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Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission

Author

Listed:
  • Sash Lopaticki

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade)

  • Robyn McConville

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
    University of Melbourne)

  • Alan John

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
    University of Melbourne)

  • Niall Geoghegan

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
    University of Melbourne)

  • Shihab Deen Mohamed

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
    University of Melbourne)

  • Lisa Verzier

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
    University of Melbourne)

  • Ryan W. J. Steel

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
    University of Melbourne)

  • Cindy Evelyn

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade)

  • Matthew T. O’Neill

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade)

  • Niccolay Madiedo Soler

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
    University of Melbourne)

  • Nichollas E. Scott

    (University of Melbourne at the Peter Doherty Institute for Infection and Immunity)

  • Kelly L. Rogers

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
    University of Melbourne)

  • Ethan D. Goddard-Borger

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
    University of Melbourne)

  • Justin A. Boddey

    (The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
    University of Melbourne)

Abstract

Tryptophan C-mannosylation stabilizes proteins bearing a thrombospondin repeat (TSR) domain in metazoans. Here we show that Plasmodium falciparum expresses a DPY19 tryptophan C-mannosyltransferase in the endoplasmic reticulum and that DPY19-deficiency abolishes C-glycosylation, destabilizes members of the TRAP adhesin family and inhibits transmission to mosquitoes. Imaging P. falciparum gametogenesis in its entirety in four dimensions using lattice light-sheet microscopy reveals defects in ΔDPY19 gametocyte egress and exflagellation. While egress is diminished, ΔDPY19 microgametes still fertilize macrogametes, forming ookinetes, but these are abrogated for mosquito infection. The gametogenesis defects correspond with destabilization of MTRAP, which we show is C-mannosylated in P. falciparum, and the ookinete defect is concordant with defective CTRP secretion on the ΔDPY19 background. Genetic complementation of DPY19 restores ookinete infectivity, sporozoite production and C-mannosylation activity. Therefore, tryptophan C-mannosylation by DPY19 ensures TSR protein quality control at two lifecycle stages for successful transmission of the human malaria parasite.

Suggested Citation

  • Sash Lopaticki & Robyn McConville & Alan John & Niall Geoghegan & Shihab Deen Mohamed & Lisa Verzier & Ryan W. J. Steel & Cindy Evelyn & Matthew T. O’Neill & Niccolay Madiedo Soler & Nichollas E. Scot, 2022. "Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32076-8
    DOI: 10.1038/s41467-022-32076-8
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    References listed on IDEAS

    as
    1. Kathryn Tunyasuvunakool & Jonas Adler & Zachary Wu & Tim Green & Michal Zielinski & Augustin Žídek & Alex Bridgland & Andrew Cowie & Clemens Meyer & Agata Laydon & Sameer Velankar & Gerard J. Kleywegt, 2021. "Highly accurate protein structure prediction for the human proteome," Nature, Nature, vol. 596(7873), pages 590-596, August.
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    3. Sash Lopaticki & Annie S. P. Yang & Alan John & Nichollas E. Scott & James P. Lingford & Matthew T. O’Neill & Sara M. Erickson & Nicole C. McKenzie & Charlie Jennison & Lachlan W. Whitehead & Donna N., 2017. "Protein O-fucosylation in Plasmodium falciparum ensures efficient infection of mosquito and vertebrate hosts," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
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