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

Periodic fever is a characteristic clinical feature of human malaria, but how parasites survive febrile episodes is not known. Although Plasmodium spp. genomes encode a full set of chaperones, they lack the conserved eukaryotic transcription factor HSF1, which activates the expression of chaperones...

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Detalles Bibliográficos
Autores principales: Tintó-Font, Elisabet, Michel-Todó, Lucas, Russell, Timothy J., Casas-Vila, Núria, Conway, David J., Bozdech, Zbynek, Llinás, Manuel, Cortés, Alfred
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390444/
https://www.ncbi.nlm.nih.gov/pubmed/34400833
http://dx.doi.org/10.1038/s41564-021-00940-w
Descripción
Sumario:Periodic fever is a characteristic clinical feature of human malaria, but how parasites survive febrile episodes is not known. Although Plasmodium spp. genomes encode a full set of chaperones, they lack the conserved eukaryotic transcription factor HSF1, which activates the expression of chaperones upon 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 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 by the proteasome inhibitor epoxomicin. We propose that PfAP2-HS contributes to maintenance of proteostasis under basal conditions and upregulates specific chaperone-encoding genes at febrile temperatures to protect the parasite against protein damage.