The microbial metabolite Chivosazole F has been described to affect the cytoskeleton and to inhibit actin polymerization in vitro. Applying orthogonal genomic and proteomics approaches, we now show for the first time that Chivosazole F exerts its effect by directly interacting with actin and demonstrate the cellular impact of Chivosazole F in an unbiased, genome-wide context in yeast and in mammalian cells. Furthermore, mutation-based resistance mapping identifies two SNPs located in the putative Chivosazole F binding site of actin. Comparing chemogenomic profiles and responses to the Chivosazole F-resistant SNPs shows a partially conserved mechanism of action for Chivosazole F and Latrunculin A, but clear divergence from Chondramide. In addition, C14orf80 is an evolutionarily highly conserved ORF, lacking any functional annotation. As editing of C14orf80 leads to Chivosazole F hyper-resistance, we propose a function for this gene product in counteracting perturbation of actin filaments.

中文翻译：

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Chivosazole F与肌动蛋白的直接相互作用引起类似于Latrunculin A的细胞反应，但与软骨酰胺不同

已经描述了微生物代谢物Chivosazole F在体外会影响细胞骨架并抑制肌动蛋白聚合。现在，应用正交基因组学和蛋白质组学方法，我们首次证明了Chivosazole F通过与肌动蛋白直接相互作用而发挥其作用，并证明了Chivosazole F在酵母和哺乳动物细胞中在无偏见的全基因组范围内的细胞影响。此外，基于突变的抗性作图可鉴定位于肌动蛋白假定的Chivosazole F结合位点的两个SNP。比较化学基因组学特征和对耐Chivosazole F的SNP的反应，显示Chivosazole F和Latrunculin A的部分保守的作用机制，但与软骨酰胺明显不同。此外，C14orf80是进化上高度保守的ORF，缺少任何功能注释。由于编辑C14orf80会导致Chivosazole F超抗性，