Inhibition of maize histone deacetylases by HC toxin, the host-selective toxin of Cochliobolus carbonum.

Abstract

HC toxin, the host-selective toxin of the maize pathogen Cochliobolus carbonum, inhibited maize histone deacetylase (HD) at 2 pM. Chlamydocin, a related cyclic tetrapeptide, also inhibited HD activity. The toxins did not affect histone acetyltransferases. After partia1 purification of histone deacetylases HD1-A, HD1-B, and HD2 from germinating maize embryos, we demonstrated that the different enzymes were similarly inhibited by the toxins. lnhibitory activities were reversibly eliminated by treating toxins with 2-mercaptoethanol, presumably by modifying the carbonyl group of the epoxidecontaining amino acid Aeo (2-amino-9,1O-epoxy-8-oxodecanoic acid). Kinetic studies revealed that inhibition of HD was of the uncompetitive type and reversible. HC toxin, in which the epoxide group had been hydrolyzed, completely lost its inhibitory activity; when the carbonyl group of Aeo had been reduced to the corresponding alcohol, the modified toxin was less active than native toxin. In vivo treatment of embryos with HC toxin caused the accumulation of highly acetylated histone H4 subspecies and elevated acetate incorporation into H4 in susceptible-genotype embryos but not in the resistant genotype. HDs from chicken and the myxomycete Physarum polycephalum were also inhibited, indicating that the host selectivity of HC toxin is not determined by its inhibitory effect o n HD. Consistent with these results, we propose a model in which HC toxin promotes the establishment of pathogenic compatibility between C. carbonum and maize by interfering with reversible histone acetylation, which is implicated in the control of fundamental cellular processes, such as chromatin structure, cell cycle progression, and gene expression.

HC toxin (a HDAC inhibitor) enhances IRS1–Akt signalling and metabolism in mouse myotubes

“…HC toxin is a cyclic tetrapeptide originally identified as a host-selective toxin from the maize pathogenic fungus Cochliobolus (Helminthosporium) carbonum (Mottamal et al 2015), and it was shown to inhibit class I HDAC enzymes (HDAC1, -2, -3 and -8) in mammalian cells (Brosch et al 1995, Hildmann et al 2006. Herein, we report that HC toxin activates two exercise-activated pathways in C2C12 myotubes: AMPK and Akt pathways.…”

Small Chemical Chromatin Effectors Alter Secondary Metabolite Production in Aspergillus clavatus

“…Other SCCEs such as trichostatin A (TSA), an antifungal compound produced by Streptomyces species [21,22] and HC-toxin, produced by Cochliobolus carbonum during maize leave infection, inhibits class I and class II HDAC activity [23]. Already in 1978 it was demonstrated that butyrate, a short chain fatty acid produced by anaerobic bacterial fermentation, induces differentiation of erythroleukemic cells via inhibition of HDACs [24].…”

Natural Products as Zinc‐Dependent Histone Deacetylase Inhibitors

“…[88] In AS1387392, the MePro residue of FR235222 is replaced by proline. [90] It can significantly inhibit HDAC activity in Physarum spp., maize, and chicken erythrocytes at a concentration of 2 mg mL À1 . AS1387392 also shows potent inhibitory activity against splenocyte proliferation (IC 50 = 4.6 nm), similar to that of FR235222 (IC 50 = 5.0 nm).…”