The novel ribosome biogenesis inhibitor usnic acid blocks nucleolar pre-60S maturation
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.
Authors
- Juliane Merl‐Pham (ORCID: https://orcid.org/0000-0002-3422-4083)
- David Haselbach (ORCID: https://orcid.org/0000-0002-5276-5633)
- Magdalena Gerhalter (ORCID: https://orcid.org/0000-0001-5545-5836)
- Gertrude Zisser
- Stefanie M. Hauck (ORCID: https://orcid.org/0000-0002-1630-6827)
- Martin Vareka (ORCID: https://orcid.org/0000-0001-6812-4454)
- Victor-Valentin Hodirnau (ORCID: https://orcid.org/0000-0003-3904-947X)
- Irina Grishkovskaya (ORCID: https://orcid.org/0000-0003-0164-9373)
- Michael Prattes (ORCID: https://orcid.org/0000-0002-2526-9896)
- Helmut Bergler (ORCID: https://orcid.org/0000-0002-7724-309X)
- Lorenz Grundmann (ORCID: https://orcid.org/0000-0002-0365-5913)
- Lisa Kofler
- Rolf Breinbauer (ORCID: https://orcid.org/0000-0001-6009-7359)
Institutions
- Institute of Science and Technology Austria (AT)
- University of Graz (AT)
- Research Institute of Molecular Pathology (AT)
- Helmholtz Zentrum München (DE)
- Graz University of Technology (AT)
- BioTechMed-Graz (AT)
- Vienna Biocenter (AT)
- Medical University of Vienna (AT)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-08-29
- DOI
- https://doi.org/10.1038/s41467-024-51754-3
- Citations
- 5
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 1.17
Funders
- Institute of Science and Technology Austria
- Austrian Science Fund
- Österreichische Forschungsförderungsgesellschaft