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

Autor: Kofler L; Institute of Molecular Biosciences, University of Graz, Graz, 8010, Austria., Grundmann L; Research Institute of Molecular Pathology (IMP), Vienna BioCenter, Vienna, 1030, Austria.; Vienna BioCenter PhD Program, Doctoral School of the University of Vienna and Medical University of Vienna, 1030, Vienna, Austria., Gerhalter M; Institute of Molecular Biosciences, University of Graz, Graz, 8010, Austria., Prattes M; Institute of Molecular Biosciences, University of Graz, Graz, 8010, Austria., Merl-Pham J; Core Facility Metabolomics and Proteomics (CF-MPC), Helmholtz Center Munich, German Center for Environmental Health GmbH, D-80939, Munich, Germany., Zisser G; Institute of Molecular Biosciences, University of Graz, Graz, 8010, Austria., Grishkovskaya I; Research Institute of Molecular Pathology (IMP), Vienna BioCenter, Vienna, 1030, Austria., Hodirnau VV; Institute of Science and Technology Austria, Klosterneuburg, Austria., Vareka M; Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, Graz, 8010, Austria., Breinbauer R; Institute of Organic Chemistry, Graz University of Technology, Stremayrgasse 9, Graz, 8010, Austria., Hauck SM; Core Facility Metabolomics and Proteomics (CF-MPC), Helmholtz Center Munich, German Center for Environmental Health GmbH, D-80939, Munich, Germany., Haselbach D; Research Institute of Molecular Pathology (IMP), Vienna BioCenter, Vienna, 1030, Austria. david.haselbach@imp.ac.at., Bergler H; Institute of Molecular Biosciences, University of Graz, Graz, 8010, Austria. helmut.bergler@uni-graz.at.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2024 Aug 29; Vol. 15 (1), pp. 7511. Date of Electronic Publication: 2024 Aug 29.
DOI: 10.1038/s41467-024-51754-3
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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