Arbeitsgruppe Stäubert

 

PD Dr. Claudia Stäubert
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Telefon: +49 (0)341 97 22 157
Telefax: +49 (0)341 97 22 159

 

 

  

Arbeitsgruppe Stäubert

 

PD Dr. Claudia Stäubert
E-Mail: Diese E-Mail-Adresse ist vor Spambots geschützt! Zur Anzeige muss JavaScript eingeschaltet sein!

Telefon: +49 (0)341 97 22 157
Telefax: +49 (0)341 97 22 159

 

 

  

Overview

G protein-coupled receptors (msGPCR) activated by intermediates of central metabolic pathways like e.g. glycolysis, citric acid cycle, β-oxidation (FAO) increasingly gain attention. This is because some of them are activated by gut- or diet-derived bacterial metabolites and thus constitute molecular mechanisms conveying physiological responses in humans to microbiota.

Our group focuses on the central scientific question: How do GPCR for (microbial-derived) energy metabolites influence physiological and pathophysiological processes?

We use different scientific approaches to address the following aspects of this question:

  1. How does activation of GPCRs by bacterial metabolites influence the human immune system and energy metabolism?

  2. Are msGPCRs localized intracellularly and signal from there?

  3. What is the role of msGPCRs in cancer cell metabolism and proliferation?

 

Research

Physiological relevance of msGPCRs as mediators between microbiota and the human host
We aim to understand the role of msGPCRs using a broad interdisciplinary approach that combines evolutionary, functional, pharmacological, immunological and pharmacokinetic methods. We successfully applied this strategy to unravel the role of hydroxycarboxylic acid receptor 3 (HCA3), a hominid-specific receptor expressed in immune cells and adipocytes. We discovered that lactic acid bacteria (LAB) fermented food derived metabolites are highly potent agonists at this receptor. In an evolutionary context, this suggests that the availability of a new food repertoire under changed ecological conditions triggered the fixation of HCA3, which took over new functions in hominids.
This study opens up several exciting scientific questions regarding immune function and metabolism. How exactly does consumption of fermented food modulate the human immune system and fat storage through HCA3? Do LAB-derived metabolites prime monocytes to an increased pro-inflammatory host response to concomitantly ingested pathogenic bacteria or to a reduced pro-inflammatory response to LAB? Do LAB-derived metabolites inhibit lipolysis in HCA3-expressing adipocytes? The relevance of microbial colonization for healthy functional organisms increasingly gains attention. Since the microbiome is species-specific, dependent on habitat and diet, we believe that an evolutionary approach to understand the relevance of msGPCRs in this context is highly adequate.

 

Pharmacology, signal transduction, trafficking and subcellular distribution of msGPCRs
One very important aspect of these receptors are a better understanding of their pharmacology, trafficking and signal transduction, since some msGPCRs are activated by metabolites that occur mainly intracellularly in effective concentrations. It is well accepted that GPCRs signal from the plasma membrane and detect extracellular ligands, but there is accumulating evidence for GPCR signaling from intracellular membranes, such as endosomes and mitochondria. Especially under certain pathological conditions, some metabolites are increasingly released intracellularly from e.g. mitochondria.
Our group systematically aims to test the hypothesis if some of these msGPCRs can reside and signal from intracellular compartments. We expect that this study will significantly increase our knowledge of the molecular mechanisms and cellular metabolic adaptations mediated by msGPCRs and extent our understanding of the subcellular distribution, signaling and pharmacology of GPCRs activated by energy metabolites.

       

 

The role of msGPCRs in cancer cell metabolism
Cancer cell metabolism is rendered to support rapid proliferation and characterized by certain metabolic features, including an altered glucose, fatty acid and glutamine metabolism, when compared to normal proliferating cells. Up until now, the role of msGPCRs in regulating cancer cell metabolism is insufficiently understood.
We aim to understand, which msGPCR-activated signaling pathways influence the metabolism of cancer cells in which way. We analyze viability, proliferation and cytotoxicity in combination with biochemical and pharmacological analyses to understand the link between msGPCRs and cancer cell metabolism. Further, we apply metabolomics analyses using global targeted and untargeted Liquid Chromatography Mass Spectrometry (LC-MS) profiles, the seahorse analyzer that determines oxygen consumption rate and extracellular acidification rate as well as FRET metabolite sensors. We analyze 2D cancer cell lines and their derived 3D tumor spheroids and slice cultures of primary human patient-derived tumor material in cooperation with the Institute of Anatomy in Leipzig and the University Cancer Centre Leipzig (UCCL).

  

Projects

The focus of our research is the understanding of the signal transduction, intracellular trafficking and ultimately the role of metabolite-sensing GPCRs:

  • for immune cell function
  • for energy homeostasis
  • for cancer cell metabolism
  • in an evolutionary context

We apply a broad combination of methods including, but not limited to:

  • high-throughput signal-transduction analyses
  • label-free dynamic mass re-distribution technology
  • evolutionary analyses
  • high-resolution fluorescence microscopy
  • high-throughput live cell imaging
  • immunological assays
  • targeted and untargeted metabolic profiling with Liquid Chromatography Mass Spectrometry
  • Live-cell metabolic assays

 

Team

  • PD Dr. Claudia Stäubert (Group Leader)
  • Philipp Rabe (PhD student)
  • Mareike Hellfritzsch (MD student)
  • Amadeus Schulze (MD student)
  • Petra Krumbholz (Technician)

Ehemalige Mitlieder:

  • Dr. Anna Peters

Publications

Peer-reviewed Publications

  1. Jäger E, Murthy S, Hahn M, Strobel S, Schmidt C, Peters A, Stäubert C, Sungur P, Venus T, Geisler M, Radusheva V, Raps S, Rothe K, Scholz R, Jung S, Pierer M, Seifert O, Chang W, Estrela-Lopis I, Raulien N, Krohn K, Sträter N, Hoeppener S, Schöneberg T, Rossol M, Wagner U (2020).
    Calcium-sensing receptor-mediated NLRP3 inflammasome response to calciprotein particles drives inflammation in rheumatoid arthritis.
    Nat Commun. 11:4243.
  2. Peters A, Rabe P, Krumbholz P, Kalwa H, Kraft R, Schöneberg T, Stäubert C (2020). 
    Natural biased signaling of hydroxycarboxylic acid receptor 3 and G protein-coupled receptor 84. 
    Cell Commun Signal. 2020; 18: 31.
  3. Peters A, Krumbholz P, Jäger E, Heintz-Buschart A, Çakir MV, Gaudl A, Ceglarek U, Schöneberg T, Stäubert C (2019)
    Metabolites of lactic acid bacteria present in fermented foods are highly potent agonists of human hydroxycarboxylic acid receptor 3. 
    PLoS Genet. 2019 May 23;15(5):e1008145.

  4. Wach S, Brandl M, Weigelt K, Lukat S, Nolte E, Al-Janabi O, Hart M, Grässer F, Giedl J, Jung R, Stöhr R, Hartmann A, Lieb V, Höbel S, Peters A, Stäubert C, Wullich B, Taubert H, Aigner A (2019)
    Exploring the miR-143 / uPAR axis for inhibition of human prostate cancer cells in vitro and in vivo.
    Mol Ther Nucleic Acids. 16:272-283.

  5. Stäubert C, Krakowsky R, Bhuiyan H, Witek B, Lindahl A, Broom O, Nordström A. (2016)
    Increased lanosterol turnover: a metabolic burden for daunorubicin-resistant leukemia cells.
    Med Oncol. 33(1):6.

  6. Stäubert C, Broom OJ, Nordström A (2015)
    Hydroxycarboxylic acid receptors are essential for breast cancer cells to control their lipid/fatty acid metabolism.
    Oncotarget. 6(23):19706-20.

  7. Stäubert C*, Bhuiyan H*, Lindahl A, Broom OJ, Zhu Y, Islam S, Linnarsson S, Lehtiö J, Nordström A (2015)
    Rewired metabolism in drug-resistant leukemia cells: A metabolic switch hallmarked by reduced dependence on exogenous glutamine.
    J Biol Chem. 290(13):8348-59.

  8. Dinter J, Khajavi N, Mühlhaus J, Wienchol CL, Cöster M, Hermsdorf T, Stäubert C, Köhrle J, Schöneberg T, Kleinau G, Mergler S, Biebermann H. (2015)
    The Multitarget Ligand 3-Iodothyronamine Modulates β-Adrenergic Receptor 2 Signaling.
    Eur Thyroid J. Suppl 1:21–29.

  9. Cöster M, Biebermann H, Schöneberg T, Stäubert C (2015)
    Evolutionary conservation of 3 iodothyronamine as agonist at the trace amine-associated receptor 1.
    Eur Thyroid J. Suppl 1:9-20.

  10. Stäubert C, Bohnekamp J, Schöneberg T (2013)
    Determinants involved in subtype-specific functions of trace amine-associated receptors 1 and 4.
    Br J Pharmacol. 168(5):1266-78

  11. Ritscher L, Engemaier E, Stäubert C, Liebscher I, Schmidt P, Hermsdorf T, Römpler H, Schulz A, Schöneberg T (2012)
    The ligand specificity of the G-protein-coupled receptor GPR34.
    Biochem J 443(3):841-50.

  12. Strotmann R, Schröck K, Böselt I, Stäubert C, Schöneberg T (2011)
    Evolution of GPCR: chance, selection and continuity.
    Molecular and Cellular Endocrinology 331(2):170-8.

  13. Stäubert C, Böselt I, Bohnekamp J, Römpler H, Enard W, Schöneberg T (2010)
    Structural and functional evolution of the trace amine-associated receptors TAAR3, TAAR4 and TAAR5 in primates.
    PloS ONE 5(6):e11133.

  14. Sensken SC, Stäubert C, Keul P, Levkau B, Schöneberg T, Gräler MH (2008)
    Selective activation of G alpha i mediated signalling of S1P3 by FTY720-phosphate.
    Cell Signal 20:1125-1133.

  15. Lalueza-Fox C, Römpler H, Caramelli D, Stäubert C, Catalano G, Hughes D, Rohland N, Pilli E, Longo L, Condemi S, de la Rasilla M, Fortea J, Rosas A, Stoneking M, Schöneberg T, Bertranpetit J, Hofreiter M (2007)
    A melanocortin 1 receptor allele suggests varying pigmentation among Neanderthals.
    Science 318:1453-1455.

  16. Römpler H, Stäubert C, Thor D, Schulz A, Hofreiter M, Schöneberg T (2007)
    G protein-coupled time travel: evolutionary aspects of GPCR research.
    Mol Interv 7:17-25.

  17. Stäubert C*, Tarnow P*, Brumm H, Pitra C, Gudermann T, Grüters A, Schöneberg T, Biebermann H, Römpler H (2007)
    Evolutionary aspects in evaluating mutations in the melanocortin 4 receptor.
    Endocrinology 148:4642-4648.

 

Other publications (Monographs, Editorials, Teaching)

  1. Peters A, Rabe P, Dintner R, Stäubert C (2018)
    Zellen beim Wachsen und Sterben zuschauen – Tumorzellmodelle in 2D und 3D.
    Biospektrum 3/18:292-293.

  2. Stäubert C, Schöneberg T (2017)
    GPCR Signaling From Intracellular Membranes - A Novel Concept.
    Bioessays. Dec;39(12)

  3. Stäubert C, Le Duc D, Schöneberg T (2014)
    Examining the Dynamic Evolution of G Protein-Coupled Receptors.
    In G Protein-Coupled Receptor Genetics, Methods in Pharmacology and Toxicology, pp 23-43.

  4. Schöneberg T, Schröck K, Stäubert C, Russ A (2011)
    The evolution of the repertoire and structure of G protein-coupled receptors.
    In: G protein-coupled receptors: Structure, Signalling and Physiology. Eds. Siehler S, Milligan G, Cambridge University Press, pp 5-31.