Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death.

Journal Article (Journal Article)

Phosphatidylinositol 3-phosphate (PI(3)P) levels in Plasmodium falciparum correlate with tolerance to cellular stresses caused by artemisinin and environmental factors. However, PI(3)P function during the Plasmodium stress response was unknown. Here, we used PI3K inhibitors and antimalarial agents to examine the importance of PI(3)P under thermal conditions recapitulating malarial fever. Live cell microscopy using chemical and genetic reporters revealed that PI(3)P stabilizes the digestive vacuole (DV) under heat stress. We demonstrate that heat-induced DV destabilization in PI(3)P-deficient P. falciparum precedes cell death and is reversible after withdrawal of the stress condition and the PI3K inhibitor. A chemoproteomic approach identified PfHsp70-1 as a PI(3)P-binding protein. An Hsp70 inhibitor and knockdown of PfHsp70-1 phenocopy PI(3)P-deficient parasites under heat shock. Furthermore, PfHsp70-1 downregulation hypersensitizes parasites to heat shock and PI3K inhibitors. Our findings underscore a mechanistic link between PI(3)P and PfHsp70-1 and present a novel PI(3)P function in DV stabilization during heat stress.

Full Text

Duke Authors

Cited Authors

  • Lu, K-Y; Pasaje, CFA; Srivastava, T; Loiselle, DR; Niles, JC; Derbyshire, E

Published Date

  • September 25, 2020

Published In

Volume / Issue

  • 9 /

PubMed ID

  • 32975513

Pubmed Central ID

  • PMC7518890

Electronic International Standard Serial Number (EISSN)

  • 2050-084X

International Standard Serial Number (ISSN)

  • 2050-084X

Digital Object Identifier (DOI)

  • 10.7554/elife.56773

Language

  • eng