Figure 5.

PfAcAS localizes to the nucleus and its inhibition affects histone acetylation state

(A and B) (A) Immunofluorescence localization of PfAcAS using an HA-epitope-expressing construct throughout the life cycle of the parasite. Shown are representative images of early-, mid-, and late-stage trophozoite and schizont-stage parasites from a mixed-stage culture. PfAcAS-HA co-localized with DAPI DNA stain throughout the majority of the parasite life cycle, consistent with nuclear localization of PfAcAS. (B) Schematic representation of the proposed function of PfAcAS in the maintenance of acetyl-CoA available for histone acetylation by histone acetyltransferases (HAT), from free acetate generated by the activity of histone deacetylases (HDAC).

(C) Dose-dependent reduction of histone acetylation by MMV019721 in wild-type 3D7 parasites but not in PfAcAS-T648M carrying drug-resistant parasites. Shown are representative western blots of a single experiment.

(D) Dose-dependent reduction in histone acetylation by MMV019721 in Dd2 parent and not in A597V mutant parasites. Shown are representative western blots of a single experiment.

See also Figures S6 and S7.