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Direct interaction of Chivosazole F with actin elicits cell responses similar to Latrunculin A but distinct from Chondramide

Filipuzzi, Ireos and Thomas, Jason and Pries, Verena and Estoppey, David and Salcius, Michael and Studer, Christian and 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

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