Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission

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. Scott, Kelly L. Rogers, Ethan D. Goddard-Borger () and Justin A. Boddey ()
Additional contact information
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
Alan John: The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
Niall Geoghegan: The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
Shihab Deen Mohamed: The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
Lisa Verzier: The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
Ryan W. J. Steel: The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
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
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
Ethan D. Goddard-Borger: The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade
Justin A. Boddey: The Walter and Eliza Hall Institute of Medical Research, 1 G Royal Parade

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-32076-8

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