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Plasmodium falciparum Atg18 localizes to the food vacuole via interaction with the multi-drug resistance protein 1 and phosphatidylinositol 3-phosphate.
- Source :
-
The Biochemical journal [Biochem J] 2021 May 14; Vol. 478 (9), pp. 1705-1732. - Publication Year :
- 2021
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Abstract
- Autophagy, a lysosome-dependent degradative process, does not appear to be a major degradative process in malaria parasites and has a limited repertoire of genes. To better understand the autophagy process, we investigated Plasmodium falciparum Atg18 (PfAtg18), a PROPPIN family protein, whose members like S. cerevisiae Atg18 (ScAtg18) and human WIPI2 bind PI3P and play an essential role in autophagosome formation. Wild type and mutant PfAtg18 were expressed in P. falciparum and assessed for localization, the effect of various inhibitors and antimalarials on PfAtg18 localization, and identification of PfAtg18-interacting proteins. PfAtg18 is expressed in asexual erythrocytic stages and localized to the food vacuole, which was also observed with other Plasmodium Atg18 proteins, indicating that food vacuole localization is likely a shared feature. Interaction of PfAtg18 with the food vacuole-associated PI3P is essential for localization, as PfAtg18 mutants of PI3P-binding motifs neither bound PI3P nor localized to the food vacuole. Interestingly, wild type ScAtg18 interacted with PI3P, but its expression in P. falciparum showed complete cytoplasmic localization, indicating additional requirement for food vacuole localization. The food vacuole multi-drug resistance protein 1 (MDR1) was consistently identified in the immunoprecipitates of PfAtg18 and P. berghei Atg18, and also interacted with PfAtg18. In contrast with PfAtg18, ScAtg18 did not interact with MDR1, which, in addition to PI3P, could play a critical role in localization of PfAtg18. Chloroquine and amodiaquine caused cytoplasmic localization of PfAtg18, suggesting that these target PfAtg18 transport pathway. Thus, PI3P and MDR1 are critical mediators of PfAtg18 localization.<br /> (© 2021 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
- Subjects :
- Amodiaquine pharmacology
Animals
Antimalarials pharmacology
Autophagy genetics
Autophagy-Related Proteins metabolism
Biological Transport
Chloroquine pharmacology
Erythrocytes drug effects
Erythrocytes parasitology
Gene Expression Regulation
Humans
Malaria parasitology
Membrane Proteins genetics
Membrane Proteins metabolism
Mice
Mice, Inbred BALB C
Multidrug Resistance-Associated Proteins metabolism
Plasmodium berghei growth & development
Plasmodium berghei metabolism
Plasmodium falciparum growth & development
Plasmodium falciparum metabolism
Protein Binding
Protozoan Proteins metabolism
Saccharomyces cerevisiae Proteins genetics
Saccharomyces cerevisiae Proteins metabolism
Vacuoles drug effects
Autophagy-Related Proteins genetics
Multidrug Resistance-Associated Proteins genetics
Phosphatidylinositol Phosphates metabolism
Plasmodium berghei genetics
Plasmodium falciparum genetics
Protozoan Proteins genetics
Vacuoles metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1470-8728
- Volume :
- 478
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- The Biochemical journal
- Publication Type :
- Academic Journal
- Accession number :
- 33843972
- Full Text :
- https://doi.org/10.1042/BCJ20210001