To ensure a rapid propagation and pathogenicity within its human host, Toxoplasma gondii require large amount of lipids, through massive scavenging of host resources and de novo fatty acid (FA) synthesis [1, 2]. FAs coming from both sources are remodeled and channeled towards lipid storage, i.e. lipid droplet (LD), avoiding an accumulation of potentially lipotoxic FAs, and being mobilized for parasite division [3]. Incorporation and remodeling of FA in glycerolipids (major membrane lipids) is conducted by a group of protein called acyltransferase. Here, we tried to understand how the vital FA fluxes of the glycerolipid pathway are regulated: we identified two key acyltransferases, TgGPAT (glycerol-3-phosphate acyltransferase) and TgDGAT2 (diacylglycerol acyltransferase). TgGPAT allows bulk membrane biogenesis and parasite formation by generating the key lipid precursor LPA. Metabolic labelling combined to lipidomics reveal major changes on FA substrate (host vs de novo) depending on the nutrient context (rich vs poor). On the other hand, TgDGAT is crucial for LD biogenesis only when the parasite lacks host nutrient. This study reveals that both proteins are essential for glycerolipid metabolism and act in a regulatory manner in different nutrient conditions. The loss of these proteins results in an accumulation of FFAs that cannot be "detoxified" by incorporating them into LDs, leading to parasite death. The nutrient-dependency of these proteins provides insight into the parasite"s metabolic flexibility: they can adapt to different environmental conditions by setting up a specific metabolic program accordingly, rendering proteins non-essential, essential, or vice-versa. Understanding FA remodelling and how these fluxes are regulated in Apicomplexa parasites will be crucial in conceptualizing a novel therapeutic strategy against the parasites.
References
[1] S. Shunmugam et al., "The flexibility of Apicomplexa parasites in lipid metabolism", PLoS Pathogens, 2022. doi: 10.1371/journal.ppat.1010313.
[2] S. Amiar et al., "Division and Adaptation to Host Environment of Apicomplexan Parasites Depend on Apicoplast Lipid Metabolic Plasticity and Host Organelle Remodeling", Cell Rep, 2020, doi: 10.1016/j.celrep.2020.02.072.
[3] S. Dass et al., "Toxoplasma LIPIN is essential in channeling host lipid fluxes through membrane biogenesis and lipid storage", Nat Commun, 2021, doi: 10.1038/s41467-021-22956-w.