Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance (original) (raw)
- Letter
- Published: 14 December 2006
- Anton Schmitz1,2,
- Imke Grüne1,2,
- Seergazhi G. Srivatsan1,2,
- Bianca Paul3,
- Waldemar Kolanus3,
- Thomas Quast3,
- Elisabeth Kremmer4,
- Inga Bauer1,2 &
- …
- Michael Famulok1,2
Nature volume 444, pages 941–944 (2006)Cite this article
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Abstract
G proteins are an important class of regulatory switches in all living systems. They are activated by guanine nucleotide exchange factors (GEFs), which facilitate the exchange of GDP for GTP1,2. This activity makes GEFs attractive targets for modulating disease-relevant G-protein-controlled signalling networks3,4,5. GEF inhibitors are therefore of interest as tools for elucidating the function of these proteins and for therapeutic intervention; however, only one small molecule GEF inhibitor, brefeldin A (BFA), is currently available6,7,8,9. Here we used an aptamer displacement screen to identify SecinH3, a small molecule antagonist of cytohesins. The cytohesins are a class of BFA-resistant small GEFs for ADP-ribosylation factors (ARFs), which regulate cytoskeletal organization10, integrin activation11 or integrin signalling12. The application of SecinH3 in human liver cells showed that insulin-receptor-complex-associated cytohesins are required for insulin signalling. SecinH3-treated mice show increased expression of gluconeogenic genes, reduced expression of glycolytic, fatty acid and ketone body metabolism genes in the liver, reduced liver glycogen stores, and a compensatory increase in plasma insulin. Thus, cytohesin inhibition results in hepatic insulin resistance. Because insulin resistance is among the earliest pathological changes in type 2 diabetes, our results show the potential of chemical biology for dissecting the molecular pathogenesis of this disease.
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Acknowledgements
We thank M. Franco for ARF6 and EFA6 plasmids, R. Quirion for the EGFP–FoxO1A plasmid, J. Kuriyan for the Ras and Sos plasmids, J.-L. Parent for the GST–GGA3 plasmid, M. Hoch for the steppke plasmid, V. Fieberg, K. Rotscheidt, N. Kuhn, R. Tolba, and A. Carney for technical assistance and the members of the Famulok laboratory for helpful discussions. This work was supported by grants from the Deutsche Forschungsgemeinschaft, the Sonderforschungsbereiche 645 and 704, the Fonds der Chemischen Industrie (to M.F.), and the Alexander von Humboldt foundation (to S.G.S.). Author Contributions M. H. and A.S. contributed equally to this work. M.H. and A.S. performed and designed, with M.F., most of the included studies. I.G. performed the aptamer displacement screen and binding and in vitro inhibition analyses of Secins. S.G.S. synthesized all Secin derivatives. W.K. provided cytohesin and ARF expression plasmids, E.K. produced the cyh3 monoclonal antibody and B.P. characterized it. T.Q. performed the analysis of Golgi integrity and ARF6 membrane recruitment. I.B. and A.S. did the immunoprecipitation experiments. M.F. supervised the research project, and assisted in the experimental design. All authors discussed the experimental results. A.S. and M.F. wrote the manuscript.
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Authors and Affiliations
- LIMES Program Unit Chemical Biology & Medicinal Chemistry, c/o Kekulé Institut für Organische Chemie und Biochemie, University of Bonn, Gerhard-Domagk-Straße 1, Bonn, 53121, Germany
Markus Hafner, Anton Schmitz, Imke Grüne, Seergazhi G. Srivatsan, Inga Bauer & Michael Famulok - Medicinal Chemistry, c/o Kekulé Institut für Organische Chemie und Biochemie, University of Bonn, Gerhard-Domagk-Straße 1
Markus Hafner, Anton Schmitz, Imke Grüne, Seergazhi G. Srivatsan, Inga Bauer & Michael Famulok - LIMES Program Unit Molecular Immune and Cell Biology, Laboratory of Molecular Immunology, University of Bonn, Karlrobert-Kreiten Straße 13, Bonn, 53115, Germany
Bianca Paul, Waldemar Kolanus & Thomas Quast - Institut für Molekulare Immunologie, GSF-Forschungszentrum für Umwelt und Gesundheit, Marchioninistr. 25, München, 81377, Germany
Elisabeth Kremmer
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Hafner, M., Schmitz, A., Grüne, I. et al. Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance.Nature 444, 941–944 (2006). https://doi.org/10.1038/nature05415
- Received: 21 September 2006
- Accepted: 03 November 2006
- Issue Date: 14 December 2006
- DOI: https://doi.org/10.1038/nature05415
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Editorial Summary
Cytohesins and insulin
Insulin resistance syndrome, a condition in which various organs respond insufficiently to insulin, is a major risk factor for the development of type 2 diabetes. For the majority of affected individuals, the underlying molecular defects are unknown. Hafner et al. now show that chemical inhibition of cytohesins, regulatory proteins not previously implicated in insulin-regulated metabolism, induces hepatic insulin resistance in mice. This points to impaired cytohesin function as a possible cause for insulin resistance and to cytohesin activators as a treatment for this disease. In a separate study the Drosophila cytohesin equivalent Steppke is shown to be an essential component of insulin signalling. Taken together, the two papers provide independent evidence for the involvement of cytohesins in the insulin pathway and demonstrate that the cytohesin-mediated control of this pathway is at least 800 million years old.