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The novel ribosome biogenesis inhibitor usnic acid blocks nucleolar pre-60S maturation

Author

Listed:
  • Lisa Kofler

    (University of Graz)

  • Lorenz Grundmann

    (Vienna BioCenter
    Doctoral School of the University of Vienna and Medical University of Vienna)

  • Magdalena Gerhalter

    (University of Graz)

  • Michael Prattes

    (University of Graz)

  • Juliane Merl-Pham

    (German Center for Environmental Health GmbH)

  • Gertrude Zisser

    (University of Graz)

  • Irina Grishkovskaya

    (Vienna BioCenter)

  • Victor-Valentin Hodirnau

    (Institute of Science and Technology Austria)

  • Martin Vareka

    (Graz University of Technology)

  • Rolf Breinbauer

    (Graz University of Technology)

  • Stefanie M. Hauck

    (German Center for Environmental Health GmbH)

  • David Haselbach

    (Vienna BioCenter)

  • Helmut Bergler

    (University of Graz)

Abstract

The formation of new ribosomes is tightly coordinated with cell growth and proliferation. In eukaryotes, the correct assembly of all ribosomal proteins and RNAs follows an intricate scheme of maturation and rearrangement steps across three cellular compartments: the nucleolus, nucleoplasm, and cytoplasm. We demonstrate that usnic acid, a lichen secondary metabolite, inhibits the maturation of the large ribosomal subunit in yeast. We combine biochemical characterization of pre-ribosomal particles with a quantitative single-particle cryo-EM approach to monitor changes in nucleolar particle populations upon drug treatment. Usnic acid rapidly blocks the transition from nucleolar state B to C of Nsa1-associated pre-ribosomes, depleting key maturation factors such as Dbp10 and hindering pre-rRNA processing. This primary nucleolar block rapidly rebounds on earlier stages of the pathway which highlights the regulatory linkages between different steps. In summary, we provide an in-depth characterization of the effect of usnic acid on ribosome biogenesis, which may have implications for its reported anti-cancer activities.

Suggested Citation

  • Lisa Kofler & Lorenz Grundmann & Magdalena Gerhalter & Michael Prattes & Juliane Merl-Pham & Gertrude Zisser & Irina Grishkovskaya & Victor-Valentin Hodirnau & Martin Vareka & Rolf Breinbauer & Stefan, 2024. "The novel ribosome biogenesis inhibitor usnic acid blocks nucleolar pre-60S maturation," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-51754-3
    DOI: 10.1038/s41467-024-51754-3
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    References listed on IDEAS

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    1. Yi Zhou & Sharmishtha Musalgaonkar & Arlen W. Johnson & David W. Taylor, 2019. "Tightly-orchestrated rearrangements govern catalytic center assembly of the ribosome," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
    2. Michael Ameismeier & Jingdong Cheng & Otto Berninghausen & Roland Beckmann, 2018. "Visualizing late states of human 40S ribosomal subunit maturation," Nature, Nature, vol. 558(7709), pages 249-253, June.
    3. Zahra Assur Sanghai & Linamarie Miller & Kelly R. Molloy & Jonas Barandun & Mirjam Hunziker & Malik Chaker-Margot & Junjie Wang & Brian T. Chait & Sebastian Klinge, 2018. "Modular assembly of the nucleolar pre-60S ribosomal subunit," Nature, Nature, vol. 556(7699), pages 126-129, April.
    4. Michael Prattes & Irina Grishkovskaya & Victor-Valentin Hodirnau & Ingrid Rössler & Isabella Klein & Christina Hetzmannseder & Gertrude Zisser & Christian C. Gruber & Karl Gruber & David Haselbach & H, 2021. "Structural basis for inhibition of the AAA-ATPase Drg1 by diazaborine," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
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