1. Biochemistry and Chemical Biology
  2. Microbiology and Infectious Disease

Critical role for isoprenoids in apicoplast biogenesis by malaria parasites

  1. Megan Okada
  2. Krithika Rajaram
  3. Russell P Swift
  4. Amanda Mixon
  5. John Alan Maschek
  6. Sean T Prigge
  7. Paul A Sigala  Is a corresponding author
  1. University of Utah School of Medicine, United States
  2. Johns Hopkins Bloomberg School of Public Health, United States
  3. University of Utah, United States
https://doi.org/10.7554/eLife.73208
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  1. Megan Okada
  2. Krithika Rajaram
  3. Russell P Swift
  4. Amanda Mixon
  5. John Alan Maschek
  6. Sean T Prigge
  7. Paul A Sigala
(2022)
Critical role for isoprenoids in apicoplast biogenesis by malaria parasites
eLife 11:e73208.
https://doi.org/10.7554/eLife.73208
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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.

Article and author information

Author details

  1. Megan Okada

    Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.

  2. Krithika Rajaram

    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4830-5471

  3. Russell P Swift

    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.

  4. Amanda Mixon

    Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.

  5. John Alan Maschek

    Metabolomics Core, University of Utah, Salt Lake City, United States
    Competing interests
    The authors declare that no competing interests exist.

  6. Sean T Prigge

    Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9684-1733

  7. Paul A Sigala

    Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, United States
    For correspondence
    p.sigala@biochem.utah.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-3464-3042

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.

Reviewing Editor

  1. Dominique Soldati-Favre, University of Geneva, Switzerland

Version history

  1. Preprint posted: August 19, 2021 (view preprint)
  2. Received: August 20, 2021
  3. Accepted: March 4, 2022
  4. Accepted Manuscript published: March 8, 2022 (version 1)
  5. Version of Record published: March 28, 2022 (version 2)

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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  1. Megan Okada
  2. Krithika Rajaram
  3. Russell P Swift
  4. Amanda Mixon
  5. John Alan Maschek
  6. Sean T Prigge
  7. Paul A Sigala
(2022)
Critical role for isoprenoids in apicoplast biogenesis by malaria parasites
eLife 11:e73208.
https://doi.org/10.7554/eLife.73208

Share this article

https://doi.org/10.7554/eLife.73208

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