Histone lactylation: a new epigenetic mark in the malaria parasitePlasmodium

Abstract

ABSTRACTIn the malaria parasitePlasmodium falciparum,epigenetic modifications such as acetylation and methylation play important roles in parasite biology and virulence. Here, we characterised a new epigenetic mark, histone lactylation, recently discovered in humans and also present inPlasmodium. It was found in two human malaria parasites,P. falciparumand the zoonotic macaque parasiteP. knowlesi, and was also foundin vivoin two rodent malaria models. Histones were lactylated rapidly in response to elevated lactate levels, either exogenously added or endogenously generated by the parasite’s own metabolism, and they were rapidly delactylated when lactate levels fell. Thus, this epigenetic mark is well-placed to act as a metabolic sensor, since severe falciparum malaria characteristically leads to hyperlactataemia in infected patients. Mass spectrometry showed that lysines on several parasite histones could be lactylated, and that this was accompanied by lactylation of many non-histone chromatin proteins. Histone lactylation was less abundant and less inducible inP. knowlesithan inP. falciparum, suggesting thatP. falciparummay have evolved particular epigenetic responses to this characteristic feature of its pathology. Finally, in the rodent modelP. yoelii, hyperlactataemia correlated with parasite transcriptomic programmes that suggested metabolic ‘dormancy’.