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A heat-shock response regulated by the PfAP2-HS transcription factor protects human malaria parasites from febrile temperatures.


ABSTRACT: 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.

SUBMITTER: Tinto-Font E 

PROVIDER: S-EPMC8390444 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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A heat-shock response regulated by the PfAP2-HS transcription factor protects human malaria parasites from febrile temperatures.

Tintó-Font Elisabet E   Michel-Todó Lucas L   Russell Timothy J TJ   Casas-Vila Núria N   Conway David J DJ   Bozdech Zbynek Z   Llinás Manuel M   Cortés Alfred A  

Nature microbiology 20210816 9


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  ...[more]

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