Schneider-Poetsch Tilman, Dang Yongjun, Iwasaki Wakana, Arata Mayumi, Shichino Yuichi, Al Mourabit Ali, Moriou Celine, Romo Daniel, Liu Jun O, Ito Takuhiro, Iwasaki Shintaro, Yoshida Minoru
Chemical Genomics Research Group, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan.
Basic Medicine Research and Innovation Center for Novel Target and Therapeutic Intervention, Ministry of Education, The Second Affiliated Hospital of Chongqing Medical University, College of Pharmacy, Chongqing Medical University, Chongqing, China.
Nat Commun. 2025 Jan 10;16(1):223. doi: 10.1038/s41467-024-54838-2.
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.
天然产物在为蛋白质生物合成提供研究探针方面有着悠久的历史，其中许多化合物可用作治疗药物。海洋天然产物吉洛林被描述为一种蛋白质合成抑制剂。然而，其确切的作用机制仍不清楚。我们在此展示的数据表明，吉洛林是翻译因子eIF5A的序列选择性调节剂。吉洛林会干扰核糖体与eIF5A的相互作用，并诱导核糖体停滞，从而阻碍翻译进程，包括在由AAA编码的赖氨酸处。我们的数据还表明，eIF5A在核糖体相关的质量控制以及维持翻译进程的效率方面发挥着生理作用。吉洛林有助于加深我们对生理环境中蛋白质产生与质量控制之间相互作用的理解，并提供了一种有效的化学工具来选择性地调节基因表达。
