Stäubert Lab

Physiological relevance of msGPCRs as mediators between microbiota and the human host

We apply a broad interdisciplinary approach that combines evolutionary, functional, pharmacological, immunological and pharmacokinetic methods to analyze msGPCRs. 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. Moreover, we could show that HCA₃ activation results in anti-inflammatory responses in immune cells and anti-lipolytic effects in adipocytes.

The relevance of microbial colonization for healthy functional organisms increasingly gains attention. Since the microbiome is species-specific and dependent on habitat and diet, we believe that an evolutionary approach to understanding the relevance of msGPCRs in this context is highly adequate.

Pharmacology, signal transduction, trafficking and subcellular distribution of msGPCRs

It is very important to better understand the pharmacology, trafficking and signal transduction of these receptors 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 that some of these msGPCRs can reside and signal from intracellular compartments. With these analyses, we aim to increase the knowledge of the molecular mechanisms and cellular metabolic adaptations mediated by msGPCRs and extend 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 is characterized by certain metabolic features, including 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.  ​

The focus of our research is the understanding of 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
• bioluminescence and fluorescence energy transfer (BRET/FRET) technologies
• Multi-parametric surface plasmon resonance (MP-SPR)
• evolutionary analyses
• fluorescence microscopy and live cell imaging
• immunological assays
• Live-cell metabolic assays
• targeted and untargeted metabolic profiling with Liquid Chromatography Mass Spectrometry
• label-free dynamic mass re-distribution technology (DMR)

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• PD Dr. Claudia Stäubert (Group Leader)
• Aenne-Dorothea Liebing (PhD student)
• Florian Flemming (PhD student)
• Mareike Gehmlich (MD student)
• Vincent Kuhlgatz (MD student)
• Petra Krumbholz (Technician)

former group members​

• Dr. Amadeus Schulze ​
• Dr. Philipp Rabe
• Dr. Anna Peters
• Dr. Rosanna Krakowsky​

1. Pillaiyar T, Wozniak M, Abboud D, Rasch A, Liebing AD, Poso A, Kronenberger T, Stäubert C, Laufer S, Hanson J (2023) Development of Ligands for the Super Conserved Orphan G protein-coupled Receptor GPR27 with improved efficacy and potency. J Med Chem; 66(24):17118-17137​
   
2. Liebing AD, Krumbholz P, Stäubert C (2023) Protocol to characterize Gi/o and Gs protein-coupled receptors in transiently transfected cells using ELISA and cAMP measurements. STAR Protocols 4 (1), 102120
3. Kempf E, Landgraf K, Stein R, Hanschkow M, Hilbert A, Abou Jamra R, Boczki P, Herberth G, Kühnapfel A, Tseng YH, Stäubert C, Schöneberg T, Kühnen P, Rayner NW, Zeggini E, Kiess W, Blüher M, Körner A (2022) Aberrant expression of agouti signaling protein (ASIP) as a cause of monogenic severe childhood obesity. Nat Metab. 2022 Dec 19.
4. Schulze AS*, Kleinau G*, Krakowsky R, Rochmann D, Das R, Worth CL, Krumbholz P, Scheerer P, Stäubert C (2022) Evolutionary analyses reveal immune cell receptor GPR84 as a conserved receptor for bacteria-derived molecules. iscience. 2022; 25(10):105087.
5. Rabe P, Gehmlich M, Peters A, Krumbholz P, Nordström A, Stäubert C (2022) Combining metabolic phenotype determination with metabolomics and transcriptional analyses to reveal pathways regulated by hydroxycarboxylic acid receptor 2. Discov Oncol. 2022; 13: 47
6. Stäubert C, Wozniak M, Dupuis N, Laschet C, Pillaiyar T, Hanson J (2022) Superconserved receptors expressed in the brain: Expression, function, motifs and evolution of an orphan receptor family.Pharmacol Ther. 2022 May 26;240:108217.
7. Peters A, Liebing AD, Rabe P, Krumbholz P, Nordström A, Jäger E, Kraft R, Stäubert C (2022) Hydroxycarboxylic acid receptor 3 and GPR84 – two metabolite-sensing G protein-coupled receptors with opposing functions in innate immune cells. Pharmacol Res. Dec 27;176:106047
8. Rabe P, Liebing AD, Krumbholz P, Kraft R, Stäubert C (2022) Succinate receptor 1 inhibits mitochondrial respiration in cancer cells addicted to glutamine. Cancer Lett. Nov 20:S0304-3835(21)00591-7 .
9. 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.
10. 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.
11. 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.
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. Cöster M, Biebermann H, Schöneberg T, Stäubert C (2015)
18. Evolutionary conservation of 3 iodothyronamine as agonist at the trace amine-associated receptor 1. Eur Thyroid J. Suppl 1:9-20.
19. 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
20. 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.
21. 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.
22. 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.
23. 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.
24. 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.
25. 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.
26. 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.