SFB 645:  Regulation and Manipulation of Information Flow within Dynamic Protein and Lipid Environments

• Subject Area: Biology
• Term: from 2005 to 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5486231

• Final Report Year: 2017

Final Report Abstract

The highly dynamic processes that involve biological membranes and that are largely determined by lipids and proteins are a central aspect for understanding cellular function and its relevance for molecular medicine, pathophysiology, health, and disease. When founded, the main goals of the CRC 645 were to study the complexity and mechanistic aspects of cell membranes and their constituents in the context of cells and model organisms. A further important aim of the initiative was to develop and employ tools for the analysis, quantification, and manipulation of membrane, lipid, and membrane protein function. Key objectives of the original application were to understand 1. "the molecular mechanisms that control the asymmetric distribution of membrane constituents" 2. "the role of lipid metabolizing enzymes in membrane composition and cellular physiology" 3. "the impact of specific lipid components on membrane protein function" 4. "the role of lipid metabolites on cell signaling", and 5. "the generation and application of novel tools (e.g. small molecule inhibitors) for the analysis of membrane function" In a highly interdisciplinary approach the CRC 645 has followed these objectives for the last twelve years, extending and adjusting experimental procedures and thematic emphasis to gain unprecedented insight into the biochemistry, dynamics, composition, maintenance, and many other aspects of lipids, membranes, and membrane constituents. The CRC 645 studied the interplay of these components in diverse model organisms and cellular contexts, and their importance for health and disease. On top of that, a variety of technologies and tools for the study of the regulation of the flow of information in dynamic protein and lipid environments and their manipulation were developed or applied, ranging from biophysical techniques such as advanced microscopy techniques, state-of-the art genomics, proteomics, and lipidomics methods, to chemical tools such as small molecule inhibitors or aptamers for the selective manipulation of lipid, membrane, and membrane-protein function. Taken together, the tools developed by the researchers of the CRC 645 will be useful beyond the CRC and its projects. In the meantime, many researchers worldwide are using them already. Moreover, the CRC 645 has fundamentally impacted on the structures of the University of Bonn and its scientific portfolio: Membrane and lipid research in Bonn has manifested its strong international standing as one of the core disciplines in the life sciences at this university and the non-university research institutions like caesar and the DZNE that participated in the CRC 645. The CRC 645 also has significantly contributed to the successful establishment of the Cluster of Excellence “ImmunoSensation”, at which many of the CRC 645 project leaders participate. The CRC was able to attract to Bonn many renowned or young life-scientists and chemists with high potential, or has helped promoting them to professorships. Several former participants of the CRC 645 have accepted calls from other renowned Universities or Research Institutions. All these facts prove that the scientific advances made by the CRC 645 projects during the three funding periods have contributed considerably to the understanding of membrane dynamics and to the international visibility of German lipid and membrane research, and that even in its aftermath the CRC will likely continue to impact the research landscape in the life and medical sciences in Bonn in a positive and fruitful way.

Publications

• 2005. A mammalian fatty acid hydroxylase responsible for the formation of alpha-hydroxylated galactosylceramide in myelin. The Biochemical journal 388:245–254
  Eckhardt M, Yaghootfam A, Fewou SN, Zoller I, Gieselmann V
  
• 2005. Inhibition of glycosphingolipid biosynthesis reduces secretion of the beta-amyloid precursor protein and amyloid beta-peptide. The Journal of biological chemistry 280:28110–28117
  Tamboli IY, Prager K, Barth E, Heneka M, Sandhoff K, Walter J
  
• 2005. Oligodendrocyte-specific ceramide galactosyltransferase (CGT) expression phenotypically rescues CGT-deficient mice and demonstrates that CGT activity does not limit brain galactosylceramide level. Glia 52:190–198
  Zoller I, Bussow H, Gieselmann V, Eckhardt M
  
• 2006. Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance. Nature 444:941–944
  Hafner M, Schmitz A, Grune I, Srivatsan SG, Paul B, Kolanus W, Quast T, Kremmer E, Bauer I, Famulok M
  
• 2006. Peripheral cannabinoid receptor, CB2, regulates bone mass. Proceedings of the National Academy of Sciences of the United States of America 103:696–701
  Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I
  
• 2006. Saposin A mobilizes lipids from low cholesterol and high bis(monoacylglycerol)phosphate-containing membranes: Patient variant Saposin A lacks lipid extraction capacity. The Journal of biological chemistry 281:32451–32460
  Locatelli-Hoops S, Remmel N, Klingenstein R, Breiden B, Rossocha M, Schoeniger M, Koenigs C, Saenger W, Sandhoff K
  
• 2006. The cytohesin Steppke is essential for insulin signalling in Drosophila. Nature 444:945–948
  Fuss B, Becker T, Zinke I, Hoch M
  
• 2007. Attenuation of allergic contact dermatitis through the endocannabinoid system. Science (New York, N.Y.) 316:1494–1497
  Karsak M, Gaffal E, Date R, Wang-Eckhardt L, Rehnelt J, Petrosino S, Starowicz K, Steuder R, Schlicker E, Cravatt B, Mechoulam R, Buettner R, Werner S, Di Marzo V, Tuting T, Zimmer A
  
• 2007. Wurst is essential for airway clearance and respiratory-tube size control. Nature cell biology 9:847–853
  Behr M, Wingen C, Wolf C, Schuh R, Hoch M
  
• 2009. Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. The Journal of biological chemistry 284:33549–33560
  Imgrund S, Hartmann D, Farwanah H, Eckhardt M, Sandhoff R, Degen J, Gieselmann V, Sandhoff K, Willecke K
  
• 2009. Direct observation of the nanoscale dynamics of membrane lipids in a living cell. Nature 457:1159–1162
  Eggeling C, Ringemann C, Medda R, Schwarzmann G, Sandhoff K, Polyakova S, Belov VN, Hein B, Middendorff C von, Schonle A, Hell SW
  
• 2009. Saposin B-dependent reconstitution of arylsulfatase A activity in vitro and in cell culture models of metachromatic leukodystrophy. The Journal of biological chemistry 284:9372–9381
  Matzner U, Breiden B, Schwarzmann G, Yaghootfam A, Fluharty AL, Hasilik A, Sandhoff K, Gieselmann V
  
• 2009. Schlank, a member of the ceramide synthase family controls growth and body fat in Drosophila. The EMBO journal 28:3706–3716
  Bauer R, Voelzmann A, Breiden B, Schepers U, Farwanah H, Hahn I, Eckardt F, Sandhoff K, Hoch M
  
• 2010. Cell-free fusion of bacteria-containing phagosomes with endocytic compartments. Proceedings of the National Academy of Sciences of the United States of America 107:20726–20731
  Becken U, Jeschke A, Veltman K, Haas A
  
• 2010. Steady-state cross-presentation of OVA is mannose receptor-dependent but inhibitable by collagen fragments. Proceedings of the National Academy of Sciences of the United States of America 107:E48-9; author reply E50-1
  Burgdorf S, Schuette V, Semmling V, Hochheiser K, Lukacs-Kornek V, Knolle PA, Kurts C
  
• 2011. Ancient ubiquitous protein 1 (AUP1) localizes to lipid droplets and binds the E2 ubiquitin conjugase G2 (Ube2g2) 1via its G2 binding region. The Journal of biological chemistry 286:5599–5606
  Spandl J, Lohmann D, Kuerschner L, Moessinger C, Thiele C
  
• 2011. Ca2+ induces clustering of membrane proteins in the plasma membrane via electrostatic interactions. The EMBO journal 30:1209–1220
  Zilly FE, Halemani ND, Walrafen D, Spitta L, Schreiber A, Jahn R, Lang T
  
• 2011. The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm. Nature 471:382–386
  Strunker T, Goodwin N, Brenker C, Kashikar ND, Weyand I, Seifert R, Kaupp UB
  
• 2012. Ablation of neuronal ceramide synthase 1 in mice decreases ganglioside levels and expression of myelinassociated glycoprotein in oligodendrocytes. The Journal of biological chemistry 287:41888– 41902
  Ginkel C, Hartmann D, Vom Dorp K, Zlomuzica A, Farwanah H, Eckhardt M, Sandhoff R, Degen J, Rabionet M, Dere E, Dormann P, Sandhoff K, Willecke K
  
• 2012. Aptamer-based affinity labeling of proteins. Angewandte Chemie (International ed. in English) 51:9176–9180
  Vinkenborg JL, Mayer G, Famulok M
  
• 2012. The CatSper channel: A polymodal chemosensor in human sperm. The EMBO journal 31:1654–1665
  Brenker C, Goodwin N, Weyand I, Kashikar ND, Naruse M, Krahling M, Muller A, Kaupp UB, Strunker T
  
• 2012. Tracing fatty acid metabolism by click chemistry. ACS chemical biology 7:2004–2011
  Thiele C, Papan C, Hoelper D, Kusserow K, Gaebler A, Schoene M, Piotrowitz K, Lohmann D, Spandl J, Stevanovic A, Shevchenko A, Kuerschner L
  
• 2013. Cellular mechanotransduction relies on tension-induced and chaperone-assisted autophagy. Current biology : CB 23:430–435
  Ulbricht A, Eppler FJ, Tapia VE, van der Ven PFM, Hampe N, Hersch N, Vakeel P, Stadel D, Haas A, Saftig P, Behrends C, Furst DO, Volkmer R, Hoffmann B, Kolanus W, Hohfeld J
  
• 2013. Inactivation of ceramide synthase 6 in mice results in an altered sphingolipid metabolism and behavioral abnormalities. The Journal of biological chemistry 288:21433–21447
  Ebel P, Vom Dorp K, Petrasch-Parwez E, Zlomuzica A, Kinugawa K, Mariani J, Minich D, Ginkel C, Welcker J, Degen J, Eckhardt M, Dere E, Dormann P, Willecke K
  
• 2014. Acid sphingomyelinase activity is regulated by membrane lipids and facilitates cholesterol transfer by NPC2. Journal of lipid research 55:2606–2619
  Oninla VO, Breiden B, Babalola JO, Sandhoff K
  
• 2014. Ceramide synthase 4 deficiency in mice causes lipid alterations in sebum and results in alopecia. The Biochemical journal 461:147–158
  Ebel P, Imgrund S, Vom Dorp K, Hofmann K, Maier H, Drake H, Degen J, Dormann P, Eckhardt M, Franz T, Willecke K
  
• 2014. Deficiency of sphingosine-1-phosphate lyase impairs lysosomal metabolism of the amyloid precursor protein. The Journal of biological chemistry 289:16761–16772
  Karaca I, Tamboli IY, Glebov K, Richter J, Fell LH, Grimm MO, Haupenthal VJ, Hartmann T, Graler MH, van Echten-Deckert G, Walter J
  
• 2014. High-density lipoprotein mediates anti-inflammatory reprogramming of macrophages via the transcriptional regulator ATF3. Nature immunology 15:152–160
  Nardo D de, Labzin LI, Kono H, Seki R, Schmidt SV, Beyer M, Xu D, Zimmer S, Lahrmann C, Schildberg FA, Vogelhuber J, Kraut M, Ulas T, Kerksiek A, Krebs W, Bode N, Grebe A, Fitzgerald ML, Hernandez NJ, Williams BRG, Knolle P, Kneilling M, Rocken M, Lutjohann D, Wright SD, Schultze JL, Latz E
  
• 2014. Murine Creld1 controls cardiac development through activation of calcineurin/NFATc1 signaling. Developmental cell 28:711–726
  Mass E, Wachten D, Aschenbrenner AC, Voelzmann A, Hoch M
  
• 2014. Transcriptome-based network analysis reveals a spectrum model of human macrophage activation. Immunity 40:274–288
  Xue J, Schmidt SV, Sander J, Draffehn A, Krebs W, Quester I, Nardo D de, Gohel TD, Emde M, Schmidleithner L, Ganesan H, Nino-Castro A, Mallmann MR, Labzin L, Theis H, Kraut M, Beyer M, Latz E, Freeman TC, Ulas T, Schultze JL
  
• 2015. Accumulation of glucosylceramide in the absence of the beta-glucosidase GBA2 alters cytoskeletal dynamics. PLoS genetics 11:e1005063
  Raju D, Schonauer S, Hamzeh H, Flynn KC, Bradke F, Vom Dorp K, Dormann P, Yildiz Y, Trotschel C, Poetsch A, Breiden B, Sandhoff K, Korschen HG, Wachten D
  
• 2015. Functional characterization of enzymes catalyzing ceramide phosphoethanolamine biosynthesis in mice. Journal of lipid research 56:821–835
  Bickert A, Ginkel C, Kol M, Vom Dorp K, Jastrow H, Degen J, Jacobs RL, Vance DE, Winterhager E, Jiang X-C, Dormann P, Somerharju P, Holthuis JCM, Willecke K
  
• 2015. Phosphatidylinositol 4-phosphate and phosphatidylinositol 3-phosphate regulate phagolysosome biogenesis. Proceedings of the National Academy of Sciences of the United States of America 112:4636–4641
  Jeschke A, Zehethofer N, Lindner B, Krupp J, Schwudke D, Haneburger I, Jovic M, Backer JM, Balla T, Hilbi H, Haas A
  
• 2015. The CatSper channel controls chemosensation in sea urchin sperm. The EMBO journal 34:379–392
  Seifert R, Flick M, Bonigk W, Alvarez L, Trotschel C, Poetsch A, Muller A, Goodwin N, Pelzer P, Kashikar ND, Kremmer E, Jikeli J, Timmermann B, Kuhl H, Fridman D, Windler F, Kaupp UB, Strunker T
  
• 2015. The translocon protein Sec61 mediates antigen transport from endosomes in the cytosol for cross-presentation to CD8(+) T cells. Immunity 42:850–863
  Zehner M, Marschall AL, Bos E, Schloetel J-G, Kreer C, Fehrenschild D, Limmer A, Ossendorp F, Lang T, Koster AJ, Dubel S, Burgdorf S
  
• 2016. Anxiety, Stress, and Fear Response in Mice With Reduced Endocannabinoid Levels. Biological psychiatry 79:858–868
  Jenniches I, Ternes S, Albayram O, Otte DM, Bach K, Bindila L, Michel K, Lutz B, Bilkei- Gorzo A, Zimmer A
  
• 2016. Ceramide Synthase 5 Is Essential to Maintain C16:0-Ceramide Pools and Contributes to the Development of Diet-induced Obesity. The Journal of biological chemistry 291:6989–7003
  Gosejacob D, Jager PS, Vom Dorp K, Frejno M, Carstensen AC, Kohnke M, Degen J, Dormann P, Hoch M
  
• 2016. Mannose receptor induces T-cell tolerance via inhibition of CD45 and up-regulation of CTLA-4. Proceedings of the National Academy of Sciences of the United States of America 113:10649–10654
  Schuette V, Embgenbroich M, Ulas T, Welz M, Schulte-Schrepping J, Draffehn AM, Quast T, Koch K, Nehring M, Konig J, Zweynert A, Harms FL, Steiner N, Limmer A, Forster I, Berberich-Siebelt F, Knolle PA, Wohlleber D, Kolanus W, Beyer M, Schultze JL, Burgdorf S
  
• 2017. A chronic low dose of ∆9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat Med
  Bilkei-Gorzo A, Albayram O, Draffehn AM, Michel K, Piyanova A, Oppenheimer H, Dvir- Ginzberg M, Rácz I, Ulas T, Imbeault I, Bab I, Schultze JL & Zimmer A
  
• 2017. Identification of a feedback loop involving beta-glucosidase 2 and its product sphingosine sheds light on the molecular mechanisms in Gaucher disease. The Journal of biological chemistry
  Schonauer S, Korschen HG, Penno A, Rennhack A, Breiden B, Sandhoff K, Gutbrod K, Dormann P, Raju DN, Haberkant P, Gerl MJ, Brugger B, Zigdon H, Vardi A, Futerman AH, Thiele C, Wachten D