Girolline as a sequence-selective probe into eIF5A function
RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
@MPI for Biology of Ageing, Auditorium
Host: Dr. Ina Huppertz, Max Planck Institute for Biology of Ageing, Cologne
ABSTRACT
We owe a lot of our understanding of the translation machinery to small molecule probes. Since large parts of the protein synthesis apparatus are essential and difficult to manipulate through genetics or molecular biology, small molecule modulators provide potent tools for dissecting specific steps in the production of new proteins. Advances in DNA sequencing technology now enable a comprehensive understanding of the physiological impact of translation perturbation. Using ribosome profiling we could demonstrate that the small marine natural product girolline (Giro) acts as a sequence-selective modulator of translation elongation factor eIF5A. Giro discourages eIF5A binding to the ribosome and leads to ribosomal stalling on difficult to translate sequence elements, including stretches containing poly-proline or AAA-encoded lysine. Giro-induced ribosome stalling triggers the ribosome-associated quality control (RQC) pathway and at least part of Giro’s cytotoxicity derives from premature activation of quality control pathways. Using CRISPR/Cas knock-out screening we were furthermore able to identify several cellular systems and quality control pathways impacted by eIF5A dysfunction. Therefore, we could not only introduce the first specific chemical probe into eIF5A activity but also follow the physiological impact of eIF5A perturbation on a cellular system.
ABOUT DR. SCHNEIDER-POETSCH
Dr. Tilman Schneider-Poetsch is a Senior Staff Scientist in the Expanded Chemical Space Research Team at RIKEN. His research bridges chemical biology and RNA regulation, with emphasis on translational control and splicing modulation. He earned his BA in Biochemistry and Molecular Biology, at the University of California, Berkeley, where he conducted early research in Robert Tjian’s lab, isolating transcriptional mediator complexes. He completed his PhD in Biochemistry at the Johns Hopkins University School of Medicine, investigating the mechanism of action of translation inhibitors such as cycloheximide and lactimidomycin in the laboratory of Jun O. Liu. After graduation, he accepted a JSPS postdoctoral fellowship at the Chemical Genetics Laboratory of Minoru Yoshida at RIKEN. His research there initially focused on mRNA splicing inhibition, later expanding to the study of the translation factor eIF5A. In 2014, Dr. Schneider-Poetsch was appointed tenured staff scientist and promoted to senior staff scientist in 2024. He has also taught chemical biology to undergraduate students in the international program at Waseda University, Tokyo, since 2014. His contributions to the field were recognized with the Omura Award in 2022 for his review article “Splicing modulators: on the way from nature to clinic”, published in the Journal of Antibiotics.