Year: 2025
Type: article
Abstract: Natural products have a long history of providing probes into protein biosynthesis, with many of these compounds serving as therapeutics. The marine natural product girolline has been described as an inhibitor of protein synthesis. Its precise mechanism of action, however, has remained unknown. The data we present here suggests that girolline is a sequence-selective modulator of translation factor eIF5A. Girolline interferes with ribosome-eIF5A interaction and induces ribosome stalling where translational progress is impeded, including on AAA-encoded lysine. Our data furthermore indicate that eIF5A plays a physiological role in ribosome-associated quality control and in maintaining the efficiency of translational progress. Girolline helped to deepen our understanding of the interplay between protein production and quality control in a physiological setting and offers a potent chemical tool to selectively modulate gene expression. The marine natural product girolline is an inhibitor of protein synthesis. Here, the authors show that girolline is a sequence-selective modulator of eIF5A that can cause ribosome stalling and activate ribosome-associated quality control.
Source: Nature Communications
Institutions: RIKEN Center for Sustainable Resource Science, Second Affiliated Hospital of Chongqing Medical University, Chongqing Medical University, RIKEN Center for Biosystems Dynamics Research, RIKEN, Centre National de la Recherche Scientifique, Institut de Chimie des Substances Naturelles, Université Paris-Saclay, Baylor University, Johns Hopkins University, Johns Hopkins Medicine, The University of Tokyo
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, National Institutes of Health, Japan Society for the Promotion of Science, RIKEN, National Institute of General Medical Sciences, Core Research for Evolutional Science and Technology
Awards: G1006851469, G1099833423, G1123254209, 先端モデル動物支援プラットフォーム, G2576085165, G2929407284, G3134877090, G3142924267, G3617209872, G4015830243, G4560890309, 細胞内顆粒P-bodyによるmRNAの空間的制御を介した細胞周期調節機構, G5690990984, G5743931246, G5792590883, G5795596920, SARS-Cov-2の5'UTR, Nsp1によるヒトリボソームの翻訳制御機構の分子基盤, G6079985485, Innovative chemical genetics on novel function of endogenous metabolites, G6718509927, G7126311957, G7207124945, G7253412405, G729497901, G7879866177, G7989560850, Survey of in organello translation through mitochondria-tailored ribosome profiling, G8265796948, Uncovering hidden functions of intrinsic metabolites using chemical genetics and informatics, Pharmacophore - Directed Retrosynthesis Applied to Bioactive Natural Products Informing Mechanism of Action Studies
OpenAlex ID: W4406232055