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ACS Chem Biol. 2017 Sep 15;12(9):2264-2269. doi: 10.1021/acschembio.7b00385. Epub 2017 Aug 15.

Direct Interaction of Chivosazole F with Actin Elicits Cell Responses Similar to Latrunculin A but Distinct from Chondramide.

Author information

1
Novartis Institutes for BioMedical Research , Novartis Pharma AG, Forum 1 Novartis Campus, CH-4056 Basel, Switzerland.
2
Novartis Institutes for BioMedical Research , 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.

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 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.

PMID:
28796488
DOI:
10.1021/acschembio.7b00385
[Indexed for MEDLINE]

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