The acyl-CoA synthetase Tg ACS1 allows neutral lipid metabolism and extracellular motility in Toxoplasma gondii through relocation via its peroxisomal targeting sequence (PTS) under low nutrient conditions

• Published in: mBio 2024-04, Vol.15 (4), p.e0042724
• Main Authors: Charital, Sarah, Shunmugam, Serena, Dass, Sheena, Alazzi, Anna Maria, Arnold, Christophe-Sébastien, Katris, Nicholas J, Duley, Samuel, Quansah, Nyamekye A, Pierrel, Fabien, Govin, Jérôme, Yamaryo-Botté, Yoshiki, Botté, Cyrille Y
• Format: Article
• Language: English
• Subjects: Biochemistry; Biochemistry, Molecular Biology; Fatty Acids - metabolism; Humans; Life Sciences; Lipid Metabolism; Malaria; Microbiology and Parasitology; Nutrients; Parasitology; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; Saccharomyces cerevisiae - metabolism; Toxoplasma - metabolism; Toxoplasmosis - parasitology
• ISSN: 2150-7511; 2161-2129; 2150-7511
• DOI: 10.1128/mbio.00427-24

Apicomplexa parasites cause major diseases such as toxoplasmosis and malaria that have major health and economic burdens. These unicellular pathogens are obligate intracellular parasites that heavily depend on lipid metabolism for the survival within their hosts. Their lipid synthesis relies on an essential combination of fatty acids (FAs) obtained from both synthesis and scavenging from the host. The constant flux of scavenged FA needs to be channeled toward parasite lipid storage, and these FA storages are timely mobilized during parasite division. In eukaryotes, the utilization of FA relies on their obligate metabolic activation mediated by acyl-co-enzyme A (CoA) synthases (ACSs), which catalyze the thioesterification of FA to a CoA. Besides the essential functions of FA for parasite survival, the presence and roles of ACS are yet to be determined in Apicomplexa. Here, we identified ACS1 as a cytosolic ACS that is involved in FA mobilization in the parasite specifically during low host nutrient conditions, especially in extracellular stages where it adopts a different localization. Heterologous complementation of yeast ACS mutants confirmed ACS1 as being an Acyl-CoA synthetase of the bubble gum family that is most likely involved in β-oxidation processes. We further demonstrate that ACS1 is critical for gliding motility of extracellular parasite facing low nutrient conditions, by relocating to peroxisomal-like area.IMPORTANCE , causing human toxoplasmosis, is an Apicomplexa parasite and model within this phylum that hosts major infectious agents, such as spp., responsible for malaria. The diseases caused by apicomplexans are responsible for major social and economic burdens affecting hundreds of millions of people, like toxoplasmosis chronically present in about one-third of the world's population. Lack of efficient vaccines, rapid emergence of resistance to existing treatments, and toxic side effects of current treatments all argue for the urgent need to develop new therapeutic tools to combat these diseases. Understanding the key metabolic pathways sustaining host-intracellular parasite interactions is pivotal to develop new efficient ways to kill these parasites. Current consensus supports parasite lipid synthesis and trafficking as pertinent target for novel treatments. Many processes of this essential lipid metabolism in the parasite are not fully understood. The capacity for the parasites to sense and metabolically adapt to the host physiological