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Transcriptional effects of actin-binding compounds: the cytoplasm sets the tone

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Abstract

Actin has emerged as a versatile regulator of gene transcription. Cytoplasmatic actin regulates mechanosensitive-signaling pathways such as MRTF–SRF and Hippo-YAP/TAZ. In the nucleus, both polymerized and monomeric actin directly interfere with transcription-associated molecular machineries. Natural actin-binding compounds are frequently used tools to study actin-related processes in cell biology. However, their influence on transcriptional regulation and intranuclear actin polymerization is poorly understood to date. Here, we analyze the effects of two representative actin-binding compounds, Miuraenamide A (polymerizing properties) and Latrunculin B (depolymerizing properties), on transcriptional regulation in primary cells. We find that actin stabilizing and destabilizing compounds inversely shift nuclear actin levels without a direct influence on polymerization state and intranuclear aspects of transcriptional regulation. Furthermore, we identify Miuraenamide A as a potent inducer of G-actin-dependent SRF target gene expression. In contrast, the F-actin-regulated Hippo-YAP/TAZ axis remains largely unaffected by compound-induced actin aggregation. This is due to the inability of AMOTp130 to bind to the amorphous actin aggregates resulting from treatment with miuraenamide. We conclude that actin-binding compounds predominantly regulate transcription via their influence on cytoplasmatic G-actin levels, while transcriptional processes relying on intranuclear actin polymerization or functional F-actin networks are not targeted by these compounds at tolerable doses.

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Acknowledgements

The authors thank the labs of Prof. Robert Grosse and Prof. Bin Zhao for the sharing of plasmids and fruitful scientific discussions. We, furthermore, thank Jana Peliskova for excellent technical assistance and Dr. Lisa Karmann for providing synthetic samples of Miuraenamide A. This work was funded by the Deutsche Forschungsgemeinschaft (DFG), SFB 1032, projects B08 and B03, and FOR1406.

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Authors and Affiliations

  1. Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians-University Munich, 81377, Munich, Germany

    Florian A. Gegenfurtner, Themistoklis Zisis, Angelika M. Vollmar & Stefan Zahler

  2. Department of Chemistry, Munich Center for Integrated Protein Science, Nanosystems Initiative Munich and Centre for Nanoscience, Ludwig-Maximilians-University Munich, 81377, Munich, Germany

    Nader Al Danaf, Waldemar Schrimpf & Don C. Lamb

  3. Department Biology II, Anthropology and Human Genomics, Ludwig-Maximilians-University Munich, 82152, Martinsried, Germany

    Zane Kliesmete, Christoph Ziegenhain & Wolfgang Enard

  4. Institute of Organic Chemistry, Saarland University, 66041, Saarbrücken, Germany

    Uli Kazmaier

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  1. Florian A. Gegenfurtner
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Gegenfurtner, F.A., Zisis, T., Al Danaf, N. et al. Transcriptional effects of actin-binding compounds: the cytoplasm sets the tone. Cell. Mol. Life Sci. 75, 4539–4555 (2018). https://doi.org/10.1007/s00018-018-2919-4

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