Research

Research Projects

 

 

The research of the newly founded chair focuses on proteolytic processes in cellular membranes. The key figures in these processes are intramembrane proteases. They play an important role in reverse signal transduction and the degradation of membrane proteins. One class of these proteases is represented by the GxGD aspartyl proteases. GxGD describes a conserved amino acid motif in the active center that distinguishes these proteases from conventional aspartyl proteases.

Intramembrane Proteolysis. (© Charlotte Spitz)

The family of signal peptide peptidase (SPP) and its homologues (SPPLs) belongs to the class of GxGD aspartyl proteases. In humans, five representatives of the SPP / SPPL protease family are known SPP, SPPL2a, SPPL2b, SPPL2c and SPPL3.

 

SPP/SPPL-Family. (© Alkmini Papadopoulou)

Despite intensive research, both the physiological function of these proteases and the process of substrate recognition and processing are only partially understood. At the same time, GxGD aspartyl proteases are increasingly coming into focus as therapeutic targets for the treatment of neurodegenerative diseases, virus infections, immunological diseases and malaria. To utilize intramembrane proteases in the future as targets to treat or even cure diseases, it is indispensable to understand their cleavage mechanisms, substrate repertoires and physiological functions in depth.

 

Therefore, it is a major aim to understand function and mode of action of this fascinating GxGD aspartyl proteases in detail.
Recently we were able to show that SPPL3, a representative of the GxGD proteases, is responsible for the release of the luminal domain of various glycosyltransferases and glycosidases.

Impact of SPPL3 on protein glycosylation. (© Matthias Voss)

 

Since the catalytic center of glycan-modifying enzymes is located in their ectodomain, the release of this domain reduces their catalytic activity in the Golgi. Consequently, the amount of SPPL3 expressed affects the glycosylation status of secreted and membrane proteins. Increased SPPL3 expression leads to hypoglycosylation of many secretory and membrane proteins, while reduced levels of SPPL3 produce hyperglycosylated proteins.

 

 

Voss Matthias, Künzel Ulrike, Higel Fabian, Kuhn Peer‐Hendrik, Colombo Alessio, Fukumori Akio, Haug‐Kröper Martina, Klier Bärbel, Grammer Gudula, Seidl Andreas, Schröder Bernd, Obst Reinhard, Steiner Harald, Lichtenthaler Stefan F, Haass Christian, Fluhrer Regina. Shedding of glycan‐modifying enzymes by signal peptide peptidase‐like 3 (SPPL3) regulates cellular N‐glycosylation. EMBO Journal 2014;33(24):2890-2905.

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In a physiological context, this enables cells to quickly change the glycan pattern of many proteins and thus the extracellular matrix by changing the expression of a single protein. Altered glycosylation patterns are observed in connection with various diseases such as dementia, tumor development and metastasis and immune diseases.

Potential role of GxGD-proteases in tumor development. (© Charlotte Spitz)

Future research projects will deal with the function of intramembrane proteases in connection with the development of these diseases. Furthermore, we will investigate how various environmental influences and diet affect these proteases.

Third-Party Funding

DFG Research Grant FL 635/2-1

 

Project FL 635/3-1 within the DFG Research Group FOR 2290

 

DFG Research Grant FL 635/2-2

Publications

Regina Fluhrer
2020 | 2019 | 2018 | 2017 | 2016 | 2015 | 2014 | 2013 | 2012 | 2011 | 2010 | 2009 | 2008 | 2007 | 2006 | 2005 | 2003 | 2002 | 2001

2020

Spitz Charlotte, Schlosser Christine, Guschtschin-Schmidt Nadja, Stelzer Walter, Menig Simon, Götz Alexander, Haug-Kröper Martina, Scharnagl Christina, Langosch Dieter, Muhle-Goll Claudia, Fluhrer Regina. Non-canonical shedding of TNFα by SPPL2a is determined by the conformational flexibility of its transmembrane helix. https://doi.org/10.1016/j.isci.2020.101775
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Mentrup Torben, Cabrera-Cabrera Florencia, Fluhrer Regina, Schröder Bernd. Physiological functions of SPP/SPPL intramembrane proteases. https://doi.org/10.1007/s00018-020-03470-6
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Papadopoulou Alkmini A., Fluhrer Regina. Signalling functions of intramembrane aspartyl-proteases. https://doi.org/10.3389/fcvm.2020.591787
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Brugger Manuel S., Baumgartner Kathrin, Mauritz Sophie C. F., Gerlach Stefan C., Röder Florian, Schlosser Christine, Fluhrer Regina, Wixforth Achim, Westerhausen Christoph. Vibration enhanced cell growth induced by surface acoustic waves as in vitro wound healing model. https://doi.org/10.1073/pnas.2005203117
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2019

Mentrup Torben, Theodorou Kosta, Cabrera-Cabrera Florencia, Helbig Andreas O., Happ Kathrin, Gijbels Marion, Gradtke Ann-Christine, Rabe Björn, Fukumori Akio, Steiner Harald, Tholey Andreas, Fluhrer Regina, Donners Marjo, Schröder Bernd. Atherogenic LOX-1 signaling is controlled by SPPL2-mediated intramembrane proteolysis. https://doi.org/10.1084/jem.20171438
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Fluhrer Regina, Hampe Wolfgang, editors. Biochemie hoch 2 und Molekularbiologie.
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Fluhrer Regina. Intramembrane proteases in neurodegenerative diseases.
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Fluhrer Regina. Intramembrane proteases in the immune system.
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Papadopoulou Alkmini A., Müller Stephan A, Mentrup Torben, Shmueli Merav D, Niemeyer Johannes, Haug‐Kröper Martina, von Blume Julia, Mayerhofer Artur, Feederle Regina, Schröder Bernd, Lichtenthaler Stefan F., Fluhrer Regina. Signal peptide peptidase‐like 2c (SPPL2c) impairs vesicular transport and cleavage of SNARE proteins. https://doi.org/10.15252/embr.201846451
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Niemeyer Johannes, Mentrup Torben, Heidasch Ronny, Müller Stephan A, Biswas Uddipta, Meyer Rieke, Papadopoulou Alkmini A., Dederer Verena, Haug‐Kröper Martina, Adamski Vivian, Lüllmann-Rauch Renate, Bergmann Martin, Mayerhofer Artur, Saftig Paul, Wennemuth Gunther, Jessberger Rolf, Fluhrer Regina, Lichtenthaler Stefan F., Lemberg Marius K, Schröder Bernd. The intramembrane protease SPPL2c promotes male germ cell development by cleaving phospholamban. https://doi.org/10.15252/embr.201846449
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Fluhrer Regina, Schröder Bernd. What is the role of the intramembrane proteases in cancer?.
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2018

Fluhrer Regina. A unique family of intramembrane proteases. https://doi.org/10.26320/SCIENTIA179
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Fluhrer Regina. Health report: the challenge of cleaving proteins in the membrane.
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Fluhrer Regina. Intramembrane proteases - regulators of cellular pathways.
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Lichtenthaler Stefan F., Lemberg Marius K., Fluhrer Regina. Proteolytic ectodomain shedding of membrane proteins in mammals - hardware, concepts, and recent developments. https://doi.org/10.15252/embj.201899456
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2017

Jules Felix, Sauvageau Etienne, Dumaresq-Doiron Karine, Mazzaferri Javier, Haug-Kröper Martina, Fluhrer Regina, Costantino Santiago, Lefrancois Stephane. CLN5 is cleaved by members of the SPP/SPPL family to produce a mature soluble protein. https://doi.org/10.1016/j.yexcr.2017.04.024
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Mentrup Torben, Fluhrer Regina, Schröder Bernd. Latest emerging functions of SPP/SPPL intramembrane proteases. https://doi.org/10.1016/j.ejcb.2017.03.002
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Mentrup Torben, Loock Ann-Christine, Fluhrer Regina, Schröder Bernd. Signal peptide peptidase and SPP-like proteases: possible therapeutic targets?. https://doi.org/10.1016/j.bbamcr.2017.06.007
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2016

Hüttl Susann, Helfrich F., Mentrup Torben, Held S., Fukumori Akio, Steiner Harald, Saftig Paul, Fluhrer Regina, Schroder B.. Substrate determinants of signal peptide peptidase-like 2a (SPPL2a)-mediated intramembrane proteolysis of the invariant chain CD74. https://doi.org/10.1042/bcj20160156
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2015

Mentrup Torben, Häsler Robert, Fluhrer Regina, Saftig Paul, Schröder Bernd. A cell-based assay reveals nuclear translocation of intracellular domains released by SPPL proteases. https://doi.org/10.1111/tra.12287
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Kamp Frits, Winkler Edith, Trambauer Johannes, Ebke Amelie, Fluhrer Regina, Steiner Harald. Intramembrane proteolysis of β-amyloid precursor protein by γ-secretase is an unusually slow process. https://doi.org/10.1016/j.bpj.2014.12.045
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Fleck Daniel, Voss Matthias, Brankatschk Ben, Giudici Camilla, Hampel Heike, Schwenk Benjamin, Edbauer Dieter, Fukumori Akio, Steiner Harald, Kremmer Elisabeth, Haug-Kröper Martina, Rossner Moritz J., Fluhrer Regina, Willem Michael, Haass Christian. Proteolytic processing of neuregulin 1 type III by three intramembrane-cleaving proteases. https://doi.org/10.1074/jbc.m115.697995
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Kuhn Peer-Hendrik, Voss Matthias, Haug-Kröper Martina, Schröder Bernd, Schepers Ute, Bräse Stefan, Haass Christian, Lichtenthaler Stefan F., Fluhrer Regina. Secretome analysis identifies novel signal peptide peptidase-like 3 (Sppl3) substrates and reveals a role of Sppl3 in multiple Golgi glycosylation pathways. https://doi.org/10.1074/mcp.m115.048298
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2014

Fluhrer Regina. Intramembrane cleaving proteases (I-CLiPs) as guardians of shuttling proteins. https://doi.org/10.4161/cc.28089
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Voss Matthias, Künzel Ulrike, Higel Fabian, Kuhn Peer‐Hendrik, Colombo Alessio, Fukumori Akio, Haug‐Kröper Martina, Klier Bärbel, Grammer Gudula, Seidl Andreas, Schröder Bernd, Obst Reinhard, Steiner Harald, Lichtenthaler Stefan F., Haass Christian, Fluhrer Regina. Shedding of glycan‐modifying enzymes by signal peptide peptidase‐like 3 (SPPL3) regulates cellular N‐glycosylation. https://doi.org/10.15252/embj.201488375
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Schneppenheim Janna, Hüttl Susann, Kruchen Anne, Fluhrer Regina, Müller Ingo, Saftig Paul, Schneppenheim Reinhard, Martin Christa L., Schröder Bernd. Signal-peptide-peptidase-like 2a is required for CD74 intramembrane proteolysis in human B cells. https://doi.org/10.1016/j.bbrc.2014.07.051
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Schneppenheim Janna, Hüttl Susann, Mentrup Torben, Lüllmann-Rauch Renate, Rothaug M., Engelke Michael, Dittmann Kai, Dressel Ralf, Araki M., Araki K., Wienands Jürgen, Fluhrer Regina, Saftig Paul, Schroder B.. The intramembrane proteases signal peptide peptidase-like 2a and 2b have distinct functions in vivo. https://doi.org/10.1128/mcb.00038-14
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2013

Voss Matthias, Schröder Bernd, Fluhrer Regina. Mechanism, specificity, and physiology of signal peptide peptidase (SPP) and SPP-like proteases. https://doi.org/10.1016/j.bbamem.2013.03.033
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Poggi Marjorie, Kara Imène, Brunel Jean-Michel, Landrier Jean-François, Govers Roland, Bonardo Bernadette, Fluhrer Regina, Haass Christian, Alessi Marie-Christine, Peiretti Franck. Palmitoylation of TNF alpha is involved in the regulation of TNF receptor 1 signalling. https://doi.org/10.1016/j.bbamcr.2012.11.009
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Bronckers Antonius LJJ, Gueneli Nur, Lüllmann-Rauch Renate, Schneppenheim Janna, Moraru Andreea P, Himmerkus Nina, Bervoets Theodore J, Fluhrer Regina, Everts Vincent, Saftig Paul, Schröder Bernd. The intramembrane protease SPPL2A is critical for tooth enamel formation. https://doi.org/10.1002/jbmr.1895
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Zahn Claudia, Kaup Matthias, Fluhrer Regina, Fuchs Hendrik. The transferrin receptor-1 membrane stub undergoes intramembrane proteolysis by signal peptide peptidase-like 2b. https://doi.org/10.1111/febs.12176
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2012

Voss Matthias, Fukumori Akio, Kuhn Peer-Hendrik, Künzel Ulrike, Klier Bärbel, Grammer Gudula, Haug-Kröper Martina, Kremmer Elisabeth, Lichtenthaler Stefan F., Steiner Harald, Schröder Bernd, Haass Christian, Fluhrer Regina. Foamy virus envelope protein is a substrate for signal peptide peptidase-like 3 (SPPL3). https://doi.org/10.1074/jbc.m112.371369
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Schneppenheim Janna, Dressel Ralf, Hüttl Susann, Lüllmann-Rauch Renate, Engelke Michael, Dittmann Kai, Wienands Jürgen, Eskelinen Eeva-Liisa, Hermans-Borgmeyer Irm, Fluhrer Regina, Saftig Paul, Schröder Bernd. The intramembrane protease SPPL2a promotes B cell development and controls endosomal traffic by cleavage of the invariant chain. https://doi.org/10.1084/jem.20121069
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2011

Fluhrer Regina, Kamp Frits, Grammer Gudula, Nuscher Brigitte, Steiner Harald, Beyer Klaus, Haass Christian. The nicastrin ectodomain adopts a highly thermostable structure. https://doi.org/10.1515/bc.2011.169
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Fluhrer Regina, Martin Lucas, Klier Bärbel, Haug-Kröper Martina, Grammer Gudula, Nuscher Brigitte, Haass Christian. The α-helical content of the transmembrane domain of the British dementia protein-2 (Bri2) determines its processing by signal peptide peptidase-like 2b (SPPL2b). https://doi.org/10.1074/jbc.m111.328104
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2010

Fukumori Akio, Fluhrer Regina, Steiner Harald, Haass Christian. Three-amino acid spacing of presenilin endoproteolysis suggests a general stepwise cleavage of gamma-secretase-mediated intramembrane proteolysis. https://doi.org/10.1523/jneurosci.1443-10.2010
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2009

Fluhrer Regina, Steiner Harald, Haass Christian. Intramembrane proteolysis by signal peptide peptidases: a comparative discussion of GXGD-type aspartyl proteases. https://doi.org/10.1074/jbc.r800040200
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Fluhrer Regina, Haass Christian. Intramembrane proteolysis by γ-secretase and signal peptide peptidases. https://doi.org/10.1007/978-3-540-87941-1_2
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Martin Lucas, Fluhrer Regina, Haass Christian. Substrate requirements for SPPL2b-dependent regulated intramembrane proteolysis. https://doi.org/10.1074/jbc.m807485200
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2008

Steiner Harald, Fluhrer Regina, Haass Christian. Intramembrane proteolysis by γ-secretase. https://doi.org/10.1074/jbc.r800010200
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Fluhrer Regina, Fukumori Akio, Martin Lucas, Grammer Gudula, Haug-Kröper Martina, Klier Bärbel, Winkler Edith, Kremmer Elisabeth, Condron Margaret M., Teplow David B., Steiner Harald, Haass Christian. Intramembrane proteolysis of GXGD-type aspartyl proteases is slowed by a familial Alzheimer disease-like mutation. https://doi.org/10.1074/jbc.m806092200
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2007

Prager Kai, Wang-Eckhardt Lihua, Fluhrer Regina, Killick Richard, Barth Esther, Hampel Heike, Haass Christian, Walter Jochen. A structural switch of presenilin 1 by glycogen synthase kinase 3beta-mediated phosphorylation regulates the interaction with beta-catenin and its nuclear signaling. https://doi.org/10.1074/jbc.m608437200
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Martin Lucas, Fluhrer Regina, Reiss Karina, Kremmer Elisabeth, Saftig Paul, Haass Christian. Regulated intramembrane proteolysis of Bri2 (Itm2b) by ADAM10 and SPPL2a/SPPL2b. https://doi.org/10.1074/jbc.m706661200
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Fluhrer Regina, Haass Christian. Signal peptide peptidases and gamma-secretase: cousins of the same protease family?. https://doi.org/10.1159/000101835
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2006

Fluhrer Regina, Grammer Gudula, Israel Lars, Condron Margaret M., Haffner Christof, Friedmann Elena, Böhland Claudia, Imhof Axel, Martoglio Bruno, Teplow David B., Haass Christian. A γ-secretase-like intramembrane cleavage of TNFα by the GxGD aspartyl protease SPPL2b. https://doi.org/10.1038/ncb1450
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2005

Krawitz Peter, Haffner Christof, Fluhrer Regina, Steiner Harald, Schmid Bettina, Haass Christian. Differential localization and identification of a critical aspartate suggest non-redundant proteolytic functions of the presenilin homologues SPPL2b and SPPL3. https://doi.org/10.1074/jbc.m501645200
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2003

Fluhrer Regina, Multhaup Gerd, Schlicksupp Andrea, Okochi Masayasu, Takeda Masatoshi, Lammich Sven, Willem Michael, Westmeyer Gil, Bode Wolfram, Walter Jochen, Haass Christian. Identification of a beta-secretase activity, which truncates amyloid beta-peptide after its presenilin-dependent generation. https://doi.org/10.1074/jbc.m211485200
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Fluhrer Regina, Friedlein Arno, Haass Christian, Walter Jochen. Phosphorylation of presenilin 1 at the caspase recognition site regulates its proteolytic processing and the progression of apoptosis. https://doi.org/10.1074/jbc.m306653200
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Fluhrer Regina. Zwei neuartige Aspartylproteasen BACE-1 und BACE-2: Charakterisierung und Vergleich der katalytischen Spezifitäten bei der Proteolyse des Alzheimer-β-Amyloid-Vorläufer-Proteins.
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München, Univ., Diss., 2003

2002

Fluhrer Regina, Capell Anja, Westmeyer Gil, Willem Michael, Hartung Bianka, Condron Margaret M., Teplow David B., Haass Christian, Walter Jochen. A non-amyloidogenic function of BACE-2 in the secretory pathway. https://doi.org/10.1046/j.1471-4159.2002.00908.x
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Capell Anja, Meyn Liane, Fluhrer Regina, Teplow David B., Walter Jochen, Haass Christian. Apical sorting of beta-secretase limits amyloid beta-peptide production. https://doi.org/10.1074/jbc.m109119200
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2001

Walter Jochen, Fluhrer Regina, Hartung Bianka, Willem Michael, Kaether Christoph, Capell Anja, Lammich Sven, Multhaup Gerd, Haass Christian. Phosphorylation regulates intracellular trafficking of beta-secretase. https://doi.org/10.1074/jbc.m011116200
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