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.

Usnic acid is a lichen secondary metabolite and has a antitumor activity. Here the authors show that usnic acid rapidly blocks large ribosomal subunit formation. This hinders pre-rRNA processing and leads to depletion of key maturation factors such as Dbp10.

Details

Title
The novel ribosome biogenesis inhibitor usnic acid blocks nucleolar pre-60S maturation
Author
Kofler, Lisa 1 ; Grundmann, Lorenz 2   VIAFID ORCID Logo  ; Gerhalter, Magdalena 1 ; Prattes, Michael 1   VIAFID ORCID Logo  ; Merl-Pham, Juliane 3   VIAFID ORCID Logo  ; Zisser, Gertrude 1 ; Grishkovskaya, Irina 4   VIAFID ORCID Logo  ; Hodirnau, Victor-Valentin 5   VIAFID ORCID Logo  ; Vareka, Martin 6 ; Breinbauer, Rolf 6   VIAFID ORCID Logo  ; Hauck, Stefanie M. 3   VIAFID ORCID Logo  ; Haselbach, David 4   VIAFID ORCID Logo  ; Bergler, Helmut 1   VIAFID ORCID Logo 

 University of Graz, Institute of Molecular Biosciences, Graz, Austria (GRID:grid.5110.5) (ISNI:0000 0001 2153 9003) 
 Vienna BioCenter, Research Institute of Molecular Pathology (IMP), Vienna, Austria (GRID:grid.473822.8) (ISNI:0000 0005 0375 3232); Doctoral School of the University of Vienna and Medical University of Vienna, Vienna BioCenter PhD Program, Vienna, Austria (GRID:grid.22937.3d) (ISNI:0000 0000 9259 8492) 
 German Center for Environmental Health GmbH, Core Facility Metabolomics and Proteomics (CF-MPC), Helmholtz Center Munich, Munich, Germany (GRID:grid.4567.0) (ISNI:0000 0004 0483 2525) 
 Vienna BioCenter, Research Institute of Molecular Pathology (IMP), Vienna, Austria (GRID:grid.473822.8) (ISNI:0000 0005 0375 3232) 
 Institute of Science and Technology Austria, Klosterneuburg, Austria (GRID:grid.33565.36) (ISNI:0000 0004 0431 2247) 
 Graz University of Technology, Institute of Organic Chemistry, Graz, Austria (GRID:grid.410413.3) (ISNI:0000 0001 2294 748X) 
Pages
7511
Publication year
2024
Publication date
2024
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
3098472899
Copyright
© The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by-nc-nd/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.