Mechanism of Action of Prethioviridamide, an Anticancer Ribosomally Synthesized and Post-Translationally Modified Peptide with a Polythioamide Structure

Shohei Takase, Rumi Kurokawa, Yasumitsu Kondoh, Kaori Honda, Takehiro Suzuki, Teppei Kawahara, Haruo Ikeda, Naoshi Dohmae, Hiroyuki Osada, Kazuo Shin-Ya, Tetsuo Kushiro, Minoru Yoshida, Ken Matsumoto

Research output: Contribution to journalArticlepeer-review

11 Citations (Scopus)

Abstract

Thioviridamide, prethioviridamide, and JBIR-140, which are ribosomally synthesized and post-translationally modified peptides (RiPPs) possessing five thioamide bonds, induce selective apoptosis in various cancer cells, especially those expressing the adenovirus oncogene E1A. However, the target protein of this unique family of bioactive compounds was previously unknown. To investigate the mechanism of action, we adopted a combined approach of genome-wide shRNA library screening, transcriptome profiling, and biochemical identification of prethioviridamide-binding proteins. An shRNA screen identified 63 genes involved in cell sensitivity to prethioviridamide, which included translation initiation factors, aminoacyl tRNA synthetases, and mitochondrial proteins. Transcriptome profiling and subsequent analysis revealed that prethioviridamide induces the integrated stress response (ISR) through the GCN2-ATF4 pathway, which is likely to cause cell death. Furthermore, we found that prethioviridamide binds and inhibits respiratory chain complex V (F1Fo-ATP synthase) in mitochondria, suggesting that inhibition of complex V leads to activation of the GCN2-ATF4 pathway. These results imply that the members of a unique family of RiPPs with polythioamide structure target mitochondria to induce the ISR.

Original languageEnglish
Pages (from-to)1819-1828
Number of pages10
JournalACS Chemical Biology
Volume14
Issue number8
DOIs
Publication statusPublished - 16 Aug 2019

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