Girolline is a sequence context-selective modulator of eIF5A activity
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.
Authors
- Daniel Romo (ORCID: https://orcid.org/0000-0003-3805-092X)
- Jun O. Liu (ORCID: https://orcid.org/0000-0003-3842-9841)
- Minoru Yoshida (ORCID: https://orcid.org/0000-0002-4376-5674)
- W. Iwasaki (ORCID: https://orcid.org/0000-0002-0161-777X)
- Shintaro Iwasaki (ORCID: https://orcid.org/0000-0001-7724-3754)
- Tilman Schneider‐Poetsch (ORCID: https://orcid.org/0009-0005-5829-1319)
- Ali Al‐Mourabit (ORCID: https://orcid.org/0000-0002-1762-6910)
- Yongjun Dang (ORCID: https://orcid.org/0000-0001-7237-1132)
- Takuhiro Ito (ORCID: https://orcid.org/0000-0003-3704-5205)
- Mayumi Arata
- Yuichi Shichino (ORCID: https://orcid.org/0000-0002-0093-1185)
- Céline Moriou (ORCID: https://orcid.org/0000-0003-2481-6461)
Institutions
- Université Paris-Sud (FR)
- Centre National de la Recherche Scientifique (FR)
- Institut de Chimie des Substances Naturelles (FR)
- Johns Hopkins University (US)
- Baylor University (US)
- Dalian Medical University (CN)
- Université Paris-Saclay (FR)
- Johns Hopkins Medicine (US)
- Second Affiliated Hospital of Chongqing Medical University (CN)
- RIKEN Center for Sustainable Resource Science (JP)
- Pioneer (Japan) (JP)
- RIKEN (JP)
- RIKEN Center for Biosystems Dynamics Research (JP)
- The University of Tokyo (JP)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-10
- DOI
- https://doi.org/10.1038/s41467-024-54838-2
- Citations
- 3
- Primary Topic
- RNA and protein synthesis mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 2.42
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