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bioRxiv · 10.1101/2021.03.15.435375

The PfAP2-HS transcription factor protects malaria parasites from febrile temperatures

Tinto-Font, E.·Michel-Todo, L.·Russell, T. J.·Casas-Vila, N.·Conway, D. J.·Bozdech, Z.·Llinas, M.·Cortes, A.
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Abstract

Periodic fever is the most characteristic clinical feature of human malaria1-3, but how parasites survive febrile episodes is not known. While Plasmodium spp. genomes encode a full complement of chaperones4, they lack an ortholog of the conserved transcription factor HSF1, which in most eukaryotes activates the expression of key chaperones upon heat shock (HS)5-8. Here we identified PfAP2-HS, a transcription factor of the ApiAP2 family9-11, as the key regulator of the P. falciparum protective HS response. The PfAP2-HS-dependent HS response is largely restricted to rapid activation of hsp70-1, the predominant direct target of PfAP2-HS, and hsp90. Deletion of PfAP2-HS dramatically reduced HS survival and also resulted in severe growth defects at 37{degrees}C, but not at 35{degrees}C, and increased sensitivity to imbalances in protein homeostasis (proteostasis) produced by artemisinin, the current frontline antimalarial drug12,13. These results demonstrate that PfAP2-HS contributes to general maintenance of proteostasis and drives a rapid chaperone-based protective response against febrile temperatures. While several ApiAP2 transcription factors regulate life cycle transitions in malaria parasites11,14,15, PfAP2-HS is the first identified Plasmodium transcription factor that controls a protective response to a within-host environmental challenge.

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Tinto-Font, E., Michel-Todo, L., Russell, T. J., Casas-Vila, N., Conway, D. J., Bozdech, Z., Llinas, M., Cortes, A.. 2021-03-15. The PfAP2-HS transcription factor protects malaria parasites from febrile temperatures. https://doi.org/10.1101/2021.03.15.435375

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