Plasmodium falciparum Hsp90 supports DNA replication.

Abstract

Plasmodium falciparum heat shock protein 90 (PfHsp90) is an attractive antimalarial target, but the molecular pathways dependent on its activity remain poorly understood. Here, we use two chemically distinct Hsp90 inhibitors, geldanamycin and XL888, to profile the PfHsp90-dependent proteome during the blood stage. We identify 131 proteins reduced in abundance following both treatments, 40% of which co-immunoprecipitate with PfHsp90. DNA replication emerges as the most enriched pathway, and PfHsp90 inhibition reduces parasite DNA content and nascent DNA synthesis during blood- and liver-stage development. Combining Hsp90 inhibition with inhibitors of DNA replication further produces synergistic antiparasitic activity. Together, these findings establish a functional connection between PfHsp90 and parasite DNA replication and define a network of conserved and Plasmodium-specific proteins dependent on Hsp90 activity.

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