Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death
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 t...
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2020-09-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/56773 |
| _version_ | 1797997653869461504 |
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| author | Kuan-Yi Lu Charisse Flerida A Pasaje Tamanna Srivastava David R Loiselle Jacquin C Niles Emily Derbyshire |
| author_facet | Kuan-Yi Lu Charisse Flerida A Pasaje Tamanna Srivastava David R Loiselle Jacquin C Niles Emily Derbyshire |
| author_sort | Kuan-Yi Lu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T10:35:02Z |
| format | Article |
| id | doaj.art-d9bd5a8b41e7406fb77b7dfdb28fae8a |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T10:35:02Z |
| publishDate | 2020-09-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-d9bd5a8b41e7406fb77b7dfdb28fae8a2022-12-22T04:29:18ZengeLife Sciences Publications LtdeLife2050-084X2020-09-01910.7554/eLife.56773Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell deathKuan-Yi Lu0https://orcid.org/0000-0002-3663-377XCharisse Flerida A Pasaje1https://orcid.org/0000-0002-9780-3680Tamanna Srivastava2David R Loiselle3https://orcid.org/0000-0002-7065-8495Jacquin C Niles4https://orcid.org/0000-0002-6250-8796Emily Derbyshire5https://orcid.org/0000-0001-6664-8844Department of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, United States; Department of Chemistry, Duke University, Durham, United StatesDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United StatesDepartment of Chemistry, Duke University, Durham, United StatesDepartment of Pharmacology and Cancer Biology, School of Medicine, Duke University, Durham, United StatesDepartment of Biological Engineering, Massachusetts Institute of Technology, Cambridge, United StatesDepartment of Molecular Genetics and Microbiology, School of Medicine, Duke University, Durham, United States; Department of Chemistry, Duke University, Durham, United StatesPhosphatidylinositol 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.https://elifesciences.org/articles/56773phosphatidylinositol 3-phosphateHsp70heat stressmalariadigestive vacuole |
| spellingShingle | Kuan-Yi Lu Charisse Flerida A Pasaje Tamanna Srivastava David R Loiselle Jacquin C Niles Emily Derbyshire Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death eLife phosphatidylinositol 3-phosphate Hsp70 heat stress malaria digestive vacuole |
| title | Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death |
| title_full | Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death |
| title_fullStr | Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death |
| title_full_unstemmed | Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death |
| title_short | Phosphatidylinositol 3-phosphate and Hsp70 protect Plasmodium falciparum from heat-induced cell death |
| title_sort | phosphatidylinositol 3 phosphate and hsp70 protect plasmodium falciparum from heat induced cell death |
| topic | phosphatidylinositol 3-phosphate Hsp70 heat stress malaria digestive vacuole |
| url | https://elifesciences.org/articles/56773 |
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