Plasmodium falciparum Acetyl-CoA Synthetase Is Essential for Parasite Intraerythrocytic Development and Chromatin Modification

• Published in: ACS infectious diseases Vol. 7; no. 12; pp. 3224 - 3240
• Main Authors: Prata, Isadora Oliveira, Cubillos, Eliana Fernanda Galindo, Krüger, Arne, Barbosa, Deibs, Martins, Joaquim, Setubal, João Carlos, Wunderlich, Gerhard
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10-12-2021
• Subjects: Acetyl Coenzyme A; Animals; Chromatin; Humans; Ligases; Parasites; Plasmodium falciparum - genetics; destabilizing domain; acetyl-CoA synthetase; histone modification; var genes; ribozyme
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.1c00414

The malaria parasite Plasmodium falciparum possesses a unique Acetyl-CoA Synthetase (PfACS), which provides acetyl moieties for different metabolic and regulatory cellular pathways. We characterized PfACS and studied its role focusing on epigenetic modifications using the var gene family as reporter genes. For this, mutant lines to modulate plasmodial ACS expression by degron-mediated protein degradation and ribozyme-induced transcript decay were created. Additionally, an inhibitor of the human Acetyl-CoA Synthetase 2 was tested for its effectiveness in interfering with PfACS. The knockdown of PfACS or its inhibition resulted in impaired parasite growth. Decreased levels of PfACS also led to differential histone acetylation patterns, altered variant gene expression, and concomitantly decreased cytoadherence of infected red blood cells containing knocked-down parasites. Further, ChIP analysis revealed the presence of PfACS in many loci in ring stage parasites, underscoring its involvement in the regulation of chromatin. Due to its central function in the plasmodial metabolism and significant differences to human ACS, PfACS is an interesting target for drug development.