Tryptophan C-mannosylation is critical for Plasmodium falciparum transmission

Author:

Lopaticki Sash,McConville Robyn,John AlanORCID,Geoghegan NiallORCID,Mohamed Shihab DeenORCID,Verzier Lisa,Steel Ryan W. J.ORCID,Evelyn CindyORCID,O’Neill Matthew T.ORCID,Soler Niccolay MadiedoORCID,Scott Nichollas E.ORCID,Rogers Kelly L.ORCID,Goddard-Borger Ethan D.ORCID,Boddey Justin A.ORCID

Abstract

AbstractTryptophan 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.

Funder

Department of Education and Training | Australian Research Council

Department of Health | National Health and Medical Research Council

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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