosche A, Marry S, Diercks BP, Müller-Kirschbaum LC, Flügel LT, Potter BVL, Odoardi F, Guse AH, Flügel A. 2-Methoxyestradiol-3,17-O,O-bis-sulfamate inhibits store-operated Ca2+ entry in T lymphocytes and prevents experimental autoimmune encephalomyelitis. Biochim Biophys Acta Mol Cell Res. 2023 Aug;1870(6):119485.
- 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.
- 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)
- Hosang L, Löhndorf A, Dohle W, Rosche A, Marry S, Diercks BP, Müller-Kirschbaum LC, Flügel LT, Potter BVL, Odoardi F, Guse AH*, Flügel A*. 2-Methoxyestradiol-3,17-O,O-bis-sulfamate inhibits store-operated Ca2+ entry in T lymphocytes and prevents experimental autoimmune encephalomyelitis. Biochim Biophys Acta Mol Cell Res. 2023 Aug;1870(6):119485
- Weiß M, Hernandez LC, Gil Montoya DC, Löhndorf A, Krüger A, Kopdag M, Uebler L, Landwehr M, Nawrocki M, Huber S, Woelk LM, Werner R, Failla AV, Flügel A, Dupont G, Guse AH, Diercks BP. Adhesion to laminin-1 and collagen IV induces the formation of Ca2+ microdomains that sensitize mouse T cells for activation. Sci Signal. 2023 Jun 20;16(790):eabn9405.
- Hosang L, Canals RC, van der Flier FJ, Hollensteiner J, Daniel R, Flügel A*, Odoardi F*. The lung microbiome regulates brain autoimmunity. Nature. 2022 Mar;603(7899):138-144.
- Merlini A, Haberl M, Strauß J, Hildebrand L, Genc N, Franz J, Chilov D, Alitalo K, Flügel-Koch C, Stadelmann C, Flügel A*, Odoardi F*. Distinct roles of the meningeal layers in CNS autoimmunity. Nat Neurosci. 2022 Jul;25(7):887-899.
- 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.
- Löhndorf A, Hosang L, Dohle W, Odoardi F, Waschkowski SA, Rosche A, Bauche A, Winzer R, Tolosa E, Windhorst S, Marry S, Flügel A, Potter BVL, Diercks BP, Guse AH. 2-Methoxyestradiol and its derivatives inhibit store-operated Ca2+ entry in T cells: Identification of a new and potent inhibitor. Biochim Biophys Acta Mol Cell Res. 2021 May;1868(6):118988.
- 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.
- 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
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. Macarena Hinrichs
Department of Biochemistry and Molecular Cell Biology
University Medical Center Hamburg-Eppendorf (UKE)

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

Dr. Viviana Granato
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. 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)

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)