Girolline as a sequence-selective probe into eIF5A function
Speaker: Tilman Schneider-Poetsch (RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan)
Title: "Girolline as a sequence-selective probe into eIF5A function"
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.
Host: Harald Groß, Heike Brötz-Oesterhelt
Date: 15.09.2025
Time: 11 a.m. (s.t.)
Venue: A Building Chemistry
Room A3M04
Auf der Morgenstelle 18
72076 Tübingen