Cytoprotective autophagy as a pro-survival strategy in ART-resistant malaria parasites
Abstract Despite several initiatives to subside the global malaria burden, the spread of artemisinin-resistant parasites poses a big threat to malaria elimination. Mutations in PfKelch13 are predictive of ART resistance, whose underpinning molecular mechanism remains obscure. Recently, endocytosis a...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2023-05-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01401-5 |
| _version_ | 1797827649430618112 |
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| author | Deepika Kannan Nishant Joshi Sonal Gupta Soumya Pati Souvik Bhattacharjee Gordon Langsley Shailja Singh |
| author_facet | Deepika Kannan Nishant Joshi Sonal Gupta Soumya Pati Souvik Bhattacharjee Gordon Langsley Shailja Singh |
| author_sort | Deepika Kannan |
| collection | DOAJ |
| description | Abstract Despite several initiatives to subside the global malaria burden, the spread of artemisinin-resistant parasites poses a big threat to malaria elimination. Mutations in PfKelch13 are predictive of ART resistance, whose underpinning molecular mechanism remains obscure. Recently, endocytosis and stress response pathways such as the ubiquitin-proteasome machinery have been linked to artemisinin resistance. With Plasmodium, however, ambiguity persists regarding a role in ART resistance for another cellular stress defence mechanism called autophagy. Therefore, we investigated whether, in the absence of ART treatment, basal autophagy is augmented in PfK13-R539T mutant ART-resistant parasites and analyzed whether PfK13-R539T endowed mutant parasites with an ability to utilize autophagy as a pro-survival strategy. We report that in the absence of any ART treatment, PfK13-R539T mutant parasites exhibit increased basal autophagy compared to PfK13-WT parasites and respond aggressively through changes in autophagic flux. A clear cytoprotective role of autophagy in parasite resistance mechanism is evident by the observation that a suppression of PI3-Kinase (PI3K) activity (a master autophagy regulator) rendered difficulty in the survival of PfK13-R539T ART-resistant parasites. In conclusion, we now show that higher PI3P levels reported for mutant PfKelch13 backgrounds led to increased basal autophagy that acts as a pro-survival response to ART treatment. Our results highlight PfPI3K as a druggable target with the potential to re-sensitize ART-resistant parasites and identify autophagy as a pro-survival function that modulates ART-resistant parasite growth. |
| first_indexed | 2024-04-09T12:52:49Z |
| format | Article |
| id | doaj.art-82d00e0c4ef44b33840f130c2bce8b29 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-04-09T12:52:49Z |
| publishDate | 2023-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-82d00e0c4ef44b33840f130c2bce8b292023-05-14T11:08:24ZengNature Publishing GroupCell Death Discovery2058-77162023-05-019111110.1038/s41420-023-01401-5Cytoprotective autophagy as a pro-survival strategy in ART-resistant malaria parasitesDeepika Kannan0Nishant Joshi1Sonal Gupta2Soumya Pati3Souvik Bhattacharjee4Gordon Langsley5Shailja Singh6Special Centre for Molecular Medicine, Jawaharlal Nehru UniversitySpecial Centre for Molecular Medicine, Jawaharlal Nehru UniversitySpecial Centre for Molecular Medicine, Jawaharlal Nehru UniversityDepartment of Life Sciences, School of Natural Sciences, Shiv Nadar UniversitySpecial Centre for Molecular Medicine, Jawaharlal Nehru UniversityInserm U1016-CNRS UMR8104, Institut CochinSpecial Centre for Molecular Medicine, Jawaharlal Nehru UniversityAbstract Despite several initiatives to subside the global malaria burden, the spread of artemisinin-resistant parasites poses a big threat to malaria elimination. Mutations in PfKelch13 are predictive of ART resistance, whose underpinning molecular mechanism remains obscure. Recently, endocytosis and stress response pathways such as the ubiquitin-proteasome machinery have been linked to artemisinin resistance. With Plasmodium, however, ambiguity persists regarding a role in ART resistance for another cellular stress defence mechanism called autophagy. Therefore, we investigated whether, in the absence of ART treatment, basal autophagy is augmented in PfK13-R539T mutant ART-resistant parasites and analyzed whether PfK13-R539T endowed mutant parasites with an ability to utilize autophagy as a pro-survival strategy. We report that in the absence of any ART treatment, PfK13-R539T mutant parasites exhibit increased basal autophagy compared to PfK13-WT parasites and respond aggressively through changes in autophagic flux. A clear cytoprotective role of autophagy in parasite resistance mechanism is evident by the observation that a suppression of PI3-Kinase (PI3K) activity (a master autophagy regulator) rendered difficulty in the survival of PfK13-R539T ART-resistant parasites. In conclusion, we now show that higher PI3P levels reported for mutant PfKelch13 backgrounds led to increased basal autophagy that acts as a pro-survival response to ART treatment. Our results highlight PfPI3K as a druggable target with the potential to re-sensitize ART-resistant parasites and identify autophagy as a pro-survival function that modulates ART-resistant parasite growth.https://doi.org/10.1038/s41420-023-01401-5 |
| spellingShingle | Deepika Kannan Nishant Joshi Sonal Gupta Soumya Pati Souvik Bhattacharjee Gordon Langsley Shailja Singh Cytoprotective autophagy as a pro-survival strategy in ART-resistant malaria parasites Cell Death Discovery |
| title | Cytoprotective autophagy as a pro-survival strategy in ART-resistant malaria parasites |
| title_full | Cytoprotective autophagy as a pro-survival strategy in ART-resistant malaria parasites |
| title_fullStr | Cytoprotective autophagy as a pro-survival strategy in ART-resistant malaria parasites |
| title_full_unstemmed | Cytoprotective autophagy as a pro-survival strategy in ART-resistant malaria parasites |
| title_short | Cytoprotective autophagy as a pro-survival strategy in ART-resistant malaria parasites |
| title_sort | cytoprotective autophagy as a pro survival strategy in art resistant malaria parasites |
| url | https://doi.org/10.1038/s41420-023-01401-5 |
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