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

Lisa Kofler, Lorenz Grundmann, Magdalena Gerhalter, Michael Prattes, Juliane Merl-Pham, Gertrude Zisser, Irina Grishkovskaya, Victor-Valentin Hodirnau, Martin Vareka, Rolf Breinbauer, Stefanie M. Hauck, David Haselbach () and Helmut Bergler ()
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Lisa Kofler: University of Graz
Lorenz Grundmann: Vienna BioCenter
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

Nature Communications, 2024, vol. 15, issue 1, 1-17

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-51754-3

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