Nuclear acetyl-CoA production by acetyl-CoA synthetase enables dynamic histone acetylation and gene expression in Plasmodium falciparum
Year: 2026
Type: preprint
Abstract: A complex transcriptional cascade drives the two-day intraerythrocytic developmental cycle of the most virulent human malaria parasite, Plasmodium falciparum , in the human host. Genes are rapidly activated at specific times, then silenced as quickly. Transcriptional activity correlates with histone acetylation, which is modulated by acetyltransferases that use acetyl-CoA and deacetylases that produce acetate. Acetyl-CoA synthetase (ACAS) uses acetate to produce acetyl-CoA and has been implicated in histone acetylation, providing an interesting link between parasite metabolism and transcription. Here, we show that ACAS becomes enriched in the nucleus at a time during the life cycle when the parasite undergoes rapid growth and increased levels of transcription. We use mass spectrometry to show that ACAS inhibition results in a rapid and global depletion of histone acetylation, which leads to a general decrease in chromatin accessibility at gene promoters. These widespread alterations in chromatin composition disrupted the transcriptional cascade, resulting in cell cycle arrest. Our study provides evidence that ACAS plays an important nuclear role in the histone acetylation cycle and insight into the dynamic nature and essentiality of histone acetylation in the parasite’s complex transcriptional program driving infection of the human host.
Institutions: Centre National de la Recherche Scientifique, Inserm, Institut Pasteur, Université Paris Cité, Biologie des interactions hôte-parasite, European Molecular Biology Laboratory, Université Paris Sciences et Lettres, Institut Curie, Institut pour l'avancée des biosciences, Université Grenoble Alpes
Language: English
Topic: Malaria Research and Control
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Ministère de l'Enseignement supérieur, de la Recherche et de l'Innovation, Université Grenoble Alpes, Infrastructures en Biologie Santé et Agronomie, Alliance Française contre les Maladies Parasitaires, Department of Biotechnology, Ministry of Science and Technology, India, Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Indo-French Centre for the Promotion of Advanced Research, Fondation pour la Recherche Médicale, Conseil Régional, Île-de-France, Centre National de la Recherche Scientifique, Institut National Du Cancer
Awards: G2331484096, Elucidating the metabolic and lipidic adaptation of Toxoplasma gondii towards its human host nutritional environment, G311957854, G3458847772, G3530154365, G4219701773, Understanding how lipid trafficking at membrane contact sites allows the survival and propagation of Toxoplasma gondii within its human host, G5428706299, G577331932, The epigenetic role of MORC in apicomplexan life cycle stage development and virulence, Alliance française contre les maladies parasitaires, G6847237939, Setting boundaries: Cohesin and mutually exclusive expression of virulence genes in the human malaria parasite, African trypanosomes Lipid Droplets: a mysterious compartment with potent crucial parasitic functions
OpenAlex ID: W7169619231