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

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.