Periodic fever is a characteristic clinical feature of human malaria, but how parasites survive febrile episodes is not known. Although the genomes of Plasmodium species encode a full set of chaperones, they lack the conserved eukaryotic transcription factor HSF1, which activates the expression of chaperones following heat shock. Here, we show that PfAP2-HS, a transcription factor in the ApiAP2 family, regulates the protective heat-shock response in Plasmodium falciparum. PfAP2-HS activates the transcription of hsp70-1 and hsp90 at elevated temperatures. The main binding site of PfAP2-HS in the entire genome coincides with a tandem G-box DNA motif in the hsp70-1 promoter. Engineered parasites lacking PfAP2-HS have reduced heat-shock survival and severe growth defects at 37 °C but not at 35 °C. Parasites lacking PfAP2-HS also have increased sensitivity to imbalances in protein homeostasis (proteostasis) produced by artemisinin, the frontline antimalarial drug, or the proteasome inhibitor epoxomicin. We propose that PfAP2-HS contributes to the maintenance of proteostasis under basal conditions and upregulates specific chaperone-encoding genes at febrile temperatures to protect the parasite against protein damage.

周期性发热是人类疟疾的特征性临床特征，但寄生虫如何在发热发作中存活尚不清楚。尽管疟原虫物种的基因组编码了一整套伴侣蛋白，但它们缺乏保守的真核转录因子 HSF1，后者在热休克后激活伴侣蛋白的表达。在这里，我们展示了 ApiAP2 家族中的转录因子 PfAP2-HS 调节恶性疟原虫的保护性热休克反应。PfAP2-HS在升高的温度下激活hsp70-1和hsp90的转录。PfAP2-HS 在整个基因组中的主要结合位点与 hsp70-1 中的串联 G-box DNA 基序一致发起人。缺乏 PfAP2-HS 的工程寄生虫在 37 °C 但在 35 °C 下降低了热休克存活率和严重的生长缺陷。缺乏 PfAP2-HS 的寄生虫对由青蒿素、一线抗疟药或蛋白酶体抑制剂环氧霉素产生的蛋白质稳态失衡（proteostasis）的敏感性也增加。我们提出 PfAP2-HS 有助于在基础条件下维持蛋白质稳态，并在发热温度下上调特定的伴侣编码基因，以保护寄生虫免受蛋白质损伤。