Filipuzzi, Ireos, Thomas, Jason, Pries, Verena, Estoppey, David, Salcius, Michael, Studer, Christian, Schirle, Markus and Hoepfner, Dominic (2017) Direct interaction of Chivosazole F with actin elicits cell responses similar to Latrunculin A but distinct from Chondramide. ACS chemical biology. ISSN 1554-8929

Abstract

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 chemo-genomic profiles and responses to the Chivosazole F-resistant SNPs show a partially conserved mechanism of action for Chivosazole F and Latrunculin A but clear divergences to Chondramide. Finally, deletion of the uncharacterized ORF C14orf80 in mammalian cells was found to lead to Chivosazole F hyper-resistance, proposing a function for this evolutionary conserved gene product in counteracting perturbation of actin filaments.

Item Type:	Article
Date Deposited:	19 Sep 2017 00:45
Last Modified:	19 Sep 2017 00:45
URI:	https://oak.novartis.com/id/eprint/32775