A divergent Plasmodium NEK4 acts as a key regulator driving the early events of meiosis

Yanase, R.; Hair, M.; Zeeshan, M.; Ferguson, D. J. P.; Brady, D.; Pasquarello, C.; Bottrill, A.; Bhanvadia, S.; Neal, A.; Tromer, E. C.; Le Roch, K. G.; Hainard, A.; Holder, A. A.; Vaughan, S.; Guttery, D. S.; Tewari, R.

doi:10.1101/2025.11.21.689802

bioRxiv · 10.1101/2025.11.21.689802

A divergent Plasmodium NEK4 acts as a key regulator driving the early events of meiosis

Yanase, R.·Hair, M.·Zeeshan, M.·Ferguson, D. J. P.·Brady, D.·Pasquarello, C.·Bottrill, A.·Bhanvadia, S.·Neal, A.·Tromer, E. C.·Le Roch, K. G.·Hainard, A.·Holder, A. A.·Vaughan, S.·Guttery, D. S.·Tewari, R.

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Abstract

Meiosis is a conserved yet evolutionarily varied process underpinning sexual reproduction in eukaryotes. In the malaria parasite Plasmodium, meiosis is unconventional: it occurs immediately after fertilisation (post-zygotic) and must be coordinated with the transformation of the zygote into a motile ookinete. The mechanisms synchronising these meiotic and morphogenetic programmes remain unknown. Here, we identify the Plasmodium berghei NIMA-related kinase NEK4 as a key regulator that couples meiotic initiation with zygote morphogenesis. Using ultrastructure expansion microscopy, we show that NEK4 accumulates at the microtubule-organising centre (MTOC) and the apical polar complex (APC) shortly after fertilisation, preceding the assembly of perinuclear and cortical microtubules. We reveal that Plasmodium zygotes undergo MTOC-associated nuclear migration, analogous to the meiotic nuclear movement in fission yeast. Deletion of the Pbnek4 gene results in complete developmental arrest: MTOC duplication and microtubule formation are blocked, chromatin remains uncondensed, and nuclear migration and cell polarity fail to establish. Transcriptomic and phosphoproteomic analyses reveal that absence of NEK4 causes a collapse in transcriptional and phosphoregulatory networks governing meiosis and cytoskeletal organisation, leading to reduced expression and phosphorylation of important players, including HOP1, REC8, and AP2-O. These findings establish NEK4 as a key regulator driving meiotic entry and zygote maturation.

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Yanase, R., Hair, M., Zeeshan, M., Ferguson, D. J. P., Brady, D., Pasquarello, C., Bottrill, A., Bhanvadia, S., Neal, A., Tromer, E. C., Le Roch, K. G., Hainard, A., Holder, A. A., Vaughan, S., Guttery, D. S., Tewari, R.. 2025-11-23. A divergent Plasmodium NEK4 acts as a key regulator driving the early events of meiosis. https://doi.org/10.1101/2025.11.21.689802

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