Critical role for isoprenoids in apicoplast biogenesis by malaria parasites
- University of Utah School of Medicine, United States
- Johns Hopkins Bloomberg School of Public Health, United States
- University of Utah, United States
Abstract
Isopentenyl pyrophosphate (IPP) is an essential metabolic output of the apicoplast organelle in Plasmodium falciparum malaria parasites and is required for prenylation-dependent vesicular trafficking and other cellular processes. We have elucidated a critical and previously uncharacterized role for IPP in apicoplast biogenesis. Inhibiting IPP synthesis blocks apicoplast elongation and inheritance by daughter merozoites, and apicoplast biogenesis is rescued by exogenous IPP and polyprenols. Knockout of the only known isoprenoid-dependent apicoplast pathway, tRNA prenylation by MiaA, has no effect on blood-stage parasites and thus cannot explain apicoplast reliance on IPP. However, we have localized an annotated polyprenyl synthase (PPS) to the apicoplast. PPS knockdown is lethal to parasites, rescued by IPP and long- (C50) but not short-chain (≤C20) prenyl alcohols, and blocks apicoplast biogenesis, thus explaining apicoplast dependence on isoprenoid synthesis. We hypothesize that PPS synthesizes long-chain polyprenols critical for apicoplast membrane fluidity and biogenesis. This work critically expands the paradigm for isoprenoid utilization in malaria parasites and identifies a novel essential branch of apicoplast metabolism suitable for therapeutic targeting.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files. Figure 1- source data 1 contains the numerical scoring data for all microscopy analyses.
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Funding
National Institute of General Medical Sciences (R35GM133764)
- Paul A Sigala
National Institutes of Health (1S10OD018210)
- John Alan Maschek
National Institutes of Health (1S10OD021505)
- John Alan Maschek
Congressionally Directed Medical Research Programs (W81XWH1810060)
- Paul A Sigala
National Institute of Allergy and Infectious Diseases (R01AI125534)
- Sean T Prigge
Burroughs Wellcome Fund (1011969)
- Paul A Sigala
Pew Charitable Trusts (32099)
- Paul A Sigala
National Institute of Diabetes and Digestive and Kidney Diseases (T32DK007115)
- Megan Okada
- Amanda Mixon
National Institute of Allergy and Infectious Diseases (T32AI007417)
- Krithika Rajaram
National Institute of Diabetes and Digestive and Kidney Diseases (U54DK110858)
- John Alan Maschek
National Institutes of Health (1S10OD016232)
- John Alan Maschek
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2022, Okada et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Critical role for isoprenoids in apicoplast biogenesis by malaria parasites
eLife 11:e73208.
https://doi.org/10.7554/eLife.73208
