Malaria, caused by Plasmodium spp., claims approximately 600,000 lives annually. Transmission from humans to mosquitoes depends entirely on the conversion of asexual blood-stage parasites into sexual gametocytes, a process master-regulated by the transcription factor AP2-G. During asexual proliferation, the ap2-g locus is locked in H3K9me3-marked heterochromatin maintained by HP1, establishing a transcriptionally silent state. GDV1 displaces HP1 to relieve this silence, but the molecular machinery that directly opens chromatin at ap2-g and activates its transcription has remained unknown.
Researchers led by Jian Li and Jing Yuan (Xiamen University) and Qingfeng Zhang (Tongji University) published in Nature Microbiology entitled "Histone H2B monoubiquitination drives sexual commitment in malaria parasites." They show that the Plasmodium Rad6B–Tex1 complex catalyzes H2B monoubiquitination (H2Bub), which opens chromatin at the ap2-g locus, activates its transcription, and initiates sexual differentiation and gametocyte formation. This mechanism is conserved across Plasmodium species, providing a foundation for understanding parasite transmission and developing blocking interventions.
Whether a dedicated ubiquitination machinery drives sexual conversion in malaria parasites was unknown. Using CRISPR/Cas9 gene editing, the team systematically deleted the genes encoding E2 ubiquitin-conjugating enzymes in P. yoelii 17XL. Five mutants showed defects in sexual development or mosquito-stage transmission. Deletion of Rad6B (orthologue of yeast/human Rad6) severely impaired gametocytogenesis; ΔRad6B parasites failed to form oocysts, completely blocking transmission.
Immunoprecipitation coupled with mass spectrometry identified Tex1 (orthologue of yeast Bre1/human RNF20/40) as the E3 ligase partner of Rad6B. Both Rad6B and Tex1 are localized to the nucleus of asexual stages but are absent from gametocytes. ΔTex1 phenocopied ΔRad6B, and further work demonstrated that Rad6B–Tex1-mediated H2Bub positively regulates ap2-g transcription.
Unlike in model eukaryotes where H2Bub globally promotes H3K4 methylation, Western blot showed that Rad6B or Tex1 deletion did not alter global H3K4 methylation levels in malaria parasites. Instead, epigenomic analyses revealed that H2Bub promotes H3K4me3 enrichment specifically at the ap2-g promoter, activating ap2-g expression and triggering sexual differentiation. This mechanism was further validated in P. falciparum, indicating conservation across Plasmodium species. These findings establish that Rad6B–Tex1-H2Bub governs sexual differentiation and gametocytogenesis.
Integrating genetic, epigenomic, and biochemical evidence, the team proposes a sequential, two-step "de-repression to activation" model for sexual commitment. Step one ("de-repression"): GDV1 competitively displaces HP1 upon host cues, converting heterochromatin to a "poised" state. Step two ("activation"): Rad6B–Tex1 is recruited to the ap2-g promoter to catalyze H2Bub, which locally promotes H3K4me3 deposition and recruits the transcriptional machinery. This model resolves the long-standing question of how parasites selectively activate ap2-g after HP1 eviction.
Other apicomplexan parasites such as Toxoplasma, Cryptosporidium, and Babesia also possess Rad6B–Tex1 homologues, suggesting phylum-wide conservation. Determining whether these proteins catalyze H2Bub and promote sexual conversion in these parasites will be important.
In summary, this study reveals a novel epigenetic mechanism that Rad6B–Tex1-mediated H2Bub activating ap2-g to drive sexual differentiation in malaria parasites, laying a foundation for deciphering the regulatory network of sexual development and offering a potential new target for transmission-blocking strategies.
Associate Professor Jian Li, Professors Qingfeng Zhang and Jing Yuan are the corresponding authors of this paper. Drs. Zhiwei Jiao and Lirong Lin from the School of Life Sciences, Xiamen University, and Dr. Ruoyu Tang from Tongji University School of Medicine are co-first authors. This research was funded by the National Key R&D Program of China, the National Natural Science Foundation of China and the Natural Science Foundation of Fujian Province.
Article link: https://www.nature.com/articles/s41564-026-02475-4
