A01: SFB 1328

A01 Project Movie

A01

From Diercks, B.-P. et al. (2018). ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+ microdomains upon T cell activation. Sci. Signal. 11, eaat0358.

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)

Shumanska M, Lodygin D, Gibhardt CS, Ickes C, Stejerean-Todoran I, Krause LCM, Pahl K, Jacobs LJHC, Paluschkiwitz A, Liu S, Boshnakovska A, Voigt N, Legler TJ, Haubrock M, Mitkovski M, Poschmann G, Rehling P, Dennerlein S, Riemer J, Flügel A, Bogeski I. Mitochondrial calcium uniporter complex controls T-cell-mediated immune responses. EMBO Rep. 2025 Jan;26(2):407-442.
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.